Increased glyceraldehyde-3-phosphate activates the PKC pathway via increased DAG formation, while elevated fructose-6-phosphate enhances flux through the hexosamine pathway by conversion to UDP-GlcNAc via GFAT. Inhibition of GAPDH leads to higher glucose levels, increasing flux through the polyol pathway where aldose reductase reduces glucose or glyceraldehyde-3-phosphate, consuming NADPH. Experimental inhibition of GAPDH mimics hyperglycemia by activating major pathways of hyperglycemic damage.
Managing diabetes requires active involvement from the individual, who is responsible for implementing the day-to-day management plan, a task that can sometimes be difficult for healthcare professionals to accept. The role of the diabetes care team is to provide support as the person navigates their condition, especially during challenging periods such as adolescence, which is marked by significant personal changes, experimentation, and adaptation.
Oral semaglutide demonstrated non-inferiority, but not superiority, compared with placebo in the PIONEER-6 trial, which investigated its cardiovascular safety in patients with type 2 diabetes, though the study was likely underpowered to detect a significant effect due to a wide confidence interval. The ongoing SOUL trial aims to further explore whether oral semaglutide has a beneficial cardiovascular effect. The AMPLITUDE-O trial investigated efpegnatide's cardiovascular safety in individuals with type 2 diabetes and established cardiovascular disease or kidney disease plus at least one cardiovascular risk factor, and was the first to show a significant reduction in major adverse cardiovascular events for an exendin-4-based GLP-1RA.
Somatostatin suppresses insulin secretion and inhibits the release of counter-regulatory hormones like growth hormone and glucagon, helping to maintain euglycemia in non-diabetic individuals. Octreotide, a somatostatin analog used for neuroendocrine tumors, has differing metabolic effects in type 1 and type 2 diabetes. In T1DM, it reduces hepatic glucose production by suppressing glucagon and growth hormone, potentially lowering blood glucose and insulin needs. In T2DM, its inhibition of endogenous insulin secretion can lead to hyperglycemia. Evidence suggests that octreotide, lanreotide, and their long-acting forms may impair glucose tolerance and occasionally induce diabetes, particularly in individuals with acromegaly who already have compromised glucose homeostasis. In acromegaly patients, long-acting somatostatin analogs reduce growth hormone-induced insulin resistance but also suppress insulin secretion from pancreatic β-cells, with the net effect on glucose metabolism depending on the balance between these actions. These effects can be inconsistent and unpredictable, sometimes resulting in worsened glucose metabolism despite improved growth hormone levels.
In Africa, type 2 diabetes (T2DM) prevalence varies between urban and rural regions, with higher rates in urbanized areas such as North Africa, while sub-Saharan Africa reports lower rates despite challenges with poverty and malnutrition. An estimated 3.8% of the adult population in the African region was affected by diabetes in 2010, projected to rise to 4.7% by 2030. Type 1 diabetes (T1DM) incidence is generally low, but atypical "ketosis-prone" diabetes occurs, presenting initially with symptoms similar to T1DM, including severe hyperglycemia and ketosis, followed by long-term remission resembling T2DM. Additionally, an early-onset form called malnutrition-related diabetes mellitus (MRDM) has been identified, linked to past or concurrent malnutrition.
The Inducing remission in Type 1 Diabetes with ALefacept (T1DAL) study evaluated the effects of alefacept in individuals aged 12–35 years with newly diagnosed type 1 diabetes. Alefacept was administered as two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause, compared to placebo. While the primary outcome of change from baseline in 2-hour C-peptide AUC during a mixed-meal tolerance test was not significantly different between groups at 12 months, the 4-hour C-peptide AUC was significantly higher in the alefacept group compared to placebo, and lower insulin requirements were reported. At 24 months, both 2-hour and 4-hour C-peptide AUC values were significantly higher in the alefacept group, indicating better preserved β-cell function. Alefacept treatment also led to reduced exogenous insulin needs and fewer severe hypoglycaemic episodes, although no difference in HbA1c was observed at either 12 or 24 months. A post hoc analysis revealed a strong inverse association between 4-hour C-peptide AUC and risk of severe hypoglycaemia, glucose variability, and insulin dose–adjusted HbA1c, with no difference between alefacept and placebo, suggesting that preserved β-cell function, whether naturally or through immune intervention, benefits individuals with new-onset type 1 diabetes.
National prevalence of diabetes varies across European countries, with data sources available for 39 out of 59 countries and territories in the IDF Diabetes Atlas, and recent data from the last five years available for 14 countries. The prevalence ranges from 4.0% in Ireland to 15.9% in Turkey.
ALT-711, also known as alagebrium, is a thiazolium compound that inhibits the accumulation of advanced glycation end-products (AGEs) by cleaving preformed AGEs, and one of its postulated mechanisms is acting as an AGE cross-link breaker.
Secondary prevention trials in diabetes focus on individuals with existing autoimmunity, such as genetically predisposed children and young adults with multiple islet autoantibodies, aiming to reduce beta-cell destruction and prevent progression to clinical diabetes. These trials are categorized into non-antigen-specific and antigen-specific approaches.
Proinflammatory cytokines produced by adipose tissue, such as TNF-α and interleukin 6 (IL-6), play a role in the development of insulin resistance by activating JNK, IKKβ, and SOCS-3, which disrupt the tyrosine kinase activity (TKA) of the β-subunit of the insulin receptor. However, preliminary clinical evaluation of a TNF-α antibody in patients with type 2 diabetes mellitus (T2DM) showed limited improvement in insulin sensitivity and raised concerns due to an increased risk of infections.
RAGE deletion in streptozotocin diabetic RAGE/ApoE knockout mice leads to a significant reduction in atherosclerotic plaque area compared to diabetic ApoE knockout mice that express RAGE, and this reduction is linked to decreased inflammation, reduced accumulation of RAGE ligands such as S100/CML, less infiltration by macrophages and T lymphocytes, and lower expression of pro-fibrotic and pro-inflammatory growth factors and cytokines.
GH deficiency in children increases insulin sensitivity, leading to fasting and easily provoked hypoglycemia, although this sensitivity decreases with age and puberty, potentially due to increased gonadal steroid production. In contrast, GH excess is diabetogenic, as acute GH administration raises fasting glucose and insulin levels while reducing insulin sensitivity, indicating that the benefit of GH replacement on glucose tolerance depends on its physiological administration.
Many pharmacological agents are in development or clinical trials for treating type 2 diabetes or obesity, but lifestyle interventions remain more cost-effective for prevention. Mobile phone messaging and similar tools have shown promise in supporting lifestyle changes. For individuals with morbid obesity, bariatric surgery significantly improves glycaemic control, with over 60% experiencing diabetes remission after gastric bypass. In a three-year follow-up in the USA, the incidence of diabetes after Roux-en-Y gastric bypass was 0.9%, compared to 3.2% after laparoscopic gastric banding.
Epeglenatide, a once-weekly medication, demonstrated cardiovascular and renal benefits in the AMPLITUDE-O trial involving 4076 participants, approximately 90% of whom had a history of coronary artery disease, stroke, or peripheral artery disease, and the remaining having kidney disease with at least one cardiovascular risk factor. Over a median follow-up of 1.81 years, epeglenatide reduced major adverse cardiovascular events (MACE) with a hazard ratio of 0.73 and lowered the risk of a composite kidney outcome involving macroalbuminuria and decreased kidney function with a hazard ratio of 0.68. A subgroup analysis revealed that these cardiovascular benefits were not influenced by the concurrent use of an SGLT-2 inhibitor, which was used by 15% of the participants. However, epeglenatide is not currently available for clinical use.
Inactivation of PTP1B enhances insulin sensitivity and maintains pancreatic β-cell mass in mice, which can prevent early onset of diabetes, while combined deficiency of IRS2 and PTP1B delays diabetes onset but eventually leads to β-cell mass loss between 8 and 9 months of age. Inhibition of PTP1B in the central nervous system improves glucose tolerance and protects against type 2 diabetes, and intranasal targeting of PTP1B and TCPTP increases insulin and leptin sensitivity, promoting weight loss and preventing diet-induced type 2 diabetes.
Managing insulin in adolescents requires adjustments due to changes from puberty, weight gain, and growth, with the goal of maintaining HbA1c below 7.0% (<53 mmol/mol) as recommended by ISPAD and ADA, and for those using CGM, achieving glucose levels within 70-180 mg/dl (3.9-10 mmol/l) for more than 70% of the time without significant hypoglycemia.
ALT711, also known as alagebrium, is a thiazolium compound that has been shown to cleave preformed advanced glycation end products (AGEs), and is considered an AGE cross-link breaker, with potential relevance to diabetes-related complications.
ALT-711, also known as alagebrium, has been shown to reverse diabetes-induced increases in large artery stiffness, increase collagen solubility, and reduce vascular and cardiac AGE accumulation in diabetic rats. It also prevents the progression of nephropathy, potentially by inhibiting PKC-α phosphorylation and thereby reducing renal expression of vascular endothelial growth factor (VEGF). In diabetic ApoE KO mice, treatment with ALT-711 significantly reduces atherosclerosis through mechanisms involving decreased vascular AGE accumulation and RAGE expression. Additionally, alagebrium reduces inflammation and lowers the expression of pro-fibrotic growth factors such as CTGF. Clinically, ALT-711 has been found to reduce pulse pressure and improve vascular compliance in individuals with systolic hypertension.
Patients with type 2 diabetes mellitus (T2DM) exhibit higher plasma levels of glucose-dependent insulinotropic polypeptide (GIP) after meals compared to healthy individuals, while findings regarding glucagon-like peptide-1 (GLP-1) levels are inconsistent and show only minor differences. Despite these hormonal levels, the incretin effect is impaired in T2DM, with reduced insulin responses to both GLP-1 and GIP. It remains uncertain whether this impaired incretin effect is a result of generalized beta-cell dysfunction, similar to the reduced insulin response to arginine. However, antidiabetic medications that enhance incretin activity or levels, such as GLP-1 analogues and dipeptidyl peptidase-IV inhibitors, have been effective in lowering glucose in T2DM.
Relamorelin (RM-131), a novel pentapeptide ghrelin receptor agonist, demonstrates increased potency in enhancing gastric emptying in animal studies compared to other ghrelin mimetics. In clinical trials involving individuals with type 1 or type 2 diabetes and delayed gastric emptying, relamorelin was shown to accelerate gastric half-emptying time of solids. Additionally, in a phase II study involving people with type 1 diabetes, relamorelin led to a reduction in upper gastrointestinal symptoms, particularly in those experiencing significant baseline vomiting.
Partial glycemic control reduces but does not eliminate the development of microvascular complications such as retinopathy, nephropathy, and neuropathy in both type 1 and type 2 diabetes, and long-term maintenance of euglycemia may potentially eliminate these complications based on extrapolated DCCT data. Follow-up of DCCT patients indicates that earlier partial glycemic control also reduces macrovascular complications in type 1 diabetes, and follow-up of the UKPDS patients suggests a macrovascular benefit from early partial glycemic control in type 2 diabetes, though randomized controlled trials have not shown a cardiovascular mortality benefit from such control. Despite the microvascular benefits of maintaining euglycemia, it is often unsafe to achieve in most patients due to the risk of hypoglycemia, leading to a glycemic goal of an HbA1c level as close to the non-diabetic range as can be safely achieved. Reducing HbA1c levels from higher to lower values, even if still above recommended targets, provides substantial long-term benefits, and glycemic goals should be individualized and adjusted over time based on disease progression, insulin deficiency, and co-morbid conditions.
DPP-4 inhibitors do not cause nausea and vomiting and are weight neutral, lacking the weight-reduction effects of GLP-1 agonists due to lower levels of GLP-1 activity. Sitagliptin, a DPP-4 inhibitor, has been studied as monotherapy and as additional treatment for patients not meeting glycemic goals on metformin or thiazolidinediones. In monotherapy studies of 18 and 24 weeks' duration, sitagliptin at a dose of 100 mg reduced HbA1c by 0.6% (7 mmol/mol) and 0.8% (9 mmol/mol), respectively. When added to either metformin or pioglitazone, it further reduced HbA1c by 0.7% (8 mmol/mol) in 24-week studies. DPP-4 inhibitors are weight neutral, likely due to an appetite effect from raising endogenous GLP-1 levels, and their glycemic effects on peak prandial control appear superior to effects on preprandial control. This complements the primarily preprandial effects of metformin or thiazolidinediones. Incretin drugs are especially favorable for prandial glycemic control and may be preferred for their positive effects on weight loss or minimal weight gain. Prandial control becomes particularly important as HbA1c nears goal, and if prandial euglycemia reduces oxidative stress, incretins could offer additional cardiovascular benefits.
Gene variants such as rs1049353 in the CNR1 gene are linked to improved insulin resistance with liraglutide treatment, while the TCF7L2 gene influences type 2 diabetes by altering insulin secretion and shows a greater reduction in post-prandial insulin peaks with exenatide treatment depending on its SNP. The TCF7L2 gene polymorphism also affects therapy response to sulfonylurea derivatives, GLP-1 receptor agonists (GLP-1 RA), and DPP-4 inhibitors. The SORCS1 gene, specifically the rs1416406 GG genotype, is associated with a greater reduction in the proinsulin/insulin ratio during exenatide treatment, indicating improved insulin resistance and β-cell function. These findings suggest that various gene polymorphisms play a role in the metabolic response to GLP-1 RA, though further research is needed to determine their impact on clinical outcomes.
Increased intestinal glucose utilization can influence postprandial glucose levels, which is relevant in the management and pathophysiology of diabetes, particularly in understanding how glucose absorption and metabolism are regulated in the gastrointestinal tract.
Telephone counseling by a pharmacist between clinic visits reduced mortality rate by 50% in patients with chronic diseases including type 2 diabetes mellitus who were receiving five or more chronic medications, and patients with type 2 diabetes without cardiorenal complications managed in a clinical trial setting had a 70% risk reduction.
Emergency medical care in some countries may be suboptimal or dangerous for diabetes-related emergencies due to limited availability of essential treatments such as insulin and intravenous fluids, which may impact the choice of holiday destination for individuals with diabetes.
Meglitinide, repaglinide, and nateglinide are prandial insulin releasers with chemical structures similar to glibenclamide (glyburide), indicating they are related in function and classification as diabetes medications.
Improved glycaemic control can alleviate glucotoxicity and partially restore $\beta$-cell function, though there is ongoing discussion about the direct effects of current glucose-lowering therapies on $\beta$-cell preservation. DPP-4 inhibitors, GLP-1 receptor agonists, and pioglitazone have been suggested to offer protective effects on $\beta$ cells. GLP-1 receptor agonists specifically protect against lipotoxicity by enhancing cellular defenses, reducing inflammation, and preventing autophagy inhibition. Glitazones may reduce oxidative stress, inflammation, and endoplasmic reticulum stress linked to lipotoxicity. Metformin, when applied at therapeutic concentrations, can increase insulin content and granule density in pancreatic islets of individuals with type 2 diabetes, improve glucose-induced insulin release, and reduce apoptosis while normalizing oxidative stress markers. Weight loss and physical activity can favorably affect $\beta$-cell function by reducing intrapancreatic fat accumulation, which is associated with impaired first-phase insulin secretion. Exercise can reduce pancreatic fat and stimulate IL-6 release, which in turn enhances GLP-1 secretion from intestinal and pancreatic cells, thereby improving insulin secretion and glycaemic control in experimental models.
Clinical and genetic factors influence drug responses in monogenic diabetes and type 2 diabetes, but the application of these findings in clinical practice is delayed due to insufficient independent validation and implementation studies that demonstrate the long-term benefits of biomarker or genetic-based personalized medicine approaches. The diabetes field could learn from oncology in integrating research into practice, requiring collaboration among scientists, regulators, physicians, and patients to shift from a one-size-fits-all to a personalized treatment strategy.
Regular childhood vaccinations are not linked to an increased risk of type 1 diabetes, and studies comparing birth cohorts before and after the introduction of rotavirus vaccination in various countries have shown no association, with some suggesting a possible inverse relationship. A randomized trial of rotavirus vaccination in Finland followed by later assessment for type 1 diabetes also found no significant difference in incidence between vaccinated and unvaccinated groups.
Malnutrition-related diabetes mellitus (MRDM) is a form of diabetes associated with poor nutrition, while non-insulin-dependent diabetes mellitus (NIDDM) refers to a type of diabetes where the body becomes resistant to insulin or does not produce enough insulin to maintain normal glucose levels. The oral glucose tolerance test (OGTT) is a diagnostic method used to assess how well the body processes glucose. Non-alcoholic fatty liver disease (NAFLD) and its more severe form, non-alcoholic steatohepatitis (NASH), are commonly associated with diabetes and reflect metabolic complications related to insulin resistance. Non-proliferative diabetic retinopathy (NPDR) is a complication of diabetes affecting the eyes, characterized by damage to the blood vessels in the retina. Nitric oxide (NO) and nitric oxide synthase (NOS) play roles in vascular function and may be implicated in diabetes-related endothelial dysfunction. N-acetylcysteine (NAC) has been studied in the context of diabetes for its potential protective effects against oxidative stress.
Treatment withdrawal in diabetes can be considered in specific circumstances, such as when a person is entering the terminal phase of life, when frequent treatment-related hypoglycaemia causes distress and management challenges, when continued insulin use poses an unacceptable hypoglycaemia risk or stricter glucose management lacks justification, and when blood pressure or lipid-lowering therapies no longer provide health benefits.
Rare genetic variants have been identified in relation to diabetes, including a nonsense p.Arg684Ter variant in TBC1D4 with an allele frequency of approximately 17% that is associated with higher two-hour glucose and serum insulin concentrations, and a rare missense variant in HNF1A (c.1522G > A [p.E508K]) linked to type 2 diabetes prevalence in a Latino population; additionally, further rare variants related to glycaemic traits were discovered through exome sequencing of 9717 individuals in the METSIM study, Finland.
Morning administration of a sulfonylurea, such as gliclazide, or morning isophane NPH insulin is recommended for once-daily steroid therapy, while twice-daily sulfonylurea or isophane insulin may be used for twice-daily steroid therapy. If hypoglycaemia is a concern, a long-acting insulin analogue such as insulin glargine or insulin degludec may be considered.
In mild or moderate symptomatic hypoglycemia with a documented blood glucose of ≤70 mg/dL (3.9 mmol/L), immediate treatment includes oral administration of 5–15 g of rapidly absorbed glucose or sucrose such as glucose tablets, "Smarties," or 4 oz (100 mL) of a sweet drink like juice or soda, with 1 g of glucose expected to raise blood glucose by 3 mg/dL (0.17 mmol/L) in adults and proportionally more in children, aiming to elevate levels to 100 mg/dL (5.6 mmol/L); if there is no or inadequate response, the treatment should be repeated after retesting blood glucose in 10–15 minutes; once symptoms improve and euglycemia is restored, especially if the initial glucose level was lower, a solid snack or meal such as fruit, bread, or cereal should be consumed to prevent recurrence.
In overweight and obese patients with type 2 diabetes mellitus (T2DM), the intestinal lipase inhibitor orlistat (120 mg three times daily with meals) can increase weight reduction by an additional 2–3 kg and lead to further decreases in HbA1c levels by 0.28–1.1% (3–12 mmol/mol), potentially improving the glucose-fatty acid cycle. Another antiobesity agent, the serotonin-norepinephrine reuptake inhibitor sibutramine, may result in slightly greater weight loss and an extra reduction in HbA1c of approximately 0.6% (7 mmol/mol), with possible metabolic benefits from its metabolites. However, antiobesity therapies come with contraindications, precautions, and side effects, and orlistat may interfere with the absorption and efficacy of certain oral antidiabetic medications, especially α-glucosidase inhibitors.
GLP-1 receptor agonists (GLP-1RAs), used in the treatment of type 2 diabetes, have raised concerns regarding pancreatic adverse effects such as pancreatitis and pancreatic cancer. Early post-marketing reports indicated a higher frequency of pancreatitis with exenatide compared to other diabetes therapies, though this may reflect a reporting bias known as the Weber effect. Regulatory agencies including the EMA and FDA reviewed available data and found inconsistencies in linking GLP-1RAs to pancreatic issues, though a definitive exclusion of a causal relationship was not possible. People with type 2 diabetes already have a higher baseline risk of pancreatitis compared to those without diabetes, complicating the interpretation of adverse event reports. Clinical trials, including cardiovascular outcome studies, reported very low and similar rates of pancreatitis in both GLP-1RA and placebo groups, although individuals at high risk for pancreatitis were often excluded from these trials. A recent meta-analysis of observational studies found no association between GLP-1RA use and pancreatic pathology. Despite this, acute pancreatitis remains listed as a potential adverse event for all GLP-1RAs, and no differences in pancreatic adverse effects have been observed between types of GLP-1RAs. Patients initiating GLP-1RA therapy should be informed of the possible risk and symptoms of acute pancreatitis, and caution is advised when prescribing these medications to individuals with a history of or risk factors for pancreatitis.
In patients with type 2 diabetes mellitus (T2DM), studies have shown mixed results regarding the effectiveness of intensive glucose control in preventing complications such as neuropathy. The UK Prospective Diabetes Study (UKPDS) found a lower rate of impaired vibration perception threshold (VPT > 25V) after 15 years in patients receiving intensive therapy compared to conventional therapy (31% vs. 52%), with a significant difference also observed at the 9-year follow-up, but not at 3, 6, or 12 years. Additionally, no differences were found between groups in the rates of absent knee and ankle reflexes or heart rate responses to deep breathing. Similarly, the ADVANCE study, which included 11,140 patients with T2DM, reported a non-significant 4% relative risk reduction (95% CI: -10% to 2%) in new or worsening neuropathy with intensive glucose control after a median of 5 years. The Veterans Affairs Diabetes Trial (VADT), involving 1,791 military veterans with poorly controlled T2DM, also found no differences between intensive and standard glucose control groups in diabetic peripheral neuropathy (DPN) or microvascular complications after a median follow-up of 5.6 years.
Efpeglenatide, an exendin-based weekly GLP-1 receptor agonist, significantly reduced MACE by 27% during a 1.81-year treatment period, regardless of SGLT-2 inhibitor use, which was present in 15% of the population. Among similar trials, only albiglutide showed a significant reduction in hospitalization for heart failure, while other trials demonstrated neutral effects on heart failure hospitalization.
Lifestyle interventions significantly reduce the risk of developing type 2 diabetes in individuals with impaired glucose tolerance (IGT), as demonstrated by multiple studies. In the Malmo Study, individuals receiving lifestyle modification (LSM) advice experienced a 63% risk reduction for developing type 2 diabetes compared to the control group, with a legacy effect showing lower mortality over 12 years. The China Da Qing Diabetes Prevention Study found that diet, exercise, and combined interventions reduced the cumulative incidence of type 2 diabetes by 43% over 20 years, with a legacy effect of spending 3.6 fewer years with diabetes. The Finnish Diabetes Prevention Study showed a 58% risk reduction with LSM over 4 years, and a continued 43% lower risk during a 7-year follow-up. The American Diabetes Prevention Program demonstrated that LSM led to the lowest incidence of type 2 diabetes compared to metformin and placebo, with incidences of 4.8, 7.8, and 11 per 100 person-years respectively over an average of 2.8 years. A Japanese trial also showed a 67.4% risk reduction in men with IGT who received LSM compared to controls over 4 years. These studies consistently highlight the effectiveness of lifestyle changes, including diet, physical activity, and weight management, in preventing or delaying the onset of type 2 diabetes.
Managing type 2 diabetes has become more complex due to the expansion of pharmacotherapy, providing clinicians with more pharmaceutical agents targeting hyperglycemia and obesity, though the disorder remains relentlessly progressive. Clinical trials emphasize the importance of glycemic control in reducing microvascular complications and long-term cardiovascular events, yet poor glycemic control, hypoglycemia, and obesity continue to pose significant challenges for clinicians.
Motor neuropathy, cheiroarthropathy, and altered gait patterns contribute to the development of the "high risk" neuropathic foot in diabetes, characterized by clawing of the toes, prominent metatarsal heads, high arch, and small muscle wasting.
In diabetes, the body's ability to regulate blood glucose is impaired, partly due to dysfunctions in the counterregulatory responses that normally defend against hypoglycemia. One such response involves the pancreatic islet α-cells increasing glucagon secretion when plasma glucose levels fall slightly below normal. This glucagon stimulates the liver to produce glucose, primarily through glycogenolysis. Glucagon secretion is mainly triggered by a decrease in intra-islet insulin and other β-cell secretory products in low glucose conditions, and secondarily by increased autonomic nervous system activity, including sympathetic, parasympathetic, and adrenomedullary inputs. When glucagon response is deficient, the third defense mechanism—increased secretion of epinephrine from the adrenomedullary system—becomes crucial, also activating as plasma glucose drops below the normal range.
Islet transplantation is indicated for individuals with type 1 diabetes characterized by a stimulated C-peptide level less than 0.3μg/L on a mixed meal tolerance test, along with intensive diabetes management involving glucose testing at least three times daily and at least three insulin injections per day or insulin pump use under specialist supervision with three clinical evaluations in the past year. Severe hypoglycemic events in the past year, defined by symptoms such as confusion, irrational behavior, seizure, or loss of consciousness accompanied by a blood glucose level below 54mg/dL, also support eligibility. Additional criteria include reduced hypoglycemia awareness (Clarke score ≥4 or HYPO score at or above the 90th percentile), marked glycemic lability with a lability index at or above the 90th percentile, or a composite of Clarke score ≥4, HYPO score ≥75th percentile, and lability index ≥75th percentile. Contraindications for islet transplantation include poor glycemic control with glycated hemoglobin ≥10%, untreated proliferative retinopathy, blood pressure over 160/100 mmHg, glomerular filtration rate below 80 mL/min/1.73 m², presence or history of macroalbuminuria exceeding 300 mg/day, presence or history of panel reactive anti-HLA antibodies, active infections such as hepatitis B, hepatitis C, HIV, or tuberculosis within the last three years, invasive fungal infections within one year, severe cardiac disease including myocardial infarction within six months or ischemia on functional cardiac testing within one year, left ventricular ejection fraction below 30%, any history of malignancy except for completely resected skin cancers, factor V deficiency, coagulopathy requiring long-term anticoagulant therapy, chronic systemic steroid use exceeding 5mg/day prednisolone equivalent, any condition interfering with safe participation in transplantation, and desired pregnancy in female recipients.
Increased oxygen-free radical levels in diabetes may reduce the vasodilator effect of nitric oxide (NO), particularly through the formation of advanced glycosylation end-products (AGEs), which generate reactive oxygen species and impair NO bioactivity. In animal models, inhibiting AGE formation has been shown to improve endothelium-dependent relaxation and restore erectile function in diabetic rats.
Regular aerobic exercise training can improve whole-body insulin sensitivity in patients with type 1 diabetes mellitus (T1DM), similar to its effects in individuals without diabetes, potentially aiding in inducing and prolonging remission in newly diagnosed cases. However, the impact of aerobic exercise on glycemic control in T1DM remains unclear due to inconsistent study outcomes; some show slight improvements in blood glucose control as indicated by reduced HbA1c levels, while others show no change or even increases in HbA1c, possibly due to excessive insulin dose reductions or increased carbohydrate intake aimed at preventing hypoglycemia during exercise.
Specific pancreatic antigens are being investigated as potential agents to modulate the autoimmune response in type 1 diabetes mellitus (T1DM) by inducing immunologic tolerance toward islet antigens. In experimental models, various antigen-specific molecules, including whole islet proteins, peptides derived from islet antigens, and DNA-based vaccines, have demonstrated the ability to induce immunologic tolerance and protect against T1DM. In human studies, a few agents such as the peptide heat shock protein 60 (DiaPep277) and alum-formulated GAD65 show potential in modulating the immune response. The mechanism of antigen-specific immunologic tolerance is believed to involve the activation of antigen-specific regulatory T lymphocytes (Treg), although standardized tools for detecting and quantifying these Treg cells are not yet available. Several clinical trials are currently ongoing to evaluate the efficacy of antigen-specific interventions in individuals with new-onset T1DM.
DPP-4 inhibitors, including sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin, are a class of medications used in the management of diabetes. These drugs work by inhibiting the enzyme dipeptidyl peptidase-4, which leads to increased levels of incretin hormones that stimulate insulin secretion and reduce glucagon release, thereby helping to lower blood glucose levels.
Pasireotide, a potent somatostatin analogue that primarily inhibits somatostatin receptor type 5 (SST5), is associated with a high prevalence of hyperglycaemia (70%) and overt diabetes in up to 40% of individuals with acromegaly due to its inhibitory effect on insulin secretion.
In hospital settings, oral agents were historically not recommended for managing hyperglycaemia due to concerns over effectiveness, side effects, and hypoglycaemia risk, leading to the preference for intravenous insulin. However, newer agents, particularly DPP-4 inhibitors like sitagliptin, have shown safety and efficacy in managing mild to moderate hyperglycaemia in hospitalized patients, including older adults and those on general medical and surgical wards, often with a lower risk of hypoglycaemia. Sitagliptin has also shown potential benefits in reducing mortality in patients admitted with SARS-CoV-2 infection. SGLT-2 inhibitors offer cardiovascular benefits in outpatient settings, especially regarding heart failure and diabetes-related kidney disease, but their use during acute hospitalization remains controversial due to risks like dehydration, worsening kidney function, and DKA. Limited studies on empagliflozin and dapagliflozin in hospitalized patients have shown mixed results with some reduction in heart failure and mortality but no significant improvement in overall outcomes, and current evidence does not support routine use of SGLT-2 inhibitors in hospital outside clinical trials.
Psychologic factors are more significant than minor sexual dysfunction in women with diabetes, and while vaginal dryness and impaired arousal are reported more frequently, they are not common issues in daily diabetes management; treatment for these conditions is consistent regardless of diabetes status, and associated issues like vaginal candidiasis or estrogen deficiency should be addressed, with counseling considered for relationship problems, and the use of PDE5 inhibitors in female sexual dysfunction requiring further research.
Higher glycemic levels, as indicated by elevated HbA₁c before hospitalization, have shown a positive association with increased mortality from COVID-19 in some studies, though findings are not consistent. High blood glucose upon admission is more consistently linked to severe disease outcomes regardless of whether a person has diabetes. In hospital settings, treating hyperglycemia with insulin infusion has been associated with reduced inflammatory and coagulation indices and improved patient outcomes. Additionally, limited evidence suggests that in-hospital use of dipeptidyl peptidase-4 inhibitors may lower fatality rates.
Managing diabetes often involves taking multiple oral hypoglycemic, antihypertensive, and lipid-lowering drugs at various times during the day. Depression can negatively affect metabolic control in people with diabetes by reducing their ability to take proper care of themselves, though there is no direct evidence supporting that improvement in depression leads to better metabolic control. Prospective data show that depressive symptoms at baseline predict poorer adherence to treatment 9 months later, but it remains unexamined whether adherence improves as depressive symptoms decrease.
DPP-4 inhibitors prevent the activity of the enzyme DPP-4, which breaks down incretin hormones such as GLP-1 and GIP, thereby increasing their circulating concentrations. These elevated incretin levels enhance nutrient-induced insulin secretion, and studies in animals have shown that this can lead to increased insulin biosynthesis and increased beta-cell mass. However, the concentrations achieved with DPP-4 inhibitors are not as high as those obtained with subcutaneously administered incretin mimetics.
AGEs (Advanced Glycation End-products) are formed through the reaction of glucose and other glycating compounds like dicarbonyls (e.g., 3-deoxyglucosone, methylglyoxal, and glyoxal) with proteins and, to a lesser extent, nucleic acids. This process involves reversible initial reactions that produce early glycation products, which can progress to irreversible changes impairing the structural, enzymatic, or signaling functions of the affected proteins. Glycated hemoglobin (HbA₁c) is a well-known example of this process, and AGEs are found in increased amounts in diabetes.
Raised fasting plasma glucose levels of 5.6 mmol/L (100 mg/dL) or higher, or a prior diagnosis of type 2 diabetes, are indicators for further evaluation, with an oral glucose tolerance test being strongly recommended if glucose levels exceed 5.6 mmol/L, although this test is not required to confirm the presence of the syndrome.
Having schizophrenia is associated with a two- to fourfold increase in the risk of developing diabetes, leading to an overall diabetes prevalence of 10–15% in Western populations, with most cases being type 2 diabetes mellitus (T2DM) and some evidence suggesting reduced rates of type 1 diabetes mellitus (T1DM) in these individuals. Studies on this association are limited by screening bias, as T2DM can remain asymptomatic for years, affecting ascertainment rates. There is also a suggestion, though less systematically studied, that patients with bipolar disorder may have a two- to threefold increased risk of developing diabetes, with similar considerations regarding treatment effects and lifestyle differences as in schizophrenia.
RAGE, which is expressed on endothelial cells and monocytes-macrophages, is relevant to diabetes-related macrovascular complications and has been implicated in inflammatory lesions associated with various disorders.
NAFLD is highly prevalent in individuals with type 2 diabetes, affecting up to nearly 70% of them, and requires healthcare professionals to be knowledgeable about its diagnosis and stages. Lifestyle changes such as weight loss and increased physical activity can effectively resolve NASH histologically, especially in early stages, while advanced cases necessitate specialist care due to risks like portal hypertension, liver failure, and HCC. Certain glucose-lowering medications used for type 2 diabetes, including pioglitazone and GLP-1 RAs like liraglutide and semaglutide, have shown efficacy in resolving NASH in around 50% of individuals with biopsy-proven NASH compared to placebo. Ongoing research into NASH pathogenesis and novel treatments suggests that combination therapies may offer the best outcomes for managing NASH in people with type 2 diabetes.
Managing diabetes during adolescence is challenging due to physical, social, and emotional changes, impacting both individuals and their healthcare teams. Recommended HbA1c goals vary, with the ADA and ISPAD suggesting a target of <7.0% (<53 mmol/mol) for young people, and more stringent goals such as <6.5% (<48 mmol/mol) for those who can achieve them without significant hypoglycaemia or excessive care burden. NICE guidelines also recommend an HbA1c goal of ≤6.5% (48 mmol/mol) for young individuals with type 1 or type 2 diabetes.
Reports of trials with ARBs indicate that these agents provide cardiovascular protection in individuals with type 2 diabetes similar to that of ACE inhibitors. In the LIFE study, losartan treatment in people with type 2 diabetes and left ventricular hypertrophy significantly reduced death from CVD and all-cause mortality. The RENAAL study showed that losartan in participants with type 2 diabetes, nephropathy, and left ventricular hypertrophy reduced cardiovascular risk to levels similar to those without left ventricular hypertrophy. The ONTARGET study demonstrated that telmisartan offered benefits comparable to ramipril, a proven ACE inhibitor, in high-risk individuals with CVD or diabetes and end-organ damage, similar to the population in the HOPE study. However, combining ramipril with telmisartan did not further reduce cardiovascular events despite additional blood pressure lowering, and was associated with more adverse effects like hypotension and renal dysfunction. Therefore, ACE inhibitors or possibly ARBs are preferred initial antihypertensive agents in people with diabetes due to their ability to prevent or delay diabetic macrovascular complications, significantly lowering cardiovascular mortality and morbidity.
Psychologic difficulties can significantly interfere with well-being and diabetes self-management, highlighting the importance of appropriate counseling techniques, diagnostic skills for non-severe psychological disorders, and timely referral to specialists when necessary.
Bariatric surgery is increasingly used in managing type 2 diabetes and obesity, with post-surgery blood glucose levels often returning to near-normal levels for prolonged periods, and HbA₁c values within the normal range, indicating diabetes in remission. The preferred test for identifying diabetes remission is HbA₁c below 48 mmol/mol (<6.5%) for three months or more without glucose-lowering medications, though the same limitations of HbA₁c apply as in diagnosis and monitoring. Individuals in remission still require ongoing monitoring for diabetes complications, including retinal screening, renal function assessment, foot evaluation, and measurement of blood pressure and weight, along with HbA₁c checks no more frequently than every three months and no less than yearly to confirm sustained remission, aligning with the monitoring of stable type 2 diabetes.
Oral agents that enhance insulin sensitivity or stimulate insulin secretion are used to manage glucocorticoid-induced hyperglycaemia, but some medications like metformin, sulfonylureas, and thiazolidinediones may not be ideal due to concerns about renal impairment, hypoglycaemia, and side effects such as weight gain and oedema. Non-sulfonylurea secretagogues and dipeptidyl peptidase-4 inhibitors are potentially better options due to quicker onset, lower hypoglycaemia risk, and effect on post-prandial glucose levels. Insulin therapy is flexible and can be tailored to the glucocorticoid regimen, with NPH insulin or premixed insulin being suitable for those taking intermediate-acting glucocorticoids like prednisone in the morning, as NPH's peak and duration align with prednisone's effects. For long-acting glucocorticoids such as dexamethasone, or higher doses of prednisone, a combination of long-acting insulin analogues and prandial insulin may be required due to fasting hyperglycaemia. Blood glucose monitoring and insulin dose adjustments are important during glucocorticoid tapering to prevent hypoglycaemia, and ongoing research comparing NPH insulin with the SGLT-2 inhibitor empagliflozin may provide further guidance on managing glucocorticoid-induced diabetes.
GIP, a glucose-dependent insulinotropic peptide, stimulates insulin secretion in a glucose-dependent manner by binding to Gs-coupled receptors on beta cells, leading to downstream cascades that promote insulin release, and it may also enhance insulin secretion through activation of phospholipase A2 and closure of KATP channels; however, GIP-related peptides are considered unlikely candidates for type 2 diabetes therapy due to their effects of stimulating glucagon secretion, inhibiting GLP-1 release, and worsening post-prandial hyperglycemia in individuals with type 2 diabetes.
Improved glycaemic management prevents and slows the progression of microvascular complications in type 1 diabetes, while improved glycaemic and blood pressure management improves both microvascular and macrovascular outcomes in type 2 diabetes, and multiple risk factor interventions improve diabetes outcomes. Early treatment has legacy effects in diabetes management. Proliferative retinopathy was first described in diabetes, and treatments such as xenon photocoagulation, argon laser therapy, and strict blood pressure control slow the progression of diabetic retinopathy and neuropathy. Combined kidney-pancreas transplants have been used in diabetes treatment. SGLT-2 inhibitors ameliorate heart failure, cardiovascular disease, and chronic kidney disease in diabetes, while GLP-1 receptor agonists improve cardiovascular outcomes. Gastric bypass surgery can lead to resolution of diabetes.
Some infections occur more frequently in people with diabetes and include malignant otitis externa, mucormycosis, emphysematous cholecystitis, cystitis, pyelonephritis, and Fournier gangrene. Additionally, more common infections that are not exclusive to diabetes can have a more complicated clinical course in individuals with diabetes due to factors such as disease duration, comorbidities like obesity and smoking, and the presence of diabetes-related complications.
GLP-1 enhances glucose-induced insulin secretion in a glucose-dependent manner by binding to its receptor on pancreatic beta cells, activating adenylate cyclase via a stimulatory G-protein, and increasing cyclic AMP (cAMP) levels, which leads to altered ion channel activity, intracellular calcium handling, and increased insulin exocytosis. The effects of GLP-1 and glucose may converge at the ATP-sensitive potassium (KATP) channels of beta cells, where GLP-1, through protein kinase A activation, can close these channels, leading to membrane depolarization and opening of voltage-sensitive calcium channels. Sulfonylurea drugs also close KATP channels, which can cause membrane depolarization and calcium influx, potentially uncoupling the glucose dependency of GLP-1 action. Approximately 30-40% of patients treated with both sulfonylurea compounds and a GLP-1 agonist experience usually mild hypoglycemia.
Having diabetes doubles one's risk of hospitalization compared to those without the condition, with the risk further increased by diabetes-related complications such as poor peripheral circulation, which raises hospitalization risk by 70%, and cardiovascular disease (CVD), which increases it by 310%. Studies show varying hospitalization rates among people with type 2 diabetes mellitus (T2DM), with 13% hospitalized over a six-month period in the Cost of Diabetes in Europe Type II Study (CODE2) and 28.8% in Germany's Cost of Diabetes Mellitus (CoDiM) study in 2001. While late-stage macrovascular or microvascular complications are the leading global causes of diabetes-related hospitalizations, lower-income regions like Ethiopia see a higher proportion—nearly two-thirds—of admissions due to acute episodes of dysglycemia.
Psychologic adaptation to diabetes diagnosis in adulthood is not fully understood due to limited longitudinal studies. The largest follow-up study on adults with type 1 diabetes mellitus (T1DM), conducted by the DCCT Research Group, found no changes in self-reported psychological symptoms over 6–9 years and no link between treatment type (conventional or intensive insulin therapy) and psychological distress. Clinically significant distress rates were higher in both treatment groups (25%) compared to depression rates in the general population (14.4%). A smaller study following adults for 2 years after T1DM diagnosis reported either stable psychological states or improvements, such as reduced depressive symptoms.
Skin tags are associated with diabetes, occurring in about 66% of individuals with the condition, and are likely linked to the proliferative effect of hyperinsulinaemia on keratinocytes and fibroblasts, similar to acanthosis nigricans. A large number of skin tags may indicate impaired glucose tolerance, and individuals with more than 30 skin tags or women with lesions under their breasts are particularly prone to diabetes.
Limited joint mobility in diabetes is characterized by joint contractures leading to decreased passive joint mobility, particularly affecting the proximal interphalangeal and metacarpophalangeal joints of the hands, with the fifth PIP joint often involved first. The condition presents with tight, waxy skin on the dorsum of the hands and can also affect large joints such as the wrists, elbows, ankles, and cervical spine, with severe cases showing reduced lung volumes. Pain is typically mild or absent early on, and there is no synovitis. It can be distinguished from systemic sclerosis by the absence of Raynaud phenomenon, normal nailfold capillary findings, negative autoantibodies, and lack of systemic features.
Replacement of added salt intake using salt substitutes containing potassium and magnesium in hypertensive individuals with type 2 diabetes mellitus (T2DM) has been shown to significantly reduce systolic blood pressure, though not diastolic blood pressure; such substitutes may be considered in selected patients but are not generally recommended for lowering high blood pressure in people with diabetes.
Norepinephrine can influence insulin secretion through its interaction with different adrenoreceptor subtypes on pancreatic β cells; it can either stimulate insulin release via β₂-adrenoreceptors or inhibit it via α₂-adrenoreceptors. The net effect depends on the relative expression levels of these receptors, and species differences in receptor expression explain why β-adrenergic agonists stimulate human islets but not rodent islets. The stimulatory effects of β₂ receptors occur through activation of adenylate cyclase and increased intracellular cAMP, whereas α₂-receptor activation inhibits secretion by reducing cAMP, cytosolic calcium, and through an unidentified mechanism in the stimulus-secretion coupling. A single nucleotide polymorphism (SNP) in the α₂A receptor gene leads to increased expression of α₂A adrenoreceptors and decreased insulin secretion, and targeting this receptor with an antagonist has been used to improve insulin secretion in individuals with type 2 diabetes.
GLP-1 reduces gastrointestinal motility and intermittent GLP-1 receptor activation significantly affects gastric emptying of both liquid and solid meals, a mechanism known as the ileal brake, where GLP-1 secreted from enteroendocrine cells in the distal small intestine slows nutrient delivery from the stomach to the small intestine. This delay in gastric emptying caused by GLP-1 leads to a reduction in postprandial plasma glucose spikes. However, prolonged activation of the GLP-1 receptor results in tachyphylaxis of this effect, explaining why short-acting GLP-1 receptor agonists have sustained effects on postprandial glucose levels while long-acting ones show diminished effects.
Improved glucose management in both type 1 diabetes and type 2 diabetes is beneficial, as demonstrated by the Diabetes Control and Complications Trial (DCCT) in 1993 and the UK Prospective Diabetes Study (UKPDS) in 1998.
Repaglinide and Nateglinide are medications used to treat diabetes by stimulating insulin secretion from the pancreas, acting quickly and with a short duration, typically taken before meals to help control postprandial blood glucose levels.
Increased glucose flux through the hexosamine biosynthetic pathway contributes to insulin resistance by impairing insulin's ability to stimulate glucose transport in adipocytes and muscle cells. This process is associated with hyperglycemia and elevated free fatty acids, which lead to increased muscle UDP-GlcNAc levels and insulin resistance as observed in rodent models. Overexpression of glutamine:fructose-6-phosphate amidotransferase (GFA) in skeletal muscle and adipose tissue enhances flux through this pathway and exacerbates insulin resistance. The mechanism involves increased O-glycosylation of key proteins such as the insulin receptor, IRS1, Akt/PKB, GLUT4, and GSK3β, which can impair their function or lead to their degradation. For example, O-glycosylation of the insulin receptor reduces its autophosphorylation in response to insulin. Additionally, O-GlcNAc modifications affect nuclear transcription factors, such as Sp1, Foxo1, C/EBPβ, and NF-κB, altering gene expression, including that of proinflammatory genes. Intracellular accumulation of glucosamine-6-P further inhibits hexokinase and glycogen synthase activity, potentially contributing to impaired glucose metabolism. However, the exact role of these mechanisms in insulin resistance among diabetic patients requires further investigation.
Otelixizumab has been studied in individuals with type 1 diabetes, showing that a dose of 8 mg led to higher C-peptide release at 18 months compared to placebo, indicating some preservation of β-cell function, although no difference in HbA1c was observed. In a four-year follow-up, individuals treated with otelixizumab required lower exogenous insulin doses, particularly in the youngest age groups who showed a higher C-peptide response to a glucose clamp. However, studies using a 3.1 mg dose in the DEFEND-1 and DEFEND-2 trials did not demonstrate C-peptide preservation. A more recent 24-month study evaluating different cumulative IV doses (9, 18, or 27 mg over 6 days) in individuals recently diagnosed with type 1 diabetes showed that adverse effects were dose-dependent, and only the 9 mg dose resulted in a significant change from baseline in C-peptide levels during a mixed-meal tolerance test at 18 months, with no β-cell function preservation seen at the higher doses of 18 and 27 mg.
Bariatric surgery, including gastric bypass and sleeve gastrectomy, improves glycaemia through mechanisms beyond weight loss, such as caloric restriction, anatomical changes in the gut leading to faster food delivery to the small intestine, increased release of GLP-1, and exclusion of duodenal nutrient exposure. Changes in gut microbiota may also play a role. The Swedish Obese Subjects study showed that after 10 years, bariatric surgery led to greater recovery from and lower incidence of type 2 diabetes compared to controls, with mean weight loss of 16.1%. Bariatric surgery is effective for improving glycaemic outcomes in individuals with type 2 diabetes and obesity class 1. Studies indicate that surgery can achieve better glycaemic control and prolonged remission compared to conventional diabetes treatment. A systematic review found that one year after surgery, 57% of gastric bypass and 47% of sleeve gastrectomy patients achieved diabetes remission, with 50% and 46% remission rates respectively after 2–5 years. Several models have been developed to predict diabetes remission after surgery, with two showing strong validation.
Patients with symptomatic diabetes developing in adolescence or young adulthood are typically diagnosed with type 1 diabetes mellitus (T1DM), but genetic testing for HNF1A mutations should be considered in young adults with apparent T1DM, a family history of diabetes, and who are antibody-negative at diagnosis. Features suggesting non-insulin dependence, such as absence of ketosis without insulin treatment, good glycemic control on low insulin doses, or detectable C peptide with plasma glucose >8 mmol/L several years post-diagnosis, increase the likelihood of a positive genetic test. Glutamine acid decarboxylase (GAD) antibodies are usually negative in monogenic diabetes, though low-titer positivity may occur in up to 1–2% of non-diabetic individuals, so it does not definitively exclude monogenic diabetes. In cases with strong clinical suspicion of HNF1A despite negative HNF1A mutation tests, particularly when there is increased birth weight or neonatal hypoglycemia, HNF4A testing should be considered.
In diabetes, HDL cholesterol levels can decrease due to several factors including the acceleration of CETP-mediated exchange of VLDL triglyceride for HDL cholesteryl esters in hypertriglyceridemia, which leads to a lower measured HDL cholesterol as triglycerides replace cholesteryl esters in HDL particles. Additionally, the triglyceride content in HDL serves as a substrate for plasma lipases, particularly hepatic lipase, which converts HDL into smaller particles that are cleared more rapidly from the plasma. Precursors of advanced glycation end-products (AGEs) can further impair HDL's ability to perform reverse cholesterol transport.
Niacin adversely affects glucose levels in a dose-related manner and causes hyperglycaemia, which is particularly relevant in individuals with diabetes. Despite this, in the Coronary Drug Project, niacin was as effective at lowering cardiovascular outcomes in individuals with hyperglycaemia as in those with normal glucose levels. The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) included 8299 persons with diabetes and found no cardiovascular benefits with niacin therapy and an increased risk of infections or thrombocytopaenia.
Matching carbohydrate to insulin dose, either as part of multiple daily insulin or continuous subcutaneous insulin regimen, is the most effective approach for the management of glycaemia in type 1 diabetes. Women with diabetes planning to become pregnant should take 5 mg of folic acid per day to prevent neural tube defects. Low-glycaemic index foods may help manage blood glucose concentrations during pregnancy.
Certain medications can influence glucose metabolism, with some having potentially potent effects on diabetes. Glucocorticoids, high-dose estrogen, thiazide diuretics (especially at high dosages), non-selective β-adrenoceptor antagonists, β2-adrenoceptor agonists such as salbutamol, ritodrine, antipsychotics, HIV protease inhibitors like indinavir, nelfinavir, and ritonavir, pentamidine, gatifloxacin, streptozocin, diazoxide, ciclosporin, tacrolimus, tensirolimus, interferon-α, and L-asparaginase may adversely affect glucose control, potentially leading to hyperglycemia or worsening of diabetes. In contrast, other agents such as oral contraceptives containing levonorgestrel, calcium-channel blockers, α1-adrenoceptor antagonists, growth hormone at physiologic doses, somatostatin analogs, selective serotonin reuptake inhibitors, nicotinic acid, lamivudine, and isoniazid are associated with minor or no effects on glucose metabolism.
Hyperglycaemia is linked to increased infection risk and poor outcomes, with studies showing that elevated admission glucose levels are associated with higher short-term mortality in pneumonia patients, regardless of diabetes status. Higher glycated haemoglobin ($\mathrm{HbA_{1c}}$) levels in people with diabetes are associated with greater risks of infection-related hospitalization. In Mexico, diabetes was linked to a fourfold increase in infectious disease deaths when $\mathrm{HbA_{1c}} < 9\%$ $(75 \mathrm{mmol/mol})$, and nearly sevenfold when $\mathrm{HbA_{1c}} \geq 9\%$ $(75 \mathrm{mmol/mol})$. People with diabetes were twice as likely to die from Covid-19 compared to those without diabetes, and during the SARS outbreak in 2003, diabetes was an independent risk factor for ICU admission, mechanical ventilation, and death, with a threefold increase in relative risk. In a Saudi Arabian study, diabetes was present in 68% of MERS cases and associated with a 60% overall fatality rate. Diabetes also correlates with more severe dengue presentations, including increased occurrence of dengue haemorrhagic fever. These findings highlight the significant impact of diabetes on the severity and outcomes of various infectious diseases.
Iatrogenic hypoglycaemia leads to recurring physical and psychological issues, increases mortality, weakens the body's ability to defend against future hypoglycaemia, and hinders the maintenance of stable blood glucose levels in people with diabetes. It causes immediate brain fuel deprivation, which, if not addressed, leads to functional brain failure that can be resolved by raising plasma glucose. Rarely, it can result in sudden death, possibly due to cardiac arrhythmia, or brain death if the hypoglycaemia is severe and prolonged. Early reports indicated that 2–4% of people with diabetes die from hypoglycaemia, while more recent data showed 6%, 7%, and 10% of deaths in type 1 diabetes patients were due to hypoglycaemia. In type 2 diabetes, up to 10% mortality during severe sulfonylurea-induced hypoglycaemia has been reported, and in one trial, 1–9% of evaluable deaths were linked to hypoglycaemia.
Inpatient diabetes management aims to minimize metabolic decompensation caused by the stress of illness and surgery, which can lead to stress-induced hyperglycemia. This condition arises from the combined effects of hormonal, cytokine, and counter-regulatory nervous system signals on glucose metabolism. During critical illness, inflammatory and counter-regulatory responses alter insulin's effects on hepatic glucose production and skeletal muscle. Stress triggers increased secretion of counter-regulatory hormones such as glucagon, epinephrine, norepinephrine, cortisol, and growth hormone, promoting hepatic glycogenolysis and gluconeogenesis while inhibiting peripheral glucose uptake. Severe hyperglycemia can result in osmotic diuresis, leading to dehydration and electrolyte imbalances involving sodium, potassium, magnesium, and phosphate, with the heightened osmotic state also having procoagulant effects.
Reprogramming of α cells into functional β cells using adenoviral- or AAV-mediated expression of Pdx1 and MafA has shown promise in treating diabetes, with reprogrammed insulin+ cells normalizing glycaemia for four months in diabetic mouse models, including alloxan-induced and non-obese diabetic (NOD) mice. This approach also converted α cells into β-like cells in human islets treated with streptozotocin and in purified human α cells before pseudo-islet reaggregation, and when transplanted into immunodeficient NOD mice, these reprogrammed cells improved hyperglycaemia and glucose tolerance for at least six months. Pseudo-islets derived from reprogrammed human α cells exhibited a molecular profile intermediate between α and β cells, which shifted closer to β cells after transplantation and showed reduced immunogenicity for type 1 diabetes autoreactive T cells. Additionally, Pdx1 and MafA expression successfully reprogrammed human γ cells to produce and secrete insulin in response to glucose.
Skin reactions can occur in people with diabetes due to the repeated use of glucose sensors and continuous glucose monitoring (CGM) devices on the same skin site, ranging from mild irritation to contact allergies. Eczematous reactions are the most common skin complications associated with insulin pumps and CGM devices, highlighting the importance of regular skin examinations during diabetes consultations and the need for interdisciplinary collaboration in classifying and treating these issues. Allergic contact dermatitis to device patches, often caused by substances like isobornyl acrylate (IBOA), can lead to immediate symptoms and may prevent further use of certain CGM systems or cause reactions to other device plasters, such as those used with insulin pumps. Despite these skin-related challenges, studies indicate that the overall quality of life for device users is mostly unaffected.
ACE inhibitors should be offered to all patients with type 1 diabetes mellitus (T1DM) who have abnormal urinary albumin excretion (UAE), even if blood pressure is normal, with the dose titrated up to the maximum recommended or tolerated level to achieve maximal antiproteinuric effect, based on evidence showing their preferential reduction in intraglomerular pressure.
Efpeglenatide is a once-weekly exendin-4-based GLP-1 receptor agonist (GLP-1RA) that is administered subcutaneously and is currently under development for the treatment of diabetes. The drug has been modified by conjugation with an IgG4-Fc fragment to prevent degradation by DPP-4 and reduce renal clearance, potentially enhancing its efficacy and duration of action in managing diabetes.
Management of hyperglycaemia guides the initiation and escalation of glucose-lowering therapy in type 2 diabetes, with tight glycaemic control shown to reduce microvascular complications. The impact of intensive glucose lowering on macrovascular events remains uncertain. HbA1c measurement is the primary tool for assessing glycaemia, reflecting average glucose levels over three months and predicting diabetes-related complications; each 1% reduction in HbA1c is associated with a 37% risk reduction in microvascular complications, 14% in myocardial infarction, and 21% in diabetes-related mortality. However, lower HbA1c levels show a U-shaped relationship with all-cause mortality and cardiac events, particularly in older or frail individuals and those with cardiovascular disease, where hypoglycaemia limits treatment intensification. A target HbA1c of <7% is recommended for most people with type 2 diabetes, though it may be adjusted lower for motivated individuals or higher, up to <8%, for those with limited life expectancy. To prevent hypoglycaemia, sulfonylureas and insulin are discouraged. Most diabetes medication studies use HbA1c as the primary outcome, with insulin regimens and GLP-1RAs showing the greatest HbA1c reduction; the dual GIP/GLP-1 receptor agonist tirzepatide achieves reductions as high as 2%.
In conditions such as haemolytic disease or blood loss, where there is a shortened lifespan of erythrocytes, $\mathrm{HbA_{1c}}$ measurements may underestimate the true value, while iron-deficiency anaemia, associated with a longer erythrocyte lifespan, can lead to overestimation of $\mathrm{HbA_{1c}}$.
MODY (Maturity-Onset Diabetes of the Young) is often difficult to distinguish from type 1 diabetes or young-onset type 2 diabetes due to mixed phenotypes, and over 80% of MODY cases remain undiagnosed or misclassified, partly due to the high cost of genetic screening. Clinical criteria for MODY testing include diabetes onset before age 25, parental history of diabetes, non-insulin dependence for HNF1α- and HNF4α-MODY, and specific glucose and HbA1c levels. These criteria are highly specific but not very sensitive, and expanding the criteria to include diagnosis under age 30 or C-peptide positivity after three years has improved detection. Additionally, common variants near the HNF1α gene affect hsCRP levels in healthy individuals, and low hsCRP levels can help distinguish HNF1α-MODY from type 1 and type 2 diabetes, increasing diagnostic sensitivity up to 90% when used with clinical criteria.
DPP-4 inhibitors are used in the management of type 2 diabetes, either as monotherapy in cases where lifestyle changes have been insufficient, or as add-on therapy when metformin or thiazolidinediones alone have not achieved target glucose levels. They can be combined with other oral agents or insulin due to their distinct mechanism of action on the β cell, which also includes reducing glucagon levels, making them potentially beneficial as adjunctive therapy to insulin. However, their full efficacy depends on adequate β-cell reserve, and adding them to a GLP-1 receptor agonist typically provides minimal additional benefit. DPP-4 inhibitors are particularly advantageous for individuals with overweight or obesity due to their neutral effect on weight and are associated with a low risk of hypoglycemia when used as monotherapy.
LDKO mice exhibit unsuppressed hepatic glucose production, hyperinsulinaemia, glucose intolerance, and diabetes due to genetic inactivation of hepatic IRS1 and IRS2. These mice show insulin resistance not only in the liver but also in white and brown adipose tissue and skeletal muscle, indicating a systemic manifestation of dysregulated hepatic metabolism. Metabolic health can be restored in LTKO mice through hepatic inactivation of FoxO1 despite the liver being mechanistically unresponsive to insulin, a finding further confirmed with other hepatic-specific mouse models such as LIRKO-FoxO1L and Akt1L-Akt2L-FoxO1L-CreAlb.
Subjects with diabetes exhibit increased levels of microsomal triglyceride transfer protein (MTP) in the intestine, which is involved in the assembly of chylomicrons and VLDL particles. Cholesterol absorption is also adversely affected in diabetes, with increased expression of Niemann-Pick C1-like 1 protein, a key player in cholesterol absorption. In contrast, the ATP-binding cassette transporters ABCG5 and ABCG8, responsible for the efflux of dietary cholesterol and non-cholesterol sterols, are reduced in both the liver and intestine in diabetes. Additionally, lipoprotein lipase (LPL), an insulin-dependent enzyme crucial for converting lipoprotein triglycerides into free fatty acids, shows reduced activity in both type 1 and type 2 diabetes, a condition further exacerbated by adipose-derived cytokines such as tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6).
Liraglutide, used in the treatment of diabetes, demonstrates dose-dependent improvements in glycemic control with initial dose escalation from 0.6 mg/day to 1.2 mg/day and in some cases up to 1.8 mg/day. Over 52 weeks, liraglutide at 1.2 mg and 1.8 mg reduced HbA₁c more effectively than glimepiride, with the 1.8 mg dose showing a significantly greater decrease compared to the 1.2 mg dose. Patients previously managed with lifestyle changes alone experienced the most pronounced reductions in HbA₁c: 1.2% (13 mmol/mol) with 1.2 mg liraglutide, 1.6% (17 mmol/mol) with 1.8 mg liraglutide, and 0.9% (10 mmol/mol) with glimepiride. Liraglutide also induced weight loss, in contrast to weight gain observed with glimepiride, resulting in a weight difference of 3.2–3.6 kg between the groups. Nausea was more common with liraglutide (29%) compared to glimepiride (9%), but hypoglycemia rates were lower with liraglutide (12 and 8 events/subject/year for 1.2 mg and 1.8 mg, respectively) than with glimepiride (24 events/subject/year). Two-year data showed sustained glycemic benefits with liraglutide, maintaining HbA₁c reductions of −0.9% (10 mmol/mol) and −1.1% (12 mmol/mol) for the 1.2 mg and 1.8 mg doses, respectively, compared to −0.6% (7 mmol/mol) with glimepiride. Weight loss was maintained in the liraglutide groups (−2.1 kg and −2.7 kg) while the glimepiride group experienced a weight increase of +1.1 kg.
Gestational diabetes can develop as early as 16–20 weeks of pregnancy, with maternal hyperglycaemia and fetal hyperinsulinaemia occurring earlier, around 14–20 weeks, and being linked to the later development of GDM and large-for-gestational-age (LGA) babies. Fasting glucose levels in the first trimester, even within the normal range up to 5.8 mmol/l (105 mg/dl), can predict GDM, LGA, and caesarean section. Diagnosing GDM in the first trimester using Carpenter–Coustan criteria is associated with higher rates of hypertension and pre-eclampsia compared to later diagnoses, and may also be linked to increased neonatal hypoglycaemia and perinatal mortality. Higher HbA1c levels at diagnosis (41–49 mmol/mol [5.9–6.6%]) are associated with more adverse outcomes such as pre-eclampsia and preterm birth, and initiating treatment before 24 weeks may reduce the rate of pre-eclampsia compared to later treatment.
In adults with type 1 diabetes mellitus (T1DM) and baseline HbA1c levels between 7–10% (53–86 mmol/mol), the use of continuous glucose monitoring (CGM) led to a significant reduction in HbA1c levels compared to control groups after 26 weeks, with a mean difference in change of -0.53% (P < 0.001). This improvement in glycemic control was not accompanied by an increase in biochemical hypoglycemia or severe hypoglycemic events. In the adult cohort, 30% of those using CGM achieved an HbA1c level below 7.0% (<53 mmol/mol) without severe hypoglycemic events, compared to 7% in the control group (P = 0.0006). These findings indicate that real-time CGM can enhance glycemic control without worsening hypoglycemia, contrasting with earlier studies like the DCCT that used intermittent capillary glucose monitoring.
In diabetes patients, blood pressure control varies across different populations and time periods, with a relatively low proportion achieving target blood pressure levels. In a US-based study from 1995–2005, 36.7% of type 2 diabetes mellitus (T2DM) patients had blood pressure ≤130/80 mmHg. A Swedish study observed an improvement from 13% of T2DM patients having blood pressure <130/80 mmHg in 1996 to 61.3% of type 1 diabetes mellitus (T1DM) patients achieving ≤130/80 mmHg by 2004. In Asia, a 1998 study reported a mean blood pressure of 135/81 mmHg among T2DM patients, with 27% having systolic blood pressure >140 mmHg and 10% having diastolic >90 mmHg. A multinational study from 2005–2010 found that 44.9% of T1DM and 19.2% of T2DM patients had blood pressure ≤130/80 mmHg, with slight variations by ethnic group.
Combined GLP-1 and GIP receptor activation is a promising therapeutic approach for type 2 diabetes, with tirzepatide being the first dual GIP and GLP-1 receptor agonist approved by the FDA for this purpose. Tirzepatide has greater affinity for the GIP receptor and is administered subcutaneously once weekly. It has been shown to be more effective in lowering HbA1c levels compared to once-weekly GLP-1RAs such as semaglutide and dulaglutide, as well as basal insulin analogues. Additionally, treatment with tirzepatide results in greater body weight reduction than GLP-1RAs, though it is associated with a higher incidence of gastrointestinal adverse events, particularly nausea. Preliminary cardiovascular data suggest that tirzepatide does not increase the risk of major cardiovascular events.
GIP antagonism, whether through pharmacologic means or metabolic surgery, may provide a new antidiabetic mechanism by improving glucose homeostasis, reducing insulin resistance, and preventing the development of obesity, as evidenced by studies in animal models and clinical observations following bariatric surgery in obese patients with diabetes.
Nateglinide is a meglitinide that stimulates insulin secretion with a faster onset and shorter duration compared to repaglinide, but it is less effective as monotherapy or in combination therapy than repaglinide.
DPP-4 inhibitors, including sitagliptin, vildagliptin, saxagliptin, alogliptin, and P32/98, are a class of medications used in the management of diabetes. These drugs work by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which leads to increased levels of incretin hormones that stimulate insulin secretion and reduce glucagon release, thereby helping to lower blood glucose levels.
Both type 1 and type 2 diabetes can impact psychological well-being and quality of life, often due to adverse events during the course of the disease or its management, with diabetes-specific distress and fear of hypoglycaemia being common. While generic health-related quality of life in people with diabetes is generally comparable to those with other chronic conditions like arthritis, lower health-related quality of life is linked to diabetes complications, being female, physical inactivity, low income, and recurrent hypoglycaemia. Diabetes-specific quality of life can be impaired by intensive management, hypoglycaemia, and complications, but may improve with flexible treatment approaches, and diabetes-related stigma, which arises from perceived or experienced judgment, blame, rejection, and discrimination, can come from various sources including the media, the public, family, and healthcare professionals, potentially leading to self-stigma and reduced psychological well-being, self-care, and healthcare access. Psychological factors such as adverse childhood experiences, chronic stress, high job strain, low stress resilience, insomnia, depression, anxiety disorders, and schizophrenia may contribute to the risk of developing type 2 diabetes, though the mechanisms are not well understood. In children, about half of type 1 diabetes cases are diagnosed in childhood, and while most show psychological resilience, some experience distress after diagnosis which typically subsides within six months; problematic adjustment may involve depressive symptoms, anxiety, social withdrawal, and sleep disturbances, and similar reactions are seen in parents, especially mothers, with increased rates of post-traumatic stress disorder. Over time, after 5–10 years of living with type 1 diabetes, anxiety, depression, and eating disorders increase, with up to one-third of adolescents meeting criteria for psychiatric disorders, and diabetes distress is most common during adolescence. Macrovascular disease, chronic foot ulceration, and proliferative retinopathy raise the risk of psychopathology, while pre-existing psychiatric disorders like depression may also increase the risk of developing macrovascular and microvascular complications, and recurrent diabetic ketoacidosis, especially in young women, is associated with psychological issues like disordered eating and family dysfunction. Glycaemic levels and psychological variables have reciprocal effects on diabetes management and outcomes, with factors like locus of control, coping style, temperament, stress, anxiety, and depression playing a role, and family functioning significantly influences outcomes in children and adolescents, with low conflict, good communication, cohesion, and marital satisfaction leading to better glycaemic control. Self-care behaviours such as medication adherence, glucose monitoring, diet, and exercise show weak associations with glycaemic outcomes, possibly due to measurement inaccuracies or the complexity of diabetes management, and several interventions, including individual or group therapy and counselling, can enhance psychological well-being.
Statins may increase insulin resistance and reduce insulin secretion, leading to small elevations in HbA1c and fasting glucose. Certain protease inhibitors and nucleoside reverse-transcriptase inhibitors, such as zidovudine, stavudine, and didanosine, are associated with hyperglycaemia and diabetes, potentially causing insulin resistance, lipodystrophy, and pancreatitis. Fluoroquinolones, particularly gatifloxacin, can induce dysglycaemia more frequently than levofloxacin, with hyperglycaemia typically occurring within one to two weeks of treatment. Post-transplant diabetes is linked to calcineurin inhibitors like cyclosporine and tacrolimus, with risk factors including older age, obesity, corticosteroid use, non-White ethnicity, hepatitis C, and genetic factors. Diazoxide is known to cause drug-induced hyperglycaemia and even diabetic ketoacidosis through mechanisms involving impaired insulin secretion, increased glucose production, and reduced peripheral glucose utilization. Insulin secretagogues, including incretin mimetics, may be preferred for managing drug-induced hyperglycaemia. Limiting exposure to drugs affecting glucose regulation is advisable, with careful monitoring and potential dose adjustment or discontinuation if hyperglycaemia occurs.
Coexistent gout can hinder exercise and weight loss in individuals with type 2 diabetes, while bariatric surgery may improve glycaemia, blood pressure, and serum urate control in those with morbid obesity. Diuretic therapy should be avoided in people with gout due to its potential to worsen hyperuricaemia unless absolutely necessary. Medications such as losartan and fenofibrate offer weak urate-lowering effects and may be beneficial for individuals with diabetes and gout when antihypertensive or lipid-lowering treatment is needed. Treatment with SGLT-2 inhibitors, unlike GLP-1 receptor agonists, may reduce gout episodes by up to 30%.
GLP-1 receptor agonists, including liraglutide, semaglutide, albiglutide, dulaglutide, and efpeglenatide, have been studied for their cardiovascular effects in patients with type 2 diabetes. The LEADER trial demonstrated that liraglutide significantly reduced three-point MACE (a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke), cardiovascular death, and all-cause mortality over 3.8 years. The SUSTAIN-6 trial showed that once-weekly injectable semaglutide significantly reduced three-point MACE by 27% over 2.1 years, primarily driven by a reduction in stroke and a trend toward fewer myocardial infarctions. Albiglutide, tested in the HARMONY OUTCOMES trial, significantly reduced three-point MACE by 22% and myocardial infarction by 25% over 1.6 years. Dulaglutide, evaluated in the REWIND trial, significantly reduced three-point MACE and stroke over a longer follow-up period of 5.7 years. Oral semaglutide, assessed in the PIONEER-6 trial, did not significantly reduce three-point MACE over 1.3 years but did lead to a 51% relative reduction in cardiovascular death and reduced all-cause mortality.
HAAF (Hypoglycemia-Associated Autonomic Failure) in diabetes is caused by antecedent hypoglycemia, exercise, or sleep, each leading to reduced sympathoadrenal and symptomatic responses to hypoglycemia. Antecedent hypoglycemia contributes to HAAF by decreasing the body's ability to respond to subsequent low blood glucose levels. Exercise-related HAAF, such as late post-exercise hypoglycemia, typically occurs 6–15 hours after strenuous activity and is often nocturnal. Sleep-related HAAF further diminishes the sympathoadrenal response to hypoglycemia during sleep, increasing the risk of undetected and prolonged low blood glucose levels in sleeping patients.
Different lipid-lowering drugs have varying effects on cardiovascular disease (CVD) in patients with diabetes, as demonstrated by several studies. The Collaborative Atorvastatin Diabetes Study (CARDS) and the Atorvastatin Study for the Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) evaluated the impact of atorvastatin on CVD outcomes in diabetic patients. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, along with its corrected data (FIELDc), examined the role of fenofibrate in reducing cardiovascular events in diabetes. Other studies such as the Greek Evaluation of Atorvastatin in Coronary Events (GREACE), the Heart Protection Study (HPS), and the Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) also contributed to understanding how lipid-lowering therapies influence cardiovascular risk in individuals with diabetes. These studies considered both primary and secondary prevention subgroups within diabetic populations, focusing on changes in lipid profiles such as low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C).
Both type 1 and type 2 diabetes can affect the psychological and neuropsychological status of children and adults, with effects often linked to events during the course of the disease or its management. Children generally show psychological resilience after diagnosis, though about one-third experience psychological distress characterized by depressive symptoms, anxiety, social withdrawal, and sleep disturbances, which typically subsides within six months; a similar adjustment reaction is seen in parents, especially mothers, with increased rates of post-traumatic stress disorder comparable to children with cancer. Adults newly diagnosed with type 1 diabetes show increased rates of depression, while type 2 diabetes does not increase the risk unless accompanied by multiple comorbidities. After 10 years of diabetes, children and adolescents have markedly increased rates of anxiety, depression, or eating disorders, with up to one-third of adolescents meeting criteria for psychiatric disorders, and adults with diabetes have depression rates twice as high as the general population, particularly those hospitalized, older individuals with multiple medical issues, those with past psychopathology, or females. Macrovascular disease, foot ulcers, and retinopathy increase the risk of psychopathology, and lifetime psychiatric disorders like depression may increase the risk of complications such as retinopathy; recurrent diabetic ketoacidosis, especially in females, is predicted by poor psychological functioning and family dysfunction. Phobic disorders are more common in adults with diabetes, with fear of blood and injury leading to less glucose monitoring and poorer control, while fear of hypoglycemia may result in premature treatment and persistent hyperglycemia. Quality of life for people with diabetes is comparable to those with other chronic conditions like arthritis, but poor health-related quality of life is linked to biomedical complications, being female, physical inactivity, low income, and recurrent hypoglycemia, with intensive diabetes management not associated with deterioration in quality of life. Interventions to reduce psychological distress include individual or group therapy, though their efficacy on mood or metabolic control is weak based on small studies, while cognitive-behavioral therapy shows promise for depressive symptoms, and pharmacotherapy with SSRIs or tricyclic antidepressants can reduce symptom severity, though some drugs may affect glycated hemoglobin levels. Cognitive dysfunction in diabetes is generally mild, but children diagnosed before age 5–7 have an elevated risk of clinically significant impairments across cognitive domains, with those diagnosed later showing modest effects on intelligence, academic achievement, and psychomotor efficiency; deficits appear early, within 2–3 years of diagnosis, and while hypoglycemia was once thought to be the cause, recent evidence suggests chronic hyperglycemia and vascular complications may play a larger role. In adults with type 1 diabetes, neurocognitive deficits are modest, affecting intelligence, psychomotor speed, and executive function, while older adults with type 2 diabetes show marked memory reductions.
Support groups and structured transition programmes for older teenagers and young adults with type 1 diabetes can lead to improvements in diabetes management and psychosocial outcomes. Monthly support groups have been associated with reduced self-reported diabetes burden and improved HbA1c levels, along with a trend toward better self-care. Programmes that include transition planning, coordinated transfer visits, extended intake appointments with adult diabetes staff, and group support sessions have resulted in improved HbA1c, fewer hypoglycaemic episodes, and increased diabetes-specific knowledge compared to standard care. The Hemsley LEAP transition programme, which offers additional diabetes education, dietitian support, case management, and access to private social networks, has been linked to better glycaemic control and psychosocial well-being. A multicentre RCT in Canada found that transition programmes with a transition coordinator led to higher clinic attendance, greater satisfaction with care, and reduced diabetes-related distress among young adults with type 1 diabetes.
Quinine and quinine derivatives can cause hypoglycemia through insulin hypersecretion due to their insulin secretagogue activity, particularly in patients with falciparum malaria who may already have reduced hepatic gluconeogenesis from cytokine effects and malnutrition. This hypoglycemia can be severe, especially in children, and may be overlooked in the clinical context. Octreotide, a long-acting somatostatin analogue, has been used effectively to inhibit insulin release and increase blood glucose levels in such cases. While quinidine and mefloquine may occasionally lead to hypoglycemia, chloroquine does not have this effect.
Children progressing to type 1 diabetes mellitus (T1DM) often exhibit multiple autoantibodies such as high titers of islet cell autoantibodies (ICA), insulinoma-associated-2 autoantibodies (IA-2Ab), and glutamic acid decarboxylase 65 autoantibodies (GAD65Ab), along with decreased first-phase insulin response (FPIR) during an intravenous glucose tolerance test (IVGTT). The combination of islet autoantibodies and reduced FPIR can improve prediction of T1DM, with studies showing an increase in predictive accuracy from 36% with autoantibodies alone to 56% when FPIR is included, over a median observation period of 3.6 years. Young age, a strong humoral response, and reduced FPIR are indicators of a progressive disease process. Additionally, reduced FPIR levels (< 50 mU/L) in autoantibody-positive individuals, particularly for ICA or insulin autoantibodies (IAA), may predict T1DM onset in first-degree relatives (FDR) with up to 92% accuracy over 10 years. C-peptide levels also serve as a predictive marker, showing significant diminishment up to 6 months before clinical diagnosis, indicating progressive β-cell functional loss. Combining FPIR and C-peptide assessments may enhance early detection of metabolic disturbances and improve prediction of T1DM onset.
Small membrane permeant oligomers of IAPP, rather than mature IAPP fibrils, are considered the cytotoxic form that contributes to β-cell dysfunction by inducing endoplasmic reticulum stress and apoptosis. While this mechanism has been observed in in vitro and animal studies, there is currently no evidence confirming the presence of these toxic oligomers in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). However, a genetic link has been identified in a rare familial form of T2DM associated with the S20G mutation of the IAPP gene, which increases the likelihood of IAPP forming oligomers.
Rosiglitazone and pioglitazone are FDA-approved for monotherapy and in combination with metformin and sulfonylureas in the treatment of diabetes, though rosiglitazone is no longer recommended with insulin or nitrate therapy due to cardiovascular concerns, while pioglitazone is approved for use with insulin. Troglitazone, a thiazolidinedione (TZD) predecessor, was withdrawn in 2000 due to fatal hepatotoxicity, a risk not observed with current TZDs. Meta-analysis of 13 randomized clinical trials showed less than 0.3% of patients on pioglitazone or rosiglitazone had ALT levels more than three times the upper limit of normal, compared to nearly 2% on troglitazone, leading to recommendations for liver function tests before starting TZD therapy and periodically afterward. Recent reports suggest that TZD therapy may improve elevated transaminase levels and liver histology in patients with type 2 diabetes and non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.
Repaglinide and nateglinide are medications taken before meals to increase prandial insulin secretion, leading to dose-dependent rises in insulin levels and reductions in postprandial hyperglycemia, with a smaller effect on fasting hyperglycemia. Their impact on HbA1c is generally similar to or less than that of sulfonylureas due to their shorter duration of action, but when used as an add-on to metformin, they can further lower HbA1c by 0.5–1.5% (6–17 mmol/mol).
Repaglinide (0.5–4 mg) or nateglinide (60–180 mg) taken before meals increases insulin concentrations in a dose-dependent manner and reduces postprandial hyperglycemia, with a smaller effect on fasting hyperglycemia. These medications lower HbA1c to a degree similar to or less than sulfonylureas due to their shorter duration of action, and when used as add-on therapy to metformin, they can reduce HbA1c by an additional 0.5–1.5% (6–17 mmol/mol).
Male sex, increasing age, overweight, and obesity are the most important factors predicting type 2 diabetes. Insulin resistance is common in metabolic syndrome, which includes visceral obesity, dyslipidaemia, hypertension, and dysglycaemia, and is also linked with hyperuricaemia, arteriosclerosis, microalbuminuria, platelet hyperaggregation, antifibrinolysis, sleep apnoea, and male hypogonadism. The risk of type 2 diabetes is higher in first-degree relatives of individuals with type 2 diabetes and in women with a history of gestational diabetes mellitus or polycystic ovary syndrome, as these groups are largely insulin resistant. It remains unclear whether chronic insulin resistance is inherited or acquired, though currently known genes associated with diabetes do not significantly improve prediction beyond factors like sex, age, and body mass index. At clinical onset, type 2 diabetes can be categorized into four endotypes based on variables including HOMA-IR, with one endotype showing severe insulin resistance, pronounced liver steatosis, and low-grade inflammation at diagnosis, while others exhibit increasing insulin resistance over time.
Active glycemic management in women with gestational diabetes mellitus (GDM), involving diet, exercise, and insulin when necessary, aiming for fasting blood glucose < 5.5 mmol/L and 2-hour postprandial levels < 7.0 mmol/L, is associated with reduced perinatal morbidity compared to no active management.
Cell dysfunction in type 2 diabetes mellitus (T2DM) arises from a combination of genetic and acquired factors, with T2DM being a polygenic disorder involving multiple genes that, individually insufficient, must be present with or without acquired abnormalities to cause diabetes. These genes can influence β-cell apoptosis, regeneration, glucose sensing, glucose metabolism, ion channels, energy transduction, microtubules/microfilaments, and other islet proteins essential for the synthesis, packaging, movement, and release of secretory granules. Confirmed genetic risk factors include an amino acid polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor-γ (PPARγ), which is expressed in insulin target tissues and β-cells and appears to increase susceptibility to adverse effects of free fatty acids (FFA) on insulin release; a gene encoding calpain-10, a cysteine protease that modulates insulin release and insulin effects on muscle and adipose tissue; and the E23K variant of the KIR6.2 gene, which is involved in potassium inwardly-rectifying channels.
In cohorts with clinical features of MODY, the proportions of young individuals with monogenic diabetes can vary widely depending on selection criteria such as C-peptide or autoimmune markers, ranging from less than 10% to over 50%. In most cohorts, more than 70% of confirmed MODY cases involve mutations in HNF1α, GCK, or HNF1β.
Some oral glucose-lowering agents may have their glucose-lowering effects influenced by drug interactions, which can impact diabetes management.
Patients with diabetic gastroparesis often have long-standing type 1 diabetes mellitus (T1DM) and other microvascular complications such as retinopathy, nephropathy, peripheral neuropathy, and various forms of autonomic dysfunction, which may manifest as abnormal pupillary responses, anhidrosis, gustatory sweating, orthostatic hypotension, impotence, retrograde ejaculation, and bladder dysfunction. Rapid gastric emptying of liquids has been suggested as an early manifestation of type 2 diabetes mellitus (T2DM). Symptoms such as vomiting undigested food hours after eating and weight loss, along with signs like a gastric succussion splash or features of autonomic neuropathy, have been used to predict delayed gastric emptying in diabetic patients with upper gastrointestinal symptoms, although studies indicate these symptoms have limited predictive value.
Alogliptin, a DPP-4 inhibitor used in the treatment of diabetes, was evaluated in the EXAMINE trial involving 5380 individuals with diabetes and recent acute coronary syndrome, showing no major differences in atherosclerotic cardiovascular disease between alogliptin and placebo groups. However, due to concerns about heart failure risk observed with saxagliptin, a separate analysis of the EXAMINE trial assessed alogliptin's effect on heart failure. Over a quarter of participants had heart failure at baseline, and while the absolute rate of heart failure hospitalization was higher with alogliptin, it was not statistically significant. Among those without a prior history of heart failure, alogliptin increased the risk of hospitalization for heart failure by 76%. This increased risk with alogliptin and saxagliptin does not appear to be a class effect, as sitagliptin in the TECOS trial involving 14,671 people with diabetes and established cardiovascular disease did not affect heart failure hospitalization risk. Similarly, linagliptin in two cardiovascular outcome trials also did not significantly alter heart failure risk compared to placebo or glimepiride.
Inherited abnormalities in muscle mitochondrial biogenesis and function can contribute to muscle insulin resistance in lean, young individuals who are severely insulin-resistant and are relatives of people with type 2 diabetes, due to decreased mitochondrial fatty acid oxidation and accumulation of intracellular lipid metabolites that impair insulin signaling. Variants such as the rs540467 polymorphism in the NDUFB6 gene, the rs2267668 A/G SNP in the PPARD gene, and the Gly482Ser SNP in the PGC1A gene affect the response to exercise training in terms of improving insulin sensitivity and physical fitness in people at risk for type 2 diabetes. Impaired mitochondrial function, as indicated by reduced ATP synthesis, is also observed in other non-obese groups at increased risk, such as those with a history of acromegaly or gestational diabetes, and these metabolic alterations in skeletal muscle lead to reduced insulin-stimulated glucose disposal and increased anaerobic glycolysis, resulting in elevated production of lactate and alanine, which serve as substrates for hepatic gluconeogenesis.
Guidelines are conflicting on the use of niacin in diabetes, with the American Diabetes Association suggesting nicotinic acid as an option for treating lipoprotein fractions other than LDL cholesterol, noting only modest changes in glucose that are generally manageable with adjustments to diabetes therapy. Previous statements and the National Institute for Health and Clinical Excellence (NICE) guidelines discourage its routine use. Large outcome studies, such as AIM-HIGH and HPS2-THRIVE, which includes a pre-specified subgroup of 6000 patients with diabetes, are investigating the effects of niacin in individuals with cardiovascular disease or at high risk, with results expected in 2011 and 2013 respectively.
Well-controlled and managed diabetes refers to maintaining blood glucose levels within a target range through lifestyle modifications, medication, and regular monitoring, which helps prevent complications such as neuropathy, retinopathy, and cardiovascular disease.
Disopyramide and cibenzoline, which are class Ia antiarrhythmic agents, can rarely cause symptomatic hypoglycemia, either with or without hyperinsulinemia, indicating possible peripheral effects. In normal individuals, disopyramide leads to a small but statistically significant decrease in fasting glucose levels. Research from a Japanese case-control study found that cibenzoline treatment was linked to an eightfold higher risk of hypoglycemia, whereas disopyramide did not show a significant overall increase in risk, though the confidence intervals were broad. The hypoglycemic effect of disopyramide seems to be dose-dependent, as evidenced by a case where a man experienced severe hypoglycemia after starting clarithromycin, an inhibitor of the liver enzymes that metabolize disopyramide, thereby increasing its blood concentration.
De Wit et al. reviewed instruments used to assess quality of life in young people with diabetes, identifying five diabetes-specific tools with limited psychometric evidence and various practical limitations [109]. The Pediatric Quality of Life Inventory (PedsQL) and the KINDL-R are considered the most suitable for assessing quality of life, but further research is needed to standardize measurement in adolescents and establish cross-cultural validity. Gender differences have been observed, with boys with type 1 diabetes reporting better diabetes-specific quality of life than girls [100]. Studies on the impact of continuous subcutaneous insulin infusion (CSII) on quality of life show mixed results, with some reporting no benefit and others suggesting modest improvements, particularly among children and their parents [110, 111]. The association between optimal metabolic management and improved diabetes-specific quality of life in adolescents has been observed in some studies [112], though it is not consistently found [113].
DPP-4 inhibitors lower blood glucose modestly and have a neutral effect on body weight, with minimal risk of hypoglycaemia when not used alongside other hypoglycaemia-inducing therapies. These medications can be used as add-on therapy to metformin or as monotherapy in type 2 diabetes patients who cannot tolerate or are contraindicated for metformin. Licensed DPP-4 inhibitors in Europe and the USA include alogliptin, linagliptin, saxagliptin, and sitagliptin, while vildagliptin is available in Europe but not approved by the FDA. Dosage adjustment based on renal function is required for most DPP-4 inhibitors except linagliptin, which is eliminated via the enterohepatic system and can be used in individuals with end-stage kidney disease.
Anti-thymocyte globulin (ATG) has been studied in various protocols for treating newly diagnosed type 1 diabetes, either alone or in combination with other agents such as prednisolone or pegylated granulocyte colony-stimulating factor (GCSF). In some trials, ATG was not found to significantly preserve β-cell function as measured by changes in 2-hour C-peptide area under the curve (AUC) during a mixed-meal tolerance test at 12 and 24 months. However, when used at a low dose followed by GCSF in individuals with established type 1 diabetes (diagnosed between 4 months and 2 years prior), the combination showed a trend toward preserving β-cell function, with a mean difference in stimulated AUC C-peptide of 0.28 nmol/l/min at 12 months compared to placebo, and lower HbA1c levels observed at six months.
Metformin, sulfonylureas, meglitinides, thiazolidinediones, glipitins, and α-glucosidase inhibitors are classes of medications used in the management of diabetes, each with varying effects on HbA1c levels, body weight, lipids, and blood pressure. Metformin reduces HbA1c by 1-2%, may decrease or have no effect on body weight, and has neutral or beneficial effects on lipids, with gastrointestinal issues as a common tolerability concern and lactic acidosis as a safety risk, particularly in patients with renal or liver dysfunction. Sulfonylureas lower HbA1c similarly but increase body weight and carry a risk of hypoglycemia. Meglitinides reduce HbA1c by 0.5-1.5%, have a neutral or minimal effect on weight, and also pose a hypoglycemia risk. Thiazolidinediones decrease HbA1c by 1-1.5%, increase body weight, may improve or worsen lipid profiles, and can lower blood pressure, though they are associated with fluid retention, anemia, heart failure, and fractures, requiring caution in patients with cardiovascular disease. Glipitins lower HbA1c by 0.5-1.5%, have no significant effect on weight or lipids, and are generally well tolerated. α-Glucosidase inhibitors reduce HbA1c by 0.5-1%, do not affect weight, and may have neutral or minor beneficial effects on lipids, with gastrointestinal side effects being common.
Patients with diabetes have an increased prevalence of gallstones due to altered gallbladder contractility and are also more susceptible to mesenteric ischemia caused by generalized atherosclerosis; however, altered gallbladder contractility alone, without gallstones, is not strongly supported as a cause of symptoms. Additionally, thoracolumbar radiculopathy can cause girdle-like abdominal pain that does not cross the midline, and specific diagnostic tests are warranted if clinical features suggest these conditions. A careful medical history is essential in evaluating abdominal pain in diabetic patients.
Patients with hyperglycemia due to glucokinase mutations often receive insulin during pregnancy to manage fasting hyperglycemia, although fetal genotype has a greater influence on birth weight than maternal treatment. Insulin has limited impact on fetal growth in these cases, partly because lowering blood glucose in glucokinase patients is challenging due to increased counter-regulation, which can lead to hypoglycemic symptoms even at non-hypoglycemic blood sugar levels. As a result, large insulin doses may be necessary to normalize fasting hyperglycemia, and in some instances, if the fetus has inherited the mutation, intensive insulin use can lead to low birth weight. A small baby is typically observed when the fetus inherits the mutation from the father and is born to a normoglycemic mother. Given the risks of in utero fetal genotype testing, treatment decisions in glucokinase-related gestational diabetes should be based on fetal growth assessments from scans rather than maternal glycemia alone; insulin may be used if abdominal circumference exceeds the 75th centile, but early delivery is often the most effective approach.
Management of obesity is a central component in the treatment strategy for type 2 diabetes mellitus (T2DM), as recent studies show that obese individuals with T2DM can achieve clinically significant weight loss. In the Look AHEAD study, an intensive lifestyle intervention resulted in an average weight loss of 8.6% of initial body weight after one year, accompanied by improvements in weight-associated risk factors and a reduction in mean HbA1c from 7.3% (56 mmol/mol) to 6.2% (44 mmol/mol), despite decreased use of glucose-lowering agents.
Strict avoidance of hypoglycaemia can reverse impaired awareness of hypoglycaemia in many individuals, and the goal of treatment is to reduce both the frequency and severity of hypoglycaemic episodes without promoting hyperglycaemia, often allowing for a reduction in HbA1c levels.
Repaglinide, a medication used in the management of type 2 diabetes mellitus (T2DM), is metabolized by CYP3A4 and CYP2C8 enzymes. Inhibition of CYP3A4 by clarithromycin increases repaglinide concentration, raising the risk of hypoglycemia. Similarly, gemfibrozil, an inhibitor of CYP2C8, significantly increases repaglinide plasma levels, which can also lead to hypoglycemia. Conversely, rifampicin, which induces CYP3A4, decreases repaglinide concentrations by approximately 25% in healthy individuals and may impair glycemic control in patients with T2DM.
Patients with glucokinase (GCK) mutations often present with hyperglycemia during pregnancy screening and account for about 3% of gestational diabetes cases in Caucasians. These patients differ clinically from others with gestational diabetes, both during and outside of pregnancy. The birth weight of infants depends on whether the GCK mutation is inherited by the fetus from the father or expressed only in the mother. If only the mother has the mutation, her hyperglycemia can lead to increased fetal insulin secretion and growth, resulting in a large for gestational age infant. In contrast, if the fetus inherits the mutation from the father, reduced fetal insulin secretion and growth result in a lower birth weight by about 500g. When both the mother and fetus carry the GCK mutation, the opposing effects balance each other, leading to a newborn of normal weight.
Certain medications can influence the risk or management of diabetes, with some having potentially potent effects on glycemic control. Glucocorticoids, high-dose oestrogen, thiazide diuretics (especially at high dosages), non-selective β-adrenoceptor antagonists, β2-adrenoceptor agonists such as salbutamol, ritodrine, antipsychotics, HIV protease inhibitors like indinavir, nelfinavir, and ritonavir, pentamidine, gatifloxacin, streptozotocin, diazoxide, cyclosporine, tacrolimus, temsirolimus, interferon-α, and L-asparaginase may significantly impact glucose metabolism. In contrast, other agents such as oral contraceptives, progestogen-only pills, levonorgestrel in combination pills, loop diuretics, calcium-channel blockers, α1-Adrenoceptor antagonists, growth hormone at physiologic doses, somatostatin analogs, androgen deprivation therapy for prostate cancer, selective serotonin reuptake inhibitors, nicotinic acid, lamivudine, and isoniazid tend to have minor or no effects on glycemic control.
In individuals with type 2 diabetes, insulin resistance leads to the release of free fatty acids from adipose tissue, which are then used by the liver to produce triglyceride-rich very low-density lipoprotein (VLDL) particles. Through the action of lipases, triglycerides from VLDL are hydrolyzed, forming intermediate-density lipoprotein (IDL) and eventually low-density lipoprotein (LDL) particles that return to the liver via LDL receptor binding and cholesterol secretion as bile acids. Triglyceride-rich lipoproteins exchange triglycerides for cholesterol from LDL and HDL particles, mediated by cholesteryl ester transfer protein (CETP), causing LDL and HDL to lose cholesterol and gain triglycerides. Hepatic lipase removes these triglycerides, resulting in smaller, denser LDL (sdLDL) and HDL particles. The smaller HDL particles are cleared more rapidly by the kidneys, contributing to low HDL cholesterol levels in type 2 diabetes, while sdLDL particles are highly atherogenic, increasing cardiovascular risk even at moderate LDL cholesterol levels.
Improved glycaemic control and management of risk factors like blood pressure and lipids are linked to lower risks of late complications and better survival in diabetes. Long-term follow-up from the DCCT and EDIC studies demonstrated that multiple daily insulin injections, the current standard treatment, significantly reduced total mortality compared to less intensive insulin therapy over 1–15 years. However, many individuals with type 1 diabetes still have suboptimal HbA1c levels, and even those with low HbA1c have higher mortality than people without diabetes. Despite this, more recent diagnoses of type 1 diabetes are associated with lower short-term mortality than earlier diagnoses, suggesting gradual improvements in treatment. Estimates suggest that type 1 diabetes reduces life expectancy by approximately 8–18 years, varying by time period, sex, and age at onset.
Clinical and genetic markers can predict responses to diabetes drugs, though application in practice is slow due to studies not being specifically designed for this purpose. Regulatory guidance in 2021 recommended genetic testing for glucose-6-phosphate dehydrogenase deficiency before using certain sulfonylureas to avoid haemolytic anaemia. Clinical guidelines suggest less stringent HbA1c targets for older people with diabetes and those with severe kidney disease, while DPP-4 inhibitors, GLP-1 receptor agonists (GLP-1 RA), and SGLT-2 inhibitors are advised for individuals with a history of recurrent hypoglycaemia. Those with chronic kidney disease or heart failure should receive SGLT-2 inhibitors, and those with cardiovascular disease should take either GLP-1 RA or SGLT-2 inhibitors due to their cardiovascular benefits. Further stratification is needed to optimize diabetes treatment for individual patients.
Treatment goals for diabetes have evolved significantly over the past two decades, with studies like the Diabetes Control and Complications Trial (DCCT) demonstrating the link between glycemic control and reduced microvascular complications in type 1 diabetes. Similar findings were observed in type 2 diabetes (T2DM) through the UK Prospective Diabetes Study (UKPDS), which showed that improved glycemic control over time led to cardiovascular risk reduction with medications such as insulin, metformin, and sulfonylureas, and for T2DM, also a decrease in mortality.
Repaglinide and nateglinide are medications used in the management of diabetes, with repaglinide belonging to the sulphonylurea class and nateglinide classified as a non-sulphonylurea.
DPP-4 inhibitors have the potential to influence physiological processes such as the hunger-satiety system and gastrointestinal motility due to their interaction with natural substrates like GLP-1 and GIP, which are involved in glucose regulation. However, there is little evidence of clinically significant changes in these processes. DPP-4 inhibitors do not appear to cause significant immune-related effects despite DPP-4 being the CD26 T-cell activation antigen. Selective DPP-4 inhibition is important because inhibition of related enzymes such as DPP-8 and DPP-9 has led to adverse effects like blood dyscrasias and skin lesions in some species. No significant drug interactions have been observed with DPP-4 inhibitors, but reproductive toxicity in animals suggests they should be discontinued during pregnancy.
Glycogen synthase kinase 3 (GSK3) regulates glucose metabolism and cognitive function, while Serine–threonine protein kinase AKT1 mediates insulin signaling and glucose metabolism, with reduced action leading to diminished phosphorylation of substrates including GSK3. The Dopamine D2 receptor (DRD2) gene is implicated in type 2 diabetes through alterations in insulin sensitivity and secretion. The Tyrosine hydroxylase gene TCF7L2 encodes a transcription factor involved in Wnt/beta-catenin signaling, which plays a role in pancreatic β-cell function and is a susceptibility gene for type 2 diabetes. Additionally, the Wnt signaling pathway is associated with insulin resistance and schizophrenia. Brain-derived neurotrophic factor and related pathway genes are involved in the regulation of cardiometabolic function and have been linked to clinical features of schizophrenia.
Managing diabetes involves addressing multiple treatment targets beyond glycemic control, including blood pressure and LDL cholesterol, as achieving at least two of these goals in patients with type 2 diabetes has been linked to a 30–50% reduced risk of developing coronary heart disease. Research such as the Steno-2 study highlights that comprehensive control of multiple risk factors can lead to a 59% relative risk reduction in cardiovascular events, likely due to the additive effects of managing each factor. In patients with diabetic nephropathy, structured care approaches have shown that a greater proportion of individuals meet at least three treatment targets (61% vs. 28% in conventional care), resulting in a 60–70% reduction in risks of premature death and end-stage renal disease.
ACE inhibitors reduce mortality and improve symptoms in moderate to severe congestive heart failure (CHF) in patients with and without diabetes, with studies showing similar effectiveness in both groups; in SOLVD, enalapril's effect on compromised left ventricular function was comparable in patients with and without diabetes, while in ATLAS, high-dose lisinopril showed at least as much mortality reduction in patients with diabetes as in those without, and GISSI 3 and SAVE trials reported beneficial effects of ACE inhibitors on morbidity and mortality in post-MI patients with diabetes.
MODY accounts for 3.6% of all diabetes cases diagnosed before 30 years of age and 2.5% of those diagnosed before 20 years of age, while the SEARCH for Diabetes in Youth study found that 1.2% of diabetes cases diagnosed under 20 years of age were MODY. A population study estimated the prevalence of glucokinase variants at 1.1 in 1000 individuals, or 1100 cases per million population, indicating that many individuals with these variants remain undiagnosed or asymptomatic. Prior estimates suggest that 80–90% of MODY cases are misdiagnosed or unrecognized, underscoring the importance of improved diagnostic strategies.
Proinflammatory cytokines and adipokines, such as TNF-α, MCP-1, PAI-1, ceramide, and RBP-4, contribute to the development of muscle insulin resistance, potentially promoting diabetes. These factors may impair insulin action through mechanisms like reduced PI3 kinase signaling and increased hepatic gluconeogenesis. Adiponectin, in contrast, may counteract insulin resistance by antagonizing the effects of proinflammatory cytokines released from adipose tissue.
GLP-1 receptor agonists (GLP-1RAs) were introduced in 2005 and have been included in treatment guidelines for type 2 diabetes since 2009 by the EASD and ADA. They are now recommended as the first injectable therapy before insulin. These agents mimic the effects of the gut hormone GLP-1, addressing multiple aspects of type 2 diabetes pathophysiology, improving glucose control with a low risk of hypoglycemia, and promoting weight loss. They also reduce cardiovascular events. Initially available only by injection, semaglutide is now available orally, which may increase their use earlier in treatment due to greater acceptance by patients and healthcare providers.
Use of CGM-reported mean glucose is superior to estimated HbA1c, glucose management indicator, and other calculations to estimate HbA1c during pregnancy. TIR can assess glycaemia in women with type 1 diabetes but does not provide actionable data for managing fasting or post-prandial hypoglycaemia or hyperglycaemia. The use of CGM is restricted by cost, typically limited to selected, educated, motivated women in experienced centers with dedicated supervision. There are no data supporting the use of TIR in women with type 2 diabetes or gestational diabetes mellitus. NICE advises offering CGM to all pregnant women on insulin therapy, especially those with problematic severe hypoglycaemia, impaired hypoglycaemic awareness, or unstable blood glucose levels to reduce variability. The American Diabetes Association recommends CGM for selected women with hypoglycaemic unawareness.
Diuretics can be effective antihypertensive agents in people with diabetes due to increased total body sodium and extracellular fluid volume, but certain diuretics that cause potassium and magnesium loss can worsen hyperglycaemia by impairing insulin secretion and reducing insulin sensitivity. High-dose thiazide diuretics, equivalent to ≥5mg/day bendroflumethiazide, increase the risk of developing diabetes up to threefold, unlike low dosages up to 2.5mg/day. Potassium depletion is most severe with chlortalidone, less so with furosemide and bendroflumethiazide, and minimal with indapamide. This mechanism is not relevant in people with type 1 diabetes who are C-peptide negative and fully dependent on exogenous insulin. Thiazides may also aggravate dyslipidaemia, though low doses likely pose minimal risk, and they are linked to gout and erectile dysfunction, making them generally unsuitable for middle-aged men with diabetes and hyperuricaemia or erectile dysfunction. Diuretics can precipitate hyperosmolar hyperglycaemic syndrome and should be avoided or used at the lowest effective dose in those with a history of this complication.
When ketonuria or ketonemia is present alongside blood glucose levels exceeding 200 mg/dl (11.1 mmol/l), management strategies include adjusting insulin dosages based on ketone levels and blood glucose concentrations, such as administering 1 unit of rapid-acting insulin for every 50 mg/dl (2.8 mmol/l) above 100 mg/dl (5.5 mmol/l) if ketones are low, or increasing the insulin dosage to 10% or 10–20% of the total daily dose when ketone levels rise, and urgent medical care is required if blood ketones exceed 3.0 mmol/l due to the likelihood of acidosis.
Lifestyle measures such as diet and exercise are important initial interventions for managing type 2 diabetes and can help achieve desired glycaemic targets. However, due to the progressive nature of the disease, most individuals will eventually require pharmacological therapy if glycaemic goals are not met or maintained. The choice of medication is influenced by comorbidities, with considerations for addressing obesity, cardiovascular or renal disease, and minimizing hypoglycaemia risk. Research into precision medicine for personalized treatment remains limited due to a lack of practical biomarkers and pharmacogenomic tools. Evidence of cardiorenal benefits from certain sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists has led to updated treatment recommendations, suggesting earlier use of these agents in individuals at high risk of cardiovascular disease.
Fasting plasma glucose (FPG) is used as a screening test for gestational diabetes mellitus (GDM), particularly in the early third trimester, due to its ease of use, reproducibility, and cost-effectiveness. However, its diagnostic accuracy varies depending on the criteria used, with different studies reporting varying sensitivities and specificities. For instance, using the Carpenter–Coustan and WHO criteria, sensitivities of 81% and 88% and specificities of 76% and 72% were found at an FPG threshold of 4.8 mmol/l (86 mg/dl), whereas studies applying IADPSG criteria reported sensitivities of 92.5% and 74% at 4.7 mmol/l (85 mg/dl). When FPG was used in the early third trimester at a threshold of 5.1 mmol/l (92 mg/dl), sensitivities were much lower at 27% and 26%, with high specificities of 95% and 90%, indicating that FPG may not be reliable for GDM screening in the first trimester.
Dual GLP-1/GIP receptor agonists, such as tirzepatide (LY3298176), have been studied in individuals with type 2 diabetes. Tirzepatide is a 39 amino acid peptide derived from the N-terminal GIP(1–14) sequence, with an N2 aminoisobutyric acid substitution to prevent degradation by DPP-4. It functions as a GLP-1 receptor agonist through its mid-sequence and includes a C20 fatty di-acid chain linked via glutamic acid to Lys20, which enhances albumin binding and prolongs its circulation time. The molecule exhibits stronger agonist activity at the GIP receptor compared to the GLP-1 receptor, reflecting the higher physiological concentrations of GIP relative to GLP-1.
HbA₁c and blood glucose are the two primary measures used to assess glycaemia in diabetes management, with HbA₁c reflecting overall glucose levels over the previous 6–8 weeks and blood glucose providing day-to-day level information. These measures help evaluate the need for therapy and monitor therapeutic response in both type 1 and type 2 diabetes. The chapter covers the tests for HbA₁c and glucose, their measurement technologies, and clinical applications, as well as the role of other glycated proteins and point-of-care testing. Emerging technologies like continuous glucose monitoring are also discussed.
Metformin at a dose of 1700 mg reduces the risk of diabetes with a hazard ratio of 0.69 (95% CI: 0.57–0.83), as shown in the DPP (2002) study. The CDPS (2001) study reported a hazard ratio of 0.23 for diabetes risk at a dose of 750 mg. The IDPP-1 (2006) study found a hazard ratio of 0.74 (95% CI: 0.65–0.81) at a dose of 500 mg. Thiazolidinediones (TZDs), such as Troglitazone at 400 mg, showed a hazard ratio of 0.45 (95% CI: 0.25–0.83) in the TRIPOD (2002) study, while Rosiglitazone at 8 mg demonstrated a hazard ratio of 0.40 (95% CI: 0.35–0.46) in the DREAM (2006) study. Acarbose at 300 mg had a hazard ratio of 0.75 (95% CI: 0.63–0.9) according to the STOP-NIDDM (2002) study.
GLP-1 and related peptides have been studied for their therapeutic potential in type 2 diabetes due to their ability to improve insulin output, inhibit glucagon secretion, delay gastric emptying, and reduce food intake, thereby helping to normalize postprandial glycaemia. However, GLP-1's short half-life of less than 2 minutes limits its clinical use. Exenatide, a GLP-1 receptor agonist derived from Gila monster lizard saliva with approximately 50% amino acid homology to GLP-1, has a longer half-life of around 2 hours due to resistance to DPP-4 degradation, making it effective for blood glucose regulation. Liraglutide, another GLP-1 receptor agonist, has an extended half-life of over 12 hours by incorporating palmitate into the GLP-1 sequence, allowing plasma albumin binding and reduced DPP-4 exposure. Oral semaglutide, a more recent GLP-1 receptor agonist, is available as an oral formulation, offering an advantage over injectable forms. DPP-4 inhibitors like sitagliptin are also used clinically to prolong the activity of endogenous GLP-1. GLP-1 and its agonists act on islet GLP-1 receptors linked via Gs to adenylate cyclase activation, increasing cAMP levels that enhance glucose-induced insulin secretion through PKA and EPACs. Enhanced postprandial GLP-1 secretion, partly due to accelerated food delivery to L cells following bariatric gastric bypass surgery, contributes to improved glucose homeostasis in type 2 diabetes.
Cystic fibrosis diabetes should be screened annually using an oral glucose tolerance test starting from 10 years of age, as recommended by ISPAD and ADA. The current diagnostic criteria for cystic fibrosis diabetes are the same as for other forms of diabetes, though there is discussion about lowering the thresholds due to associations between sub-threshold glycaemia and worsened lung function and weight loss. The oral glucose tolerance test is preferred but should not be conducted during acute pulmonary exacerbations, especially when glucocorticoids are used. Glycated haemoglobin (HbA1c) may have diagnostic utility, though it is not currently recommended, and the role of continuous glucose monitoring is under evaluation. While some individuals may initially respond to sulfonylureas, most eventually require insulin therapy, which has added benefits for body weight, pulmonary function, and pancreatic function. Early diagnosis and treatment of cystic fibrosis diabetes can help preserve lung function, and annual monitoring for diabetes complications is advised, beginning five years after diagnosis.
Omentin, a peptide derived from visceral adipose tissue, enhances insulin-stimulated glucose uptake in adipocytes, suggesting a potential therapeutic role in diabetes.
Diagnosis of gestational diabetes mellitus (GDM) in early pregnancy is recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) using the same diagnostic thresholds as those applied in non-pregnant individuals, with most international bodies endorsing first-trimester screening via blood tests to identify undiagnosed type 2 diabetes, although there is agreement that IADPSG thresholds should not apply to early pregnancy. Prevalence rates of GDM have increased two- to threefold, potentially leading to overdiagnosis and affordability concerns, yet this is supported by the high prevalence of prediabetes in women of this age group outside of pregnancy. Methodological concerns include variability and poor reproducibility of the oral glucose tolerance test (OGTT), with the IADPSG's 1.75 risk ratio considered too low, and a lack of randomized controlled trial data for reliability, favoring more robust clinical outcomes. Logistical challenges involve the increasing number of individuals with diabetes and the need for strategies like algorithm-guided management to avoid diverting resources from pregestational diabetes care. Medicalization concerns arise as pregnancies previously deemed healthy may now receive a GDM label, leading to increased medical intervention regardless of glycaemia or fetal growth, with psychological and economic consequences for women identified as low risk. Cost-economic data are conflicting, with some criteria derived from models using different thresholds, majority of women treatable with diet alone, and existing datasets often lacking blinding or long-term outcome considerations.
MODY (maturity-onset diabetes of the young) is characterized by onset before 25 years of age and autosomal inheritance, with over 80% of Caucasian patients having mutations in HNF-1α or glucokinase. Other MODY subtypes involving HNF-4α, HNF-1β, and IPF-1 mutations are less common. The frequency of HNF-1α mutations varies by population, ranging from 25–50% in French, 36% in German, 13–18% in British, 8% in Japanese, and 5% in Chinese patients. In young Chinese patients with diabetes, 5–10% have been found to carry glucokinase or HNF-1α mutations.
In type 2 diabetes mellitus (T2DM), insulin requirements can vary, with some patients needing similar amounts to those with type 1 diabetes, while for others, insulin initiation and intensification is typically a more gradual process. Treatment approaches differ regarding the choice of insulin, especially when adding it to oral hypoglycemic therapy. Before long-acting basal insulin analogs were available, many patients were started on twice-daily premixed insulin, often alongside metformin, with sulfonylureas typically discontinued. Clinical trials have supported the use of long-acting basal analogs due to their low rates of hypoglycemia compared to NPH insulin, leading to their inclusion in treatment guidelines for T2DM. These insulins are commonly used in community settings to introduce patients to insulin therapy. However, despite their popularity, some healthcare professionals find it challenging to achieve adequate glycemic control with this regimen, and many patients may need a second insulin injection with mealtime coverage within 6–12 months.
Having diabetes during pregnancy or giving birth to a baby weighing more than 4 kg increases the risk of developing diabetes later in life. It is recommended to check blood sugar levels at least once a year and follow lifestyle modification measures to manage this risk.
In diabetes, altered immune responses contribute to macrovascular disease, with elevated reactive oxygen species (ROS) promoting the expression of pro-inflammatory genes that lead to foam cell formation. Nox-derived ROS, particularly from Nox1 and Nox4 isoforms, play a key role in diabetes-associated atherosclerosis by modulating both innate and adaptive immune cell responses. Nox4 induction in monocytes and macrophages is necessary for oxidized low-density lipoprotein (oxLDL)-stimulated ROS production and cytotoxicity, while Nox1-derived ROS contribute to monocyte adhesion and macrophage accumulation in atherosclerotic lesions, as observed in diabetic ApoE−/− mice. Additionally, T cells from human atherosclerotic plaques recognize and respond to oxLDL, highlighting the involvement of immune mechanisms in diabetes-related vascular complications.
CSII therapy has been studied in children with type 1 diabetes, showing varying results depending on the duration of diabetes. In a UK RCT involving children aged 7 to 15 years, CSII showed no clinical benefit over MDI in the first year following diagnosis, and neither regimen achieved optimal glycaemic targets. However, observational studies in paediatric populations with longer diabetes duration demonstrated better glycaemic outcomes with CSII. A study by Korkmaz et al. found that over a five-year period, CSII was associated with better glycaemic control compared to MDI in individuals with a mean diabetes duration of 10.7 years. Another retrospective multicentre study showed that CSII led to significant improvements in HbA1c during follow-up in children and adolescents with an average diabetes duration of 6.3 years, although the major benefit was observed in boys only.
Patients typically exhibit mild fasting hyperglycemia from birth, ranging between 5.5–8.0 mmol/L, with minimal deterioration in fasting glucose levels as they age. They do not experience symptoms of hyperglycemia, and post-meal glucose levels are only mildly elevated, often showing a small increase of less than 3 mmol/L in 70% of patients during an oral glucose tolerance test. This pattern contributes to near-normal HbA1c levels and a low risk of complications. HbA1c values exceeding 7.5% suggest the possibility of an alternative diagnosis.
Cotadutide (MEDI0382), an oxyntomodulin-based GLP-1/glucagon receptor co-agonist, has been studied in a 49-day phase 2 randomized placebo-controlled trial involving 65 overweight and obese individuals with type 2 diabetes. Daily subcutaneous injections of cotadutide, starting at 50 μg and escalated to 300 μg, resulted in clinically significant reductions in body weight (~3 kg), HbA1c (~0.7%; 8 mmol/mol), and both basal and post-prandial glucose levels, along with increased meal-stimulated insulin secretion. The co-agonist combination leverages appetite-suppressing, insulin-releasing, and energy-expending effects to promote weight loss, while the GLP-1 agonist component suppresses endogenous glucagon secretion and counteracts the hyperglycemic effects of the glucagon moiety, leading to overall glucose lowering.
LET7 miRNA interferes with multiple components of the insulin signaling pathway, including the insulin receptor, IRS2, PIK3IP1, AKT2, TSC1, and RICTOR, which can impact insulin sensitivity and glucose homeostasis. This interference can be counteracted by RNA binding proteins Lin28a and Lin28b, which inhibit the maturation of LET7, thereby enhancing the translation of insulin signaling components. The interaction between LET7 and the insulin → PI3K → mTOR signaling pathway is associated with glucose homeostasis and insulin sensitivity, which are key factors in diabetes.
Hyperglycaemia can be caused or exacerbated by medications such as corticosteroids, which are commonly used in hospital settings, yet glucose monitoring remains underutilized in patients receiving these drugs. A significant proportion of hospitalized individuals on corticosteroids have pre-existing diabetes, and many without a prior diagnosis also experience hyperglycaemia. The use of corticosteroids, particularly dexamethasone, has been linked to reduced mortality in patients with moderate SARS-CoV-2 infection requiring oxygen therapy, highlighting the importance of managing hyperglycaemia in this context. People with diabetes face a higher risk of hospitalization due to SARS-CoV-2 and tend to have worse outcomes compared to those without diabetes or hyperglycaemia. Guidelines from the Joint British Diabetes Societies Inpatient Care Group and Diabetes UK offer recommendations for managing hyperglycaemia and diabetes in both non-COVID and COVID-19-related hospital admissions.
Increased levels of glycation in diabetes lead to glycation-induced dysfunction or inactivation of complement-regulatory proteins such as CD59, which normally prevents the deleterious effects of complement overactivation by inhibiting the membrane attack complex (MAC). Hyperglycaemia generates advanced glycation end-products (AGEs) that create neo-epitopes, promoting binding of lectin pathway pattern-recognition molecules like MBL and ficolins. The combined effects of CD59 inactivation and complement activation are proposed to increase tissue deposition of MAC, activating intracellular signaling pathways that release pro-inflammatory cytokines and growth factors. Three proposed pathways leading to late complications of diabetes include: complement-dependent pathways involving MAC and lectin pathway activation through glycation of receptor carbohydrates, complement-independent pathways such as the polyol pathway, and pathways triggered by hyperglycaemia and/or MAC such as PKC and NF-κB signaling.
Higher baseline HbA₁c values and persistent depression are associated with an increased risk of diabetic retinopathy progression in patients with type 2 diabetes, with baseline HbA₁c accounting for 21% of the progression and persistent depression contributing an additional 6% in a regression model. Patients with high depression scores at both baseline and follow-up had significantly higher baseline HbA₁c levels and were more likely to develop proliferative diabetic retinopathy.
Patients and families should be aware of risk factors related to diabetes, such as the increased likelihood of hypoglycemia during, immediately after, and up to 2–12 hours following exercise, which may necessitate adjustments in glucose monitoring and insulin regimens; additionally, untreated celiac disease and Addison disease can further elevate the risk of hypoglycemia.
Adrenaline affects glucose homeostasis by inhibiting insulin secretion and increasing hepatic glucose output. It acts on pancreatic β cells via α₂ adrenoceptors and on the liver through β₂ adrenoceptors, causing a transient increase in glycogenolysis and a more sustained effect on gluconeogenesis. Adrenaline also enhances hepatic gluconeogenesis indirectly by stimulating lipolysis in adipose tissue via β₁ and β₃ adrenoceptors, releasing lactate, alanine, and glycerol as precursors for gluconeogenesis. Additionally, β₂-adrenergic effects impair glucose utilization in muscle, contributing to hyperglycaemia, where adrenaline is more potent than noradrenaline due to its higher affinity for β₂ receptors.
Clinical guidelines for managing type 2 diabetes, such as the International Diabetes Foundation’s Global Guideline for Managing Type 2 Diabetes and the RACGP/Diabetes Australia guidelines, include sections on end-of-life care as part of their recommendations.
Several medications initially developed for type 2 diabetes, such as GLP-1 receptor agonists (e.g., semaglutide, liraglutide, dulaglutide), not only improve glycemic control but also lead to significant weight loss and reduce cardiovascular risk factors like blood pressure and lipids. These drugs work in a glucose-dependent manner to enhance insulin secretion and suppress glucagon production, minimizing the risk of hypoglycaemia. Additionally, they influence appetite regulation by slowing gastric emptying and activating receptors in the hypothalamus, promoting satiety. Clinical trials show that liraglutide and semaglutide result in 33% and 13% of individuals achieving 10% weight loss, respectively. Importantly, in type 2 diabetes patients, GLP-1 receptor agonists lower the risk of fatal and nonfatal cardiovascular events.
Women with GCK gene variants often develop hyperglycaemia during pregnancy screening and account for 2% of gestational diabetes cases in white European women. Identifying these variants is crucial due to differences in clinical progression compared to other gestational diabetes cases. The birth weight of the infant is influenced by whether the mother or fetus carries the GCK variant. When only the mother has the variant, her hyperglycaemia can lead to increased fetal insulin production and growth, resulting in a large-for-gestational-age infant, and infants without the maternal variant are at higher risk of macrosomia and related obstetric complications. If the fetus inherits the variant from the father, birth weight decreases by about 500g due to reduced fetal insulin secretion and growth. If both mother and fetus have the GCK variant, the opposing effects balance out, leading to a normal birth weight as long as maternal blood glucose remains untreated.
Rosiglitazone, a thiazolidinedione used in diabetes management, has been associated with an increased risk of myocardial infarction and cardiovascular death, although its effect on stroke remains uncertain with one study showing a nonsignificant reduction. In contrast, pioglitazone, another medication in the same class, did not show adverse cardiovascular effects and was linked to a 16% reduction in a secondary outcome combining all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke.
Autoantibodies to zinc transporter 8 (ZnT8Ab) are present in 60–65% of patients with type 1 diabetes mellitus (T1DM), compared to less than 2% in controls, making them a highly specific and independent marker of islet cell autoimmunity. These autoantibodies are detected in individuals who may otherwise test negative for islet autoantibodies (IAA) and have been found to appear before the onset of T1DM in first-degree relatives (FDR) of patients and high-risk individuals from the general population. ZnT8 is a protein located in the membrane of beta-cell secretory vesicles, functioning as a zinc ion transporter, and its targeted autoimmunity contributes to the pathogenesis of T1DM.
Albiglutide, a GLP-1 receptor agonist, was shown in the Harmony Outcomes trial to reduce major adverse cardiovascular events (MACE) in people with type 2 diabetes and established cardiovascular disease, with a hazard ratio of 0.78 compared to placebo. It was also the only GLP-1RA to significantly reduce the incidence of myocardial infarction in this population, with a hazard ratio of 0.75. The trial involved 9463 participants and had a median follow-up of 1.6 years. Despite these benefits, albiglutide was withdrawn from the market in the USA and Europe for economic reasons.
Impairment of glucose tolerance is observed in 30–60% of cases, and overt diabetes occurs in 20–50% of cases, particularly in individuals predisposed to diabetes, such as those with a family history of the disorder. Diabetes resembling type 2 diabetes mellitus (T2DM) can result from glucocorticoid excess, which causes hyperglycemia primarily by inducing insulin resistance, as evidenced by hyperinsulinemia. This condition is characterized by reduced insulin-stimulated glucose uptake and utilization by peripheral tissues, along with increased hepatic glucose production due to stimulation of gluconeogenesis. Glucocorticoids directly activate hepatic gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and increase the supply of glucogenic substrates like amino acids and glycerol, which are generated by muscle proteolysis and peripheral adipose tissue lipolysis. Additionally, glucocorticoids have permissive effects on gluconeogenesis induced by epinephrine.
Teplizumab, when used in the TrialNet (TN-10) study involving first-degree relatives of individuals with type 1 diabetes, demonstrated the ability to delay the onset of clinical type 1 diabetes, with 57% of participants in the intervention group remaining diabetes-free at the end of the trial. The annual incidence rates of type 1 diabetes were significantly lower in the teplizumab group (14.9%) compared to the placebo group (35.9%), with a statistically significant p-value of 0.006. The intervention resulted in a two-year delay in diagnosis, which is considered clinically meaningful, especially for children who made up approximately 70% of the 76 total participants. Biomarkers were useful in identifying participants most likely to respond to teplizumab, and future research into repeated dosing or combination therapies may enhance its effectiveness. Based on these findings, teplizumab injection was approved by the FDA in November 2022 to delay the onset of stage 3 type 1 diabetes in individuals aged 8 years and older who have stage 2 type 1 diabetes.
Increased lipid availability, particularly elevated fatty acid flux, raises the intramyocellular long-chain fatty acyl-CoA pool, which can either undergo mitochondrial oxidation or be used to synthesize diacylglycerols (DAGs) for triglyceride (TAG) storage. When fatty acid uptake exceeds the capacity for mitochondrial oxidation and DAG incorporation into TAGs, intramyocellular DAG levels rise, leading to increased plasma membrane sn-1,2-DAGs. This elevation activates novel protein kinase C (nPKC) isoforms, specifically PKCε and PKCθ, with PKCε translocation to the membrane resulting in phosphorylation of the insulin receptor on threonine1160, contributing to insulin resistance in human skeletal muscle.
Late eating is associated with decreased insulin sensitivity, which can contribute to impaired metabolic control relevant to diabetes. Consuming the majority of daily energy intake early in the day is linked to a lower risk of developing overweight or obesity, factors that are known to influence diabetes risk. Regular meal patterns with early energy intake and overnight fasting periods offer metabolic benefits, such as reduced inflammation and a more favourable microbiome profile, which may support better glucose regulation. Additionally, intermittent fasting has shown short-term benefits in reducing body weight among adults with overweight and obesity, potentially impacting diabetes prevention or management.
GLP-1 and PYY play important roles in glucose metabolism, and both GLP-1 agonists and DPP-4 inhibitors are used in the treatment of type 2 diabetes. The intestinal microbiome, through the production of short-chain fatty acids (SCFAs), can modulate GLP-1 and PYY secretion, potentially influencing the risk of insulin resistance and type 2 diabetes. Studies in mice show that SCFAs can induce GLP-1 secretion via GPR41 and GPR43 receptors, with impaired responses observed in knockout models. While acute prebiotic interventions have not consistently increased GLP-1 or PYY secretion, longer-term studies in humans, including those with overweight or obesity, have reported elevated postprandial GLP-1 and PYY levels following prebiotic supplementation. A 12-month study involving hyperinsulinaemic adults also found increases in both basal and postprandial GLP-1 concentrations with high-fibre cereal supplementation, which promotes SCFA production. These findings support a link between SCFAs and incretin hormone secretion, suggesting that modulating the intestinal microbiota may help address disrupted incretin signaling in metabolic diseases such as type 2 diabetes.
In diabetes, the reduction of glucose to sorbitol by NADPH contributes to the depletion of NADPH, which is necessary for regenerating reduced glutathione, an important scavenger of reactive oxygen species (ROS), potentially leading to increased intracellular oxidative stress. Overexpression of aldose reductase in diabetic mice has been shown to increase atherosclerosis and reduce the expression of genes involved in glutathione regeneration, with decreased glutathione levels observed in the lens of diabetic rats and transgenic mice overexpressing aldose reductase. Decreased glutathiolation of proteins in diabetes is linked to reduced nitric oxide availability, which lowers S-nitrosoglutathione levels, though restoring nitric oxide levels in animal models can improve glutathiolation, inhibit aldose reductase activity, and prevent sorbitol accumulation. Hyperglycaemia may further reduce NADPH availability by inhibiting glucose-6-phosphate dehydrogenase, the main source of NADPH regeneration, particularly in vascular cells and neurons. In diabetic vascular cells, glucose may not be the primary substrate for aldose reductase due to its low intracellular concentration compared to the enzyme's high Michaelis constant for glucose, suggesting that glycolytic metabolites like glyceraldehyde-3-phosphate, which have higher affinity for aldose reductase, may be the physiologically relevant substrates.
For individuals with type 1 diabetes mellitus (T1DM) who have achieved optimal HbA1c levels using intermittent capillary blood glucose monitoring, minimizing the risk of hypoglycemia becomes the primary therapeutic challenge. In a trial involving individuals with baseline HbA1c <7.0% (<53 mmol/mol), the primary endpoints focused on changes in hypoglycemia rather than HbA1c itself. At 26 weeks, continuous glucose monitoring (CGM) showed less frequent biochemical hypoglycemia ≤3.9 mmol/L (70 mg/dL), though not statistically significant, with median time spent at ≤3.3 mmol/L (60 mg/dL) being 18 vs. 15 minutes/day in the CGM and control groups, respectively (P=0.05). Severe hypoglycemic events were similar between groups, but the trial lacked sufficient power to detect differences. A greater proportion of CGM users experienced a decrease in HbA1c ≥0.3% without severe hypoglycemia compared to the control group (28% vs. 5%, P<0.01).
Optimal glycaemic management involves behavioural modification, oral antidiabetic drugs (OAD), and insulin, with a target HbA1c of ≤5.5–7% (48–53 mmol/mol), and individual adaptation of dose. Pathogenesis-oriented treatments include α-lipoic acid (thioctic acid), which is administered either as a 600 mg IV infusion or 600–1800 mg orally, and has been studied in RCTs lasting 3 to 4 weeks with NNT values of 6.3 and 2.8–4.2 respectively. Actovegin is given as 2 g IV or 1.8 g orally in RCTs lasting 6 months with an NNT of 8.3, and benfotiamine at 600 mg orally in RCTs lasting 6 weeks, although its NNT remains uncertain. Symptomatic treatment options for neuropathic pain include tricyclic antidepressants such as amitriptyline, desipramine, imipramine, clomipramine, and nortriptyline, with doses ranging from (10–)25–150 mg and varying NNMH values. Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine are used at 60–120 mg, with an effective dose of 60 mg and an NNT of 6.4 (95% CI 5.2 to 8.4). α2–δ ligands like gabapentin and pregabalin are used at doses of 900–3600 mg and 300–600 mg respectively, with NNT values of 7.2 (5.9 to 9.1) and 7.7 (6.5 to 9.4). Weak opioids such as tramadol are used at 50–400 mg with an NNT of 4.7 (3.6 to 6.7). Local treatments include capsaicin cream (0.025%) applied four times daily for a maximum of 6–8 weeks with an NNT of 5.7, and capsaicin 8% applied once as 179 mg topically, repeatable after 3 months, with an NNT of 10.6 (7.4 to 18.8). Strong opioids are used with an NNT of 4.3 (3.4 to 5.8). For pain resistant to standard pharmacotherapy, oxycodone and tapentadol may be used as add-on treatments, or electrical spinal cord stimulation may be considered, which is invasive and requires a specialist.
General diagnostic questionnaires for eating disorders are unsuitable for individuals with type 1 diabetes as they fail to capture unique features such as insulin omission, and certain aspects of diabetes management may be misinterpreted as disturbed eating in the general population; specialized tools like the 16-item DEPS-R and the five-item mSCOFF questionnaire are designed for diabetes-specific screening, but neither replaces a comprehensive assessment by a multidisciplinary team experienced in both diabetes and eating disorders.
High body mass index (BMI) can exacerbate or even be a prerequisite for the negative effects of the ENPP1 K121Q variant on insulin resistance-related phenotypes and type 2 diabetes mellitus (T2DM). The Q121 variant has been associated with an increased risk of both morbid obesity and hyperglycemia in various populations, including French children and adults, German children, and British adults. Obesity plays a significant role in impairing glucose homeostasis, and differences in the effect of the Q121 variant on BMI across studies may contribute to the inconsistent findings regarding its impact on diabetes risk. A recent meta-analysis of case-control studies found that individuals carrying the Q121 variant have approximately a 20% higher risk of developing T2DM, although the results were not fully consistent across all samples.
In type 2 diabetes, glucagon concentrations are typically inappropriately elevated, contributing to high blood glucose levels. Lowering blood glucose can be achieved by suppressing glucagon secretion from pancreatic α cells, which can be done using GLP-1 receptor agonists, somatostatin analogues, or non-peptide inhibitors. Alternatively, glucagon action can be suppressed through the use of peptide glucagon receptor antagonists, anti-glucagon antibodies, or glucagon receptor antisense oligonucleotides. Small-molecule glucagon receptor antagonists have also been studied, but their use is associated with compensatory hyperglucagonaemia, leading to rebound hyperglycaemia if treatment is stopped. Additionally, adverse liver effects have complicated the therapeutic use of glucagon receptor antagonism.
Social determinants of health, such as living and working conditions, significantly influence both the risk of developing type 2 diabetes and outcomes related to its prevention and control, with long-term exposure to resource-deprived environments—marked by poverty, poor education, or limited healthcare—contributing to disparities in diabetes risk, diagnosis, and management.
The RECORD study evaluated 4447 patients with type 2 diabetes mellitus (T2DM) on metformin or sulfonylurea monotherapy, with a mean HbA1c of 7.9% (63 mmol/mol), who were randomly assigned to receive added rosiglitazone or continue with metformin and sulfonylurea. Over 5.5 years, the primary endpoint of cardiovascular hospitalization or cardiovascular death occurred in 321 patients in the rosiglitazone group and 323 in the control group, showing non-inferiority (HR 0.99; 95% CI 0.85–1.16). There were no significant differences in cardiovascular death (HR 0.84; 0.59–1.18), myocardial infarction (HR 1.14; 0.80–1.63), or stroke (HR 0.72; 0.49–1.06). However, rosiglitazone was associated with a higher incidence of heart failure leading to hospitalization or death (HR 2.10; 1.35–3.27) and increased limb fracture rates, particularly in women. At 5 years, the mean HbA1c was lower by approximately 0.25% (3 mmol/mol) in the rosiglitazone group compared to the control group. The study suggests that while rosiglitazone does not increase the risk of ischemic heart disease, it does not provide a clear cardiovascular benefit either.
GLP-1 stimulates insulin secretion in vitro and in vivo, and its activity is terminated by DPP-4, which cleaves two amino acids from the N-terminus of full-length GLP-1 (1-37), converting it into the truncated, biologically active forms GLP-1 (7-36) amide and GLP-1 (7-37).
Poor metabolic management in individuals with diabetes is often linked to inadequate oral hygiene, highlighting the importance of dental health education and monitoring in this population.
Oral semaglutide was evaluated in the PIONEER 6 trial for its efficacy in patients with diabetes, particularly those with established cardiovascular disease, chronic kidney disease, or cardiovascular risk factors. The trial demonstrated that once-daily oral semaglutide was non-inferior to placebo in preventing major adverse cardiovascular events (MACE), with a lower incidence in the semaglutide group (3.8%) compared to placebo (4.8%). Additionally, treatment with oral semaglutide was associated with reduced all-cause mortality and cardiovascular mortality, although the trial was not designed or powered to confirm superiority over placebo for these outcomes.
People with type 1 diabetes, typically with a duration of more than five years, and some individuals with type 2 diabetes may be candidates for whole pancreas transplantation if they meet specific criteria, such as low exogenous insulin requirement, a body mass index greater than 30 kg/m², HbA1c levels above 7.5–8.0% (58–64 mmol/mol) despite expert diabetes management, or problematic hypoglycemia with at least two episodes of severe hypoglycemia per year. Severe hypoglycemia is defined as blood glucose below 54 mg/dL (3 mmol/L) accompanied by symptoms like memory loss, confusion, behavioural changes, impaired consciousness, seizure, or visual disturbances, where the person is unable to self-treat and requires carbohydrate or glucagon administration. Impaired awareness of hypoglycemia or extreme glycemic lability, as measured by tools like the Clarke score (≥4), HYPO score (≥1000), or lability index (≥400), may also be considered. Additional factors include a composite score of Clarke ≥4, HYPO score ≥75th percentile (≥423), and lability index ≥75th percentile (≥329), or major fear of maladaptive behavior related to hypoglycemia. Recurrent episodes of diabetic ketoacidosis or severe, rapidly progressing diabetes complications may also be considered. Candidates for pancreas-kidney or islet-kidney transplants must meet criteria for kidney transplantation alone. Contraindications for pancreas transplantation include age over 60 years, high body mass index (above 30 kg/m², with 28 preferred for whole pancreas transplantation), insulin requirements over 1.0 U/kg/day or HbA1c above 10.0% (85 mmol/mol), untreated proliferative retinopathy, high cardiovascular risk including uncontrolled hypertension, myocardial infarction within six months, evidence of ischemia on cardiac testing in the past year, or left ventricular ejection fraction below 30%, history of malignancy except for completely resected skin cancers, untreated infections including hepatitis B or C and HIV, recent opportunistic infections, inability to comply with immunosuppression and follow-up, or any medical or psychiatric condition that could interfere with safe participation post-transplant.
Gestational diabetes is often managed at the specialist level, but due to the large number of women diagnosed, this can overwhelm diabetes pregnancy clinics and reduce the level of care for women with pre-existing type 1 diabetes (T1DM) and type 2 diabetes mellitus (T2DM). The morbidity of gestational diabetes is relatively low compared to T1DM and T2DM, suggesting that managing gestational diabetes in the community with appropriate protocols and guidelines, along with access to specialist services when needed, may be a more efficient use of resources.
Persistent hyperglycaemia, when present at baseline and 24 hours after admission, is inversely associated with neurological improvement in the first 7 days, 30-day functional outcome, and 90-day negligible dependence, and is positively associated with increased mortality at 90 days and parenchymal haemorrhage. Transient hyperglycaemia, which is absent at baseline but present at 24 hours after admission, similarly correlates with worse 90-day outcomes, including negligible dependence, mortality, and parenchymal haemorrhage. However, baseline hyperglycaemia alone without persistence at 24 hours does not associate with poor outcomes, suggesting that persistent hyperglycaemia, rather than stress response hyperglycaemia, may be more detrimental in the acute stroke setting.
GLP-1 receptor agonists have been shown to reduce the risk of major adverse cardiovascular events (MACE), which include cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, with some trials also including hospitalization for unstable angina. These drugs also lower the risk of heart failure hospitalizations, sometimes combined with cardiovascular death in certain studies. Regarding kidney outcomes, GLP-1 RAs reduce the likelihood of persistent macroalbuminuria, persistent doubling of serum creatinine levels, a decline in eGFR to ≤45 ml/min/1.73 m² or <45 ml/min/1.73 m² depending on the trial, the need for renal replacement therapy, and renal disease-related death, with some trials using a composite outcome of a 40% eGFR decline, renal replacement, or renal death, or a sustained 30% decline in eGFR along with development of macroalbuminuria or chronic renal replacement therapy.
Several risk scores have been developed to predict heart failure in people with diabetes. The PROactive study created a risk score with 12 variables including demographics, medical history, medication use, and lab measurements, showing moderate discrimination (C-statistic 0.75). The WATCH-DM risk score, derived from the ACCORD trial using machine learning, demonstrated fair calibration and moderate discrimination (C-statistic 0.72) and has been validated across different populations. The TRS-HFDM risk score, developed using data from the SAVOR-TIMI 53 and validated in the DECLARE-TIMI 58 trial, showed good discrimination (C-index 0.81) and can assess heart failure risk in people with or without a prior history of heart failure.
Poor control of diabetes and limited access to medicines and care contribute to high mortality rates, as seen in a Tanzanian cohort of individuals with type 1 diabetes where mean glycated haemoglobin (HbA1c) was 11.1%, leading to high rates of complications such as retinopathy (22%) and neuropathy (29%) despite the young average age of 21.1 years and a relatively short diabetes duration of 6.2 years. In type 2 diabetes, diagnosis often occurs later in disease progression, with many individuals already having complications at diagnosis. In sub-Saharan Africa, the prevalence of complications varies widely, with retinopathy ranging from 7% in Kenya to 63% in South Africa, neuropathy from 27% in Cameroon to 66% in Sudan, and microalbuminuria from 10% in Tanzania to 83% in Nigeria.
Glycemic control is essential in managing type 2 diabetes to address acute symptoms and prevent chronic microvascular and macrovascular complications. The disease's progression, influenced by insulin resistance, declining β-cell function, and defects in regulatory hormones and nutrient metabolism, necessitates ongoing adjustments in therapy. Lifestyle modifications like diet and exercise are crucial from diagnosis onward, and drug treatment should be initiated promptly if lifestyle changes are insufficient. Treatment strategies should consider the underlying pathophysiology, often requiring combinations of different drug classes for additive effects. Metformin, typically the first-line oral therapy, reduces hepatic glucose production, enhances skeletal muscle glucose uptake, and offers cardiovascular benefits without causing hypoglycemia or weight gain, though gastrointestinal side effects and the risk of lactic acidosis in certain populations limit its use. Sulfonylureas stimulate insulin secretion by acting on pancreatic β-cells, but their efficacy depends on remaining β-cell function and they carry a risk of hypoglycemia, especially in the elderly. Meglitinides, rapid-acting insulin secretagogues taken before meals, help manage postprandial glucose levels and are often combined with agents that reduce insulin resistance. Thiazolidinediones improve insulin sensitivity through peroxisome proliferator-activated receptor γ activation, can be used alone or in combination therapy, and have a low risk of hypoglycemia but may lead to weight gain, fluid retention, and increased risk of heart failure, particularly when used with insulin.
Canagliflozin, at doses of 100 mg or 300 mg, was studied for its cardiovascular effects in 10,142 individuals with type 2 diabetes as part of the CANVAS Program, which included data from the Canagliflozin Cardiovascular Assessment Study (CANVAS) and CANVAS-Renal (CANVAS-R). The primary aim of CANVAS was to meet 2008 FDA cardiovascular safety requirements, which limited its ability to test for a positive cardiovascular benefit. To enhance statistical power for detecting potential benefits on cardiovascular and kidney outcomes, CANVAS-R was conducted with a similar design. In the combined analysis, participants were either over 50 years old with at least two cardiovascular risk factors or had a history of cardiovascular disease, with approximately 65% having prior cardiovascular disease. Over a median follow-up of 126 weeks, canagliflozin was associated with a lower incidence of MACE (major adverse cardiovascular events) compared to placebo, with a hazard ratio (HR) of 0.86 (95% CI 0.75 to 0.97). Additionally, canagliflozin reduced hospitalization for heart failure (HR 0.67; 95% CI 0.52 to 0.87) and the composite kidney outcome of sustained reduction in eGFR, need for renal-replacement therapy, or renal death (HR 0.60; 95% CI 0.47 to 0.77).
Haemoglobin variants such as HbS, HbC, and HbE can interfere with the accuracy of HbA₁c as a marker for long-term glycaemic control due to structural changes that may alter the rate of glycation at the β chain's N-terminal valine. In individuals with conditions like HbSS, HbCC, and HbSC, factors such as anaemia, increased red-cell turnover, and transfusion requirements further compromise the reliability of HbA₁c. For these cases, alternative tests like glycated serum protein (fructosamine) or glycated albumin are recommended to assess glycaemic levels.
An oral formulation of the GLP-1 receptor agonist semaglutide mimics the incretin effect to enhance nutrient-stimulated insulin secretion and suppress excess glucagon secretion with a low risk of hypoglycaemia; it also delays gastric emptying and promotes satiety, often leading to weight loss. The GLP-1 receptor agonist class has demonstrated improved outcomes in atherosclerotic cardiovascular disease and albuminuria in type 2 diabetes trials. Thiazolidinediones, such as pioglitazone, lower glucose levels by increasing insulin sensitivity through stimulation of the transcription factor peroxisome proliferator-activated receptor γ, altering insulin-sensitive gene expression, enhancing adipogenesis, and rebalancing the glucose-fatty acid (Randle) cycle. These agents carry a low risk of hypoglycaemia but often result in weight gain, and due to potential fluid retention and increased risk of congestive heart failure, they are not recommended for individuals at high risk for cardiac decompensation or women with reduced bone density. α-Glucosidase inhibitors, including acarbose, miglitol, and voglibose, reduce postprandial glucose excursions by delaying carbohydrate digestion through competitive inhibition of intestinal α-glucosidase enzymes without stimulating insulin secretion, and they do not cause weight gain or hypoglycaemia as monotherapy. Dopamine D2 receptor agonist bromocriptine and bile sequestrant colesevelam have glucose-lowering indications in type 2 diabetes with unclear mechanisms, but neither causes weight gain nor carries a significant risk of hypoglycaemia. As type 2 diabetes progresses, combinations of glucose-lowering agents with different mechanisms are often necessary, and when β-cell function is severely impaired, insulin therapy should be initiated while continuing other appropriate agents.
Certain genetic variations have been linked to insulin resistance and type 2 diabetes mellitus (T2DM). A common polymorphism at codon 905 in the gene encoding the glycogen-associated regulatory subunit of protein phosphatase 1 (PP1), which is involved in glycogen synthesis and breakdown in skeletal muscle, has been associated with insulin resistance and hypersecretion of insulin in Danish individuals with T2DM. A missense mutation in the intestinal fatty acid binding protein 2 (FABP2) gene on chromosome 4q has been linked to increased fatty acid binding, increased fat oxidation, and insulin resistance among Pima Indians, a group with the highest reported prevalence of T2DM. A rare P387L variant in protein tyrosine phosphatase-1B (PTP-1B), which negatively regulates insulin and leptin signaling, has been associated with a 3.7 genotype-relative risk of T2DM in Danish Caucasians due to impaired serine phosphorylation of the PTP-1B protein. Additionally, studies on the PTPN1 gene locus have found associations between multiple single nucleotide polymorphisms (SNPs) and T2DM in Caucasian American populations, with some variants influencing metabolic traits related to insulin resistance and dyslipidemia.
Some diabetes medications have gastrointestinal side effects and may rarely cause lactic acidosis, particularly in patients with impaired renal or hepatic function or conditions associated with hypoxemia. Certain drugs can lead to fluid retention, anemia, and an increased risk of heart failure, especially in susceptible individuals, and require monitoring for cardiovascular disease. Others carry a risk of hypoglycemia, which can be severe, while some primarily reduce post-prandial hyperglycemia with less effect on fasting glucose and HbA1c levels. These agents generally pose a lower risk of severe hypoglycemia compared to sulfonylureas, and some require monitoring of liver function, particularly with vildagliptin.
Liraglutide, a GLP-1 analog with 97% homology to human GLP-1, has been approved by the US FDA and European Medicines Agency for the treatment of type 2 diabetes mellitus (T2DM). In a 52-week phase 3 clinical trial involving 746 patients with early T2DM, liraglutide was administered as monotherapy or in combination with other oral agents such as metformin or sulfonylureas. Patients were randomly assigned to receive once-daily liraglutide at doses of 1.2 mg or 1.8 mg, or glimepiride 8 mg. The primary outcome was the change in HbA1c levels from baseline, analyzed by intention-to-treat. At 52 weeks, HbA1c levels decreased by 0.84% with liraglutide 1.2 mg and by 1.14% with liraglutide 1.8 mg, compared to a decrease of 0.51% with glimepiride. Some patients discontinued liraglutide treatment due to vomiting, particularly in the 1.2 mg group. Blood glucose monitoring showed effective fasting glucose control with liraglutide, though postprandial glucose blunting was less pronounced compared to findings from some exenatide studies.
Gliptins can be used as monotherapy in patients with type 2 diabetes mellitus (T2DM) who have not responded adequately to lifestyle measures, though this use is not licensed in all countries. They are more commonly used as add-on therapy in patients inadequately controlled by metformin or thiazolidinediones. Gliptins act on the β-cell differently from sulfonylureas and meglitinides and can reduce glucagon levels, making them potentially useful as add-on therapy with insulin. However, their full efficacy in T2DM requires adequate β-cell reserve. They are suitable for overweight and obese patients due to the lack of weight gain and have a low risk of hypoglycemia when used as monotherapy or with non-insulin-releasing agents, making them favorable for patients with slightly raised basal glycemia, those near glycemic targets, or those with unpredictable meal times.
Diabetes has been recognized for over 3500 years, with the term derived from the Greek word for a syphon, and the adjective mellitus (honeyed) added in the late eighteenth century due to the sweet taste of diabetic urine, later identified as glucose by Chevreul in 1815. Bernard showed in the 1840s that glucose is present in blood and stored in the liver as glycogen for release during fasting. In 1889, Minkowski and von Mering found that removing the pancreas caused severe diabetes in dogs, and in 1893, Laugesse suggested that the pancreatic islets described by Langerhans in 1869 produced an internal secretion regulating glucose metabolism. Insulin was discovered in 1921 by Banting, Best, Macleod, and Collip from pancreatic extracts and first used for treatment in 1922. Diabetes was clinically classified into lean and obese types by Lancereaux in 1880, and later into insulin-sensitive and insulin-insensitive types by Falta and Himsworth in the 1930s, leading to the modern classification into type 1 and type 2 diabetes. Type 2 diabetes is characterized by insulin resistance and β-cell failure, with the insulin clamp method being a key technique for measuring insulin action. Maturity-onset diabetes of the young was identified as a distinct variant of type 2 diabetes by Tattersall in 1974. Lymphocytic infiltration of the islets, noted as early as 1901 and highlighted by Gepts in 1965, was suggested as a marker of autoimmunity, with islet cell antibodies discovered in 1979. Insulin's primary sequence was determined in 1955 by Sanger, and its three-dimensional structure reported by Hodgkin in 1969. Proinsulin was discovered in 1967 by Steiner, and the human insulin gene sequence identified by Bell in 1980. The radioimmunoassay for insulin was developed by Yalow and Berson in 1956, insulin receptors were deduced in 1971 by Freychet, and the receptor protein isolated in 1972 by Cuatrecasas.
Certain medications can precipitate or aggravate hyperglycemia through various mechanisms, such as inducing insulin resistance, impairing insulin secretion, or increasing hepatic glucose production. Examples include non-selective β-adrenoceptor antagonists, which inhibit insulin secretion and impair glucose tolerance; diazoxide, which inhibits insulin secretion; β2-receptor agonists like salbutamol and ritodrine, which increase hepatic glucose production; protease inhibitors such as indinavir, nelfinavir, ritonavir, and saquinavir, which induce insulin resistance; antipsychotics, which contribute to insulin resistance through weight gain; and drugs like streptozocin, pentamidine, and ciclosporin, which cause β-cell toxicity. In contrast, loop diuretics such as furosemide are less likely to cause hyperglycemia. Cardioselective β1-adrenoceptor blockers have much less pronounced effects on glucose metabolism compared to non-selective β-adrenoceptor antagonists.
More aggressive management of risk factors using statins, antiplatelet therapy, and antihypertensive medications, along with improvements in glycaemic management and smoking cessation, may have contributed to reduced mortality rates in people with diabetes. Due to their initially higher mortality risk compared to those without diabetes, population-wide changes in risk factors are likely to have resulted in a greater absolute risk reduction among individuals with diabetes. However, despite stable or declining incidence rates, the falling mortality associated with diabetes is expected to lead to an increasing prevalence of the condition, resulting in more years lived with diabetes and potentially contributing to the emergence of new diabetes-related complications that previously had not significantly impacted the overall diabetes burden.
GLP-1 receptor agonists (GLP-1RAs) such as dulaglutide, liraglutide, and subcutaneous semaglutide reduce the composite cardiovascular endpoint of non-fatal myocardial infarction, stroke, and cardiovascular death in individuals with type 2 diabetes. Oral semaglutide reduces cardiovascular death, while extended-release exenatide and lixisenatide have neutral effects on cardiovascular outcomes. Dulaglutide and subcutaneous semaglutide decrease the incidence of stroke, and extended-release exenatide, liraglutide, and oral semaglutide reduce all-cause mortality. The cardiovascular benefits of GLP-1RAs are not solely due to improved glycemic control but may involve positive effects on body weight, blood pressure, and cholesterol profile. Emerging evidence also suggests these drugs may independently slow the progression of atherosclerosis. As a result, GLP-1RAs are recommended for people with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors, regardless of HbA1c levels, acknowledging their glucose-independent cardiovascular benefits. This is reflected in the updated labeling of dulaglutide, liraglutide, and subcutaneous semaglutide, which now includes the reduction of major cardiovascular events as part of their indication.
Lipoatrophy, an allergic response characterized by the disappearance or atrophy of subcutaneous tissue at injection sites, was predominantly seen with older animal insulins and is now rare. Lipohypertrophy, a more common condition, is not an allergic reaction but rather an increase in adipose tissue due to insulin's trophic effect, often resulting from poor injection technique and lack of site rotation. It can lead to unsightly appearance and, when injected into affected areas, may cause poor and delayed insulin absorption, affecting blood glucose control. Lipohypertrophy typically improves when injections are avoided in the affected area. Other injection site issues include mild ulceration, pitting, and bruising, which can be managed by switching injection sites and using shorter needles, especially when bruising occurs.
MODY (Maturity-Onset Diabetes of the Young) includes several subtypes caused by mutations in specific genes, such as the glucose sensing enzyme glucokinase (GCK) and transcription factors involved in beta-cell development and function. These genetic mutations lead to varying clinical presentations summarized in Table 15.2, with subtypes including familial mild fasting hyperglycemia due to GCK mutations (GCK MODY), familial young-onset progressive diabetes from HNF1A and HNF4A mutations (transcription factor MODY), and renal cysts and diabetes syndrome (RCAD) caused by HNF1B mutations. The diversity among MODY subtypes highlights the importance of identifying the underlying genetic cause.
Niacin adversely affects glycemic control in people with diabetes, with the effect being dose-related. Studies have shown that at a dose of 1.5 g, extended-release niacin caused an increase in HbA1c from 7.2% to 7.5% after 16 weeks, while no significant change was observed in the 1 g group. Despite concerns about hyperglycemia as a side effect, long-term outcome trials have not been conducted in diabetic patients, and clinical practice shows wider variations in response. However, data from the Coronary Drug Project indicated that niacin was equally effective in lowering cardiovascular outcomes in patients with hyperglycemia compared to those with normoglycemia.
In diabetes, activation of PKC-β isoforms contributes to diabetes-related decreases in retinal and renal blood flow, potentially by reducing the production of the vasodilator nitric oxide (NO) and increasing endothelin-1, a potent vasoconstrictor. PKC overactivity is associated with reduced NO production in the glomerulus and in smooth muscle cells under high glucose conditions, and it inhibits insulin-stimulated expression of endothelial NO synthase (eNOS) in cultured endothelial cells. Hyperglycemia enhances the ability of endothelin-1 to activate mitogen-activated protein kinase (MAPK) in glomerular mesangial cells through PKC isoform activation. High glucose-induced PKC activation also increases endothelial cell permeability via PKC-α and stimulates the expression of the permeability-enhancing factor VEGF in smooth muscle cells.
Tight glycaemic management in newly diagnosed type 2 diabetes reduces microvascular complications, as shown in the UK Prospective Diabetes Study (UKPDS) in 1998, and a 10-year follow-up revealed significant reductions in myocardial infarction and cardiovascular mortality in intensively treated patients. However, three subsequent multicentre randomized controlled trials involving over 23,000 participants with type 2 diabetes and established cardiovascular disease or risk factors found no significant reduction in major cardiovascular events with intensive glycaemic control, and in the ACCORD trial, mortality actually increased. Severe hypoglycaemia rates in ACCORD were four to five times higher compared to the ADVANCE trial, where mortality did not increase, suggesting a potential link between hypoglycaemia and cardiovascular mortality. Hypoglycaemia has also been associated with cardiovascular mortality in type 1 diabetes, though less consistently, and it remains uncertain whether this association is causal or due to confounding factors such as comorbidities like frailty, liver disease, and kidney disease, which both increase hypoglycaemia risk and independently raise cardiovascular mortality risk.
For individuals with diabetes, dietary management is crucial, with recommendations including a well-balanced diet where carbohydrates make up 50–55% of daily energy intake, fat 30–35%, and protein 10–15%. Carbohydrate intake should include less than 10% total energy from sucrose. Fat intake should prioritize monounsaturated fats up to 20%, with less than 10% from polyunsaturated, saturated, and trans fatty acids, and a minimum of 0.15g/day of n-3 fatty acids. Maintaining a regular meal and snack schedule helps manage blood glucose levels, with snacks used strategically to prevent and treat hypoglycemia, particularly in children who may require mid-morning, mid-afternoon, or bedtime snacks depending on activity level and blood glucose readings. Energy intake should be adjusted to maintain a healthy weight and avoid overinsulinization and excessive snacking, which can lead to weight gain. Eating disorders are common in diabetic teenagers, especially girls. Fiber intake is recommended at 2.8–3.4g/MJ for children over 1 year old, and for those over 2 years, fiber intake should be age in years plus 5g/day. High-sodium foods should be avoided to reduce hypertension risk, with a target salt intake of less than 6g/day. Excessive protein intake and supplements are discouraged, and vitamin and mineral needs are generally the same as for non-diabetic children, although vitamin D deficiency is common and should be screened for and supplemented if necessary. Artificial sweeteners are safe within acceptable daily limits, but diabetic-labeled foods are discouraged due to high fat content, cost, and potential laxative effects from sugar alcohols like sorbitol. Alcohol consumption, although generally prohibited in youth, can cause prolonged hypoglycemia in individuals with diabetes, requiring carbohydrate intake and possibly reduced insulin dosage, especially with physical activity. Around 10% of type 1 diabetes patients show serologic evidence of celiac disease, and those with confirmed diagnosis or symptoms should follow a gluten-free diet, replacing wheat, rye, barley, and triticale with alternatives like potato, rice, soy, and oats, as untreated celiac autoimmunity may have long-term consequences.
Increased expression of the p85 regulatory subunit of PI3 kinase is associated with worsened insulin sensitivity, as observed in patients with gestational diabetes or obesity who have elevated levels of p85 in skeletal muscle. The p85 subunit contributes to insulin resistance by competing with the p85-p110 complex for recruitment to IRS phosphotyrosine docking sites, thereby impairing insulin signaling. Additionally, p85 engages in cross-talk with stress-kinase pathways by promoting the activation of c-Jun NH2 terminal kinase (JNK), which suppresses insulin action in conditions like high-fat diet-induced obesity. Furthermore, p85 enhances the activity of PTEN, a phosphatase that degrades PI(3,4,5)P3 and inhibits downstream insulin signaling, thus contributing to reduced insulin sensitivity.
In obese individuals with type 2 diabetes mellitus (T2DM) who are on insulin and oral antidiabetic drugs, adding exenatide leads to significant weight loss of 6.5 kg and a reduction in HbA1c by 0.6% (7 mmol/mol) over 26 weeks. Exenatide also reduces the required doses of rapid-acting and premix insulin by 28% and 60%, respectively, without affecting basal insulin dosage. However, replacing insulin with exenatide in T2DM patients previously treated with insulin results in a slight increase in HbA1c by 0.3% (3 mmol/mol), indicating that such a substitution is less effective in controlling blood glucose levels.
Improved glycated hemoglobin (HbA1c) levels are associated with a reduced risk of major adverse cardiovascular events (MACE) in patients with diabetes.
Undiagnosed diabetes and stress hyperglycaemia are common in hospitalized individuals, with many presenting hyperglycaemia without a prior diabetes diagnosis. Some of these individuals have previously undiagnosed diabetes and continue to have elevated glucose levels post-discharge, while others experience transient hyperglycaemia during hospitalization, known as stress hyperglycaemia, which resolves after discharge. The criteria for stress hyperglycaemia vary, with some defining it as a fasting glucose level above 7.0 mmol/l (126 mg/dl) or a random blood glucose above 11.1 mmol/l (200 mg/dl), whereas the ADA and AACE define it as any glucose level above 7.8 mmol/l (140 mg/dl) in those without prior diabetes. Collectively, the prevalence of diabetes or transient hyperglycaemia in hospitalized patients ranges from 32% to 38% on general wards and between 28% and 80% in critically ill patients or those undergoing cardiac surgery.
Inhibition of protein tyrosine phosphatase 1B (PTP1B) enhances insulin sensitivity by preventing the dephosphorylation and deactivation of the insulin receptor β-subunit, IRS1, and IRS2, leading to improved glycemic control in insulin-resistant diabetic animals. PTP1B inhibitors, such as benzonaphthofurans, thiophenes, and acylsulfonamido compounds, have shown therapeutic potential in improving insulin signaling and are considered templates for new diabetes treatments. PTP1B knockout mice exhibit increased insulin sensitivity, higher metabolic rates, and resistance to diet-induced obesity. Antisense oligonucleotides against PTP1B improve insulin signaling through increased phosphorylation of the insulin receptor, IRS1/2, GSK3, and enhanced activity of PI3K and Akt. Additionally, PTP1B inhibition may aid in weight management by increasing leptin sensitivity and improving endothelial function via enhanced insulin-induced eNOS production. Vanadium salts, which inhibit PTP1B, also enhance insulin and possibly leptin actions.
Patients with type 2 diabetes mellitus (T2DM) exhibit neural slowing, reduced cerebral blood flow, and structural brain changes such as decreased gray matter volume, increased subcortical atrophy, and larger white matter lesion volume. These structural changes are more pronounced in women and correlate with higher HbA1c levels and older age, but not with diabetes duration, hypertension, or hyperlipidemia. Compared to those with type 1 diabetes mellitus (T1DM), individuals with T2DM show greater cortical atrophy and deep white matter lesions despite shorter diabetes duration and fewer microvascular complications. Macrovascular disease and atherosclerotic risk factors, along with impaired glucose or insulin regulation, may contribute to these central nervous system changes. Additionally, the hippocampus is smaller in adults with T2DM compared to controls, which may explain memory impairments in older adults with the condition, with hippocampal atrophy being strongly predicted by HbA1c levels.
Hyperglycaemia in diabetes arises from an imbalance between insulin's glucose-lowering effects and counter-regulatory glucose-raising mechanisms, primarily due to increased gluconeogenesis and glycogenolysis, along with impaired glucose uptake in peripheral tissues. Skeletal muscle and fat breakdown contribute to this by increasing gluconeogenic amino acids and free fatty acids delivered to the liver, effects that are worsened by fasting or prolonged starvation. In non-diabetic individuals, compensatory insulin secretion counteracts these catabolic processes, but in diabetes, the absence of insulin's regulatory action leads to elevated activity of key gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and pyruvate carboxylase. Stress or illness exacerbates hyperglycaemia by increasing counter-regulatory hormones, which induce insulin resistance, enhance hepatic glucose production, and reduce peripheral glucose utilization. Severe hyperglycaemia causes osmotic diuresis, leading to dehydration and electrolyte loss of sodium, potassium, magnesium, and phosphate, while also increasing plasma osmolality and promoting a pro-coagulant state. Additionally, hyperglycaemia elevates inflammatory cytokines like tumour necrosis factor α, interleukin-6, interleukin-1β, interleukin-8, and C-reactive protein, which contribute to insulin resistance by interfering with post-receptor insulin signaling pathways, with cytokine levels decreasing as blood glucose normalizes.
Various gene products delivered via viral or non-viral methods have been studied for their effects in diabetic animal models, aiming to improve β-cell survival, proliferation, and revascularization or to induce immunotolerance. HGF and IL-1Ra delivered by adenovirus in STZ-induced-diabetic NOD-SCID mice promoted β-cell survival, proliferation, and increased revascularization, while HGF alone supported β-cell survival and proliferation in an allogeneic transplantation rat model. IL-10 delivered by adenovirus or AAV aimed to induce immunotolerance in STZ-induced diabetic rats and in models of autoimmune recurrence. Other approaches included sCD40-Ig and TNFR-Ig, both delivered via adenovirus, targeting immunotolerance in allogeneic transplantation and allotransplant diabetic models, respectively. XIAF improved β-cell survival in chemically diabetic immunodeficient mice and STZ-induced diabetic mice undergoing allotransplantation. Akt, IRAP, MnSOD, and TGF-β1, each delivered by adenovirus, focused on β-cell survival or protection against oxidative damage in various diabetic mouse models. VEGF, delivered through non-viral means, aimed to increase revascularization in diabetic mice, and Bcl2 supported β-cell survival in xenotransplantation and diabetic SCID mice models.
Candidate genes associated with type 2 diabetes mellitus (T2DM) include the insulin promoter, class III alleles upstream of the insulin gene, PPARG, KCNJ11 which encodes the Kir6.2 subunit of the β-cell inwardly rectifying KATP channel, and other genes such as IRS-1, ACDC, and ENPP1 that may contribute minor susceptibility in the context of obesity or diabesity. Genome scans have identified T2DM loci on multiple chromosomes, with NIDDM1 on chromosome 2q found to code for calpain 10, a protease involved in β-cell apoptosis. Genome-wide association studies have identified additional T2DM-susceptibility genes including TCF7L2, HHEX, SLC30A8 (ZnT8), CDKAL1, and IGF2BP2, which are involved in β-cell development and function. While individual genetic variants have a small effect on T2DM risk prediction, a combined genotype score based on multiple risk alleles can significantly increase the risk of developing T2DM, highlighting the importance of identifying high-risk individuals for targeted preventive measures.
Healthy adults with type 1 diabetes mellitus (T1DM) generally report overall life satisfaction and indicate that diabetes has little impact on their lives, regardless of whether they receive conventional or intensive insulin therapy. Studies show that long-term intensive insulin treatment (over 6–9 years) does not negatively affect quality of life and may even improve diabetes-related quality of life in the short term (4 months). The positive experience of patients in intensive treatment programs, such as those in the Diabetes Control and Complications Trial (DCCT), may be influenced by the increased psychological and medical support provided in clinical trials or by the limitations of the measures used to assess quality of life.
New inhibitors of sodium–glucose cotransporters (SGLT-1 and SGLT-2) are becoming available.
Blocking complement signaling may have therapeutic potential in diabetic nephropathy, as demonstrated in experimental studies using a type 1 diabetic mouse model. Thrombomodulin, a protein that inhibits both coagulation and complement activation through its lectin-like domain, was shown to protect against renal damage. Diabetic mice lacking this domain exhibited increased complement activation and more severe nephropathy compared to wild-type diabetic mice. Administration of enoxaparin, a low molecular weight heparin, reduced albuminuria and podocyte injury in these mutant mice. In vitro findings further supported that the lectin-like domain of thrombomodulin prevents glucose-induced complement injury to podocytes, indicating its protective role in diabetic renal damage by limiting glucose-induced complement activation.
Insulin pump and multiple daily injection (MDI) therapy involve carbohydrate counting, where the grams of carbohydrate to be consumed are measured and a corresponding insulin dose is given, allowing greater flexibility in food choices but requiring expert education and commitment. This method may not be suitable for all situations, such as school lunches or for teenagers. Tools like books and apps are available to improve the accuracy of carbohydrate counting. Alternative methods include carbohydrate exchanges, which categorize carbohydrates into 10 or 15 gram servings and promote a more consistent daily intake without precise gram counting, and the constant carbohydrate meal plan, which was commonly used with older insulin regimens like NPH and regular insulin. The latter approach, involving consistent carbohydrate intake and insulin dosing, is now considered overly restrictive and potentially conflict-inducing.
GLP-1 receptors are present on pancreatic β-cells and belong to the glucagon subfamily of G protein-coupled receptors. Activation of these receptors triggers intracellular signaling pathways that lead to increased cyclic adenosine monophosphate levels, closure of ATP-sensitive K+ channels, elevated cytosolic Ca2+ concentrations, and insulin granule exocytosis. Notably, GLP-1 stimulates insulin secretion only when glucose levels exceed 4–5 mmol/L, acting as a β-cell sensitizer that enhances glucose-induced insulin release. Beyond its insulinotropic effect, GLP-1 promotes insulin biosynthesis and gene transcription, and is involved in β-cell growth, differentiation, and protection from apoptosis. However, the relevance of these effects in human physiology and in relation to GLP-1 receptor agonist treatment requires further clarification.
THCV, a non-psychoactive cannabinoid found in cannabis, has been shown to reduce blood glucose levels in type 2 diabetes, highlighting the potential for cannabis extracts and synthetic cannabinoids to have varying effects on diabetes through their interactions with cannabinoid receptor subclasses.
α-glucosidase inhibitors commonly cause gastrointestinal side effects, particularly when the dosage is too high relative to the amount of complex carbohydrate in a meal, leading to undigested oligosaccharides passing into the large bowel where they are fermented, causing flatulence, abdominal discomfort, and sometimes diarrhea. These side effects often improve with slower titration and time. Hypoglycemia is uncommon with these inhibitors, and there are no clinically significant drug interactions, although their use with agents affecting gut motility or cholestyramine is not recommended. In the STOP-NIDDM trial, 31% of acarbose-treated patients compared to 19% on placebo discontinued treatment early due to adverse effects.
Several psychological factors are associated with an increased risk of developing type 2 diabetes, including emotional stress, job stress, childhood adversity, and sleep disturbances. High levels of psychological distress can increase diabetes risk by 33%, potentially mediated by low energy levels and impaired health status. Both short sleep duration (≤5–6 hours per night) and long sleep duration (>8–9 hours per night) raise diabetes risk by 28% and 48%, respectively, while difficulty initiating and maintaining sleep increases risk by 57% and 84%. Job strain, characterized by high demand and low control, is linked to a 16% higher diabetes risk, with a stronger effect in women (relative risk 1.48). Adverse childhood experiences are associated with a 32% increased risk of type 2 diabetes, with the strongest association for neglect (pooled odds ratio 1.92), followed by physical abuse (1.30) and sexual abuse (1.39). Chronic emotional stress, particularly in individuals with psychiatric conditions, may serve as a common factor contributing to elevated diabetes risk.
Patients who remained off insulin after a transplant had the best blood glucose control with a median HbA1c of 6.2% (44 mmol/mol), comparable to those back on insulin but still retaining C peptide, who had a median HbA1c of 6.7% (50 mmol/mol), while those who lost all graft function had poor glucose control with a median HbA1c of 9.0% (75 mmol/mol) and required more insulin than before the transplant.
Angiotensin II receptor blockers such as losartan, irbesartan, valsartan, candesartan, and telmisartan are effective antihypertensive drugs in people with diabetes and slow the progression of nephropathy in those with diabetes and varying degrees of albuminuria. Losartan has been shown to reduce cardiovascular endpoints by 25% and total mortality by 40% in high-risk people with type 2 diabetes with hypertension and left ventricular hypertrophy. Combining an ACE inhibitor with an AT1 antagonist has been shown to be more effective than either agent alone in lowering blood pressure and urinary albumin excretion in people with type 2 diabetes, although the combination did not show additional benefits on cardiovascular endpoints compared with monotherapy in the ONTARGET study. Due to the risk of adverse renal effects, the combination of an ACE inhibitor and an AT1 receptor blocker is discouraged for the treatment of hypertension in people with diabetes.
GLP-1 contributes to glucose homeostasis by acting on pancreatic islet cells, where it enhances glucose-induced insulin secretion when blood glucose levels exceed 4–5 mmol/l and suppresses glucagon secretion in a glucose-dependent manner. Additionally, GLP-1 slows gastric emptying, reducing postprandial glucose spikes, and acts in the hypothalamus to promote satiety and decrease food intake. These effects make GLP-1 an important hormone in the regulation of blood glucose levels, particularly relevant to diabetes management.
Self-monitoring of capillary blood glucose is a key element in managing type 1 diabetes and is also recommended for individuals with insulin-treated type 2 diabetes, offering benefits when integrated into broader diabetes education for guiding treatment and self-care. Advances in lancing devices and lancets have made frequent blood glucose testing more manageable, with adjustable penetration depth and thinner lancets helping to minimize discomfort. Modern blood glucose meters have also improved with features such as lower blood sample requirements, increased accuracy, reduced interference, and enhanced data presentation.
HbA1c measurements are used to monitor diabetes, with varying frequencies and availability across different healthcare settings and regions. In primary care in the USA, between 16% and 55–80% of patients had HbA1c measured in the last year, with improvements noted between 1995 and 1997. In the Netherlands and the USA, 80.7% and 57.4% respectively had more than one measurement over 12 months. In Denmark at the Steno Diabetes Center, over 99.5% of patients with type 1 diabetes had HbA1c measured in the last year, with a mean frequency of 3 tests per year. In Germany, 69.5% of insulin-treated patients, 64.3% on a single oral antidiabetic agent, and 41.1% on diet alone had HbA1c measured in the last year. In Asia, Eastern Europe, and Latin America, 77.6% of patients with type 1 diabetes and 64.2% with type 2 diabetes had HbA1c ever monitored, with variations by region. In the Veterans Affairs system in the USA, the percentage of patients with HbA1c measured increased from 59% in 1995 to 94% in 2000.
Managing type 1 diabetes mellitus (T1DM) requires multidisciplinary care, including dietary counseling focused on carbohydrate counting and intensive education on the use of insulin infusion pumps, which are not widely available in the community. Due to the lower prevalence of T1DM, many primary care physicians lack sufficient exposure to effectively manage these patients, making specialist-level care more appropriate for this population.
Increased oxygen free-radical levels in diabetes reduce the vasodilator effect of nitric oxide (NO), partly due to the formation of advanced glycation end-products (AGEs), which generate reactive oxygen species and impair NO bioactivity. AGEs contribute to the development of microvascular and macrovascular complications in diabetes, and inhibiting their formation has been shown in animal models to improve endothelium-dependent relaxation and restore erectile function in diabetic rats.
ACE inhibitors and ARBs are used in the management of diabetic nephropathy, helping to slow the progression of kidney disease by reducing intraglomerular pressure and proteinuria. These medications are often recommended as first-line therapy for patients with diabetes who have hypertension or evidence of kidney damage.
ACE inhibitors demonstrated a 16% relative risk reduction in death among people with diabetes and a 15% reduction among those without diabetes in a meta-analysis, with a potentially larger absolute benefit in diabetic individuals due to their higher mortality rate. These inhibitors, along with ARBs, show comparable benefits in heart failure irrespective of diabetes status, as seen with candesartan in the CHARM programme. The PARADIGM-HF trial found that sacubitril-valsartan reduced cardiovascular disease risk in participants with HFrEF regardless of diabetes status, with 35% of participants having diabetes. Sacubitril-valsartan also showed additional benefits over three years in reducing HbA1c, insulin use, and oral anti-diabetes medication use in those with comorbid HFrEF and diabetes. Furthermore, enalapril and candesartan have been associated with reduced incidence of diabetes in people with HFrEF or left ventricular dysfunction, though their effects on glucose levels in individuals already with diabetes and HFrEF remain unclear. Collectively, these findings suggest that inhibition of the renin-angiotensin system may influence both HFrEF and glucose homeostasis, offering therapeutic benefits for both conditions.
ACE inhibitors do not have adverse metabolic effects and may improve insulin sensitivity; they are associated with a low incidence of hypoglycaemia. These drugs are especially beneficial in diabetic nephropathy by reducing albuminuria and potentially slowing the progression of renal damage. The antiproteinuric effect of ACE inhibitors may result from the relaxation of efferent arterioles in the glomerulus, which are highly sensitive to angiotensin II-induced vasoconstriction, thereby lowering intraglomerular hypertension that is thought to promote albumin filtration, although the significance of this mechanism is debated.
Improved metabolic control in insulin-treated patients was achieved through a forced titration strategy involving weekly insulin dose increases of 2 to 8 units based on average fasting plasma glucose (FPG) measurements from two days. Starting with an initial dose of 10 units, this approach led to a reduction in FPG from 206 mg/dL to 116 mg/dL and a decrease in HbA1c from 8.6% to 6.9% by week 18. FPG values can be converted to mmol/L by dividing by 18, and HbA1c results can be calculated from IFCC values using the formula: DCCT (%) = (0.0015 × IFCC result in mmol/mol) + 2.15.
Bariatric surgery can lead to longstanding remissions of type 2 diabetes mellitus (T2DM) in most patients, with those undergoing Roux-en-Y procedures often experiencing a rapid reduction in insulin requirements within days to weeks. Patients who are candidates for the surgery typically have a BMI greater than 40 kg/m² or 35 kg/m² with comorbidities and have failed lifestyle interventions and/or pharmacotherapy for obesity. Many of these patients are already on combination therapies for diabetes, but during the hypocaloric diet preceding surgery, there is often a significant decrease in the need for insulin and other diabetes medications. Following surgery, most patients who were on insulin can discontinue its use unless they have a very long history of diabetes, and insulin dosages often need to be reduced by half or more postoperatively to prevent hypoglycemia. The physiological mechanisms behind these benefits remain poorly understood, and paradigms for identifying suitable surgical candidates for managing cardiometabolic risk are still evolving.
Avoidance of hypoglycaemia is particularly important in individuals with impaired kidney or liver function due to delayed clearance of antidiabetes medications. Glycaemic goals and medication use should be regularly reviewed with increasing age, especially when cognitive impairment or frailty develops. Declining weight, malnutrition, and frailty may reduce the need for antidiabetes medications while increasing hypoglycaemia risk. Studies have shown that antidiabetes medications can be safely withdrawn in frail older individuals, including those in nursing homes or attending outpatient clinics, without worsening glycaemic control, particularly when they exhibit significant weight loss, increased comorbidities such as dementia, polypharmacy, and recurrent hypoglycaemia. Higher doses of statins should be avoided in frail older people due to the risk of drug-related myopathy, and non-steroidal anti-inflammatory drugs should be used cautiously in those with chronic kidney disease because of the increased risk of acute kidney injury. Polypharmacy is common among older people with diabetes, often involving more than four drugs, including those for cardiovascular disease prevention, which may be inappropriate in those with limited life expectancy. Regular medication review in care home residents with diabetes can help reduce costs and minimize adverse drug reactions such as hypoglycaemia and hospitalization.
In type 2 diabetes, inhibition of the renin-angiotensin system (RAS) is recommended as a key therapeutic approach when albuminuria is elevated, as it slows the progression from moderate to severe albuminuria and promotes regression to normal albumin excretion, with benefits that are partially independent of blood pressure reduction. In advanced diabetic nephropathy, RAS inhibition using angiotensin receptor blockers (ARBs) helps reduce the risk of doubling serum creatinine, end-stage kidney disease (ESKD), or death. Patients with type 2 diabetes and increased albuminuria should receive a RAS inhibitor at the highest tolerated dose, although hyperkalemia is a common complication that increases the risk of kidney failure. Management strategies for hyperkalemia include dietary modifications, diuretics, adjusting potassium-raising medications, and using potassium binders rather than discontinuing RAS inhibitors. Initiation of RAS inhibitors may cause an initial acute decline in glomerular filtration rate (GFR), which typically stabilizes afterward, with those experiencing the largest initial drop showing slower subsequent kidney function decline.
Somatostatin secreted by islet δ cells tonically inhibits insulin and glucagon secretion through activation of SSTR5 and SSTR2 receptors, which are coupled to inhibitory G-proteins that reduce cAMP formation and cause β-cell membrane hyperpolarization with decreased intracellular calcium, and δ cells regulate β cells within the islet via neural-like processes.
Poor metabolic control in diabetes leads to hyperglycemia and ketoacidosis, which can allow normally non-pathogenic organisms to cause infections in traumatized skin, including phycomycete infections in leg ulcers or non-healing surgical wounds. Deep Phycomyces infection, such as rhinocerebral mucormycosis, is a rare but life-threatening complication of diabetes, particularly in the elderly, presenting with fever, facial cellulitis, pericorbital edema, proptosis, and occasionally blindness. The infection can spread through the nasal structures and sinuses, potentially reaching the brain or major blood vessels, and should be suspected in diabetic patients with sinusitis, nasal discharge, altered mental status, and tissue infarction in the nose or palate. Treatment includes correcting acid-base imbalances, aggressive debridement of dead tissue, and intravenous antifungal therapy.
DPP-4 inhibitors, also known as gliptins, are a class of medications used in the management of diabetes. Examples of these drugs include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin. These inhibitors work by blocking the enzyme dipeptidyl peptidase 4, which increases the levels of incretin hormones, thereby enhancing insulin secretion and reducing blood glucose levels.
These discoveries may enhance understanding of the biological mechanisms that maintain glucose homeostasis and uncover hidden molecular defects leading to chronic hyperglycemia, potentially enabling the development of more targeted antidiabetic drugs or gene-based therapies. Pharmacogenetic testing could help predict individual responses to different drug classes, while the identification of T2DM genes may allow for early detection of high-risk individuals, enabling timely behavioral or medical interventions to prevent diabetes onset, ultimately reducing diabetes-related morbidity, mortality, and treatment costs.
Continuous IV infusion of soluble human insulin at a dose of 0.1 units/kg/hour is recommended after initial volume expansion in the management of diabetes, particularly in cases requiring correction of metabolic acidosis, while avoiding an IV bolus of insulin due to the risk of cerebral edema. The insulin infusion should aim for a gradual reduction in blood glucose levels by 50–100 mg/dL/hour, and if blood glucose decreases too rapidly or becomes too low before acidosis resolves, IV dextrose concentration may be increased to 12.5% to prevent hypoglycemia. Insulin infusion rates should generally not fall below 0.05 U/kg/hour unless the patient is hypoglycemic, as lower rates may prolong ketogenesis. Monitoring blood ketones, specifically β-hydroxybutyrate, is more effective than blood gases for adjusting insulin and glucose infusion rates.
The Chennai Population Study (CUPS) in 2008 reported an incident diabetes rate of 20.2 cases per 1000 person-years, later confirmed by a study showing an incidence of 22.2 per 1000 person-years, with 59% of those with pre-diabetes progressing to diabetes over a mean follow-up of 9.1 years. To address this, the Indian Diabetes Risk Score (IDRS), a risk score specific to the Indian population, was developed using four clinical variables: age, family history, regular exercise, and waist circumference, with a score of >21 identifying individuals with diabetes at a sensitivity and specificity of nearly 60%. Lifestyle modification has been shown to effectively reduce the progression from impaired glucose tolerance to diabetes in the Indian population. Additionally, the Ministry of Health and Family Welfare launched the pilot phase of the National Programme on Diabetes, Cardiovascular Disease, and Stroke (NPCDS) in 2008 to improve awareness, prevent disease through screening and targeted intervention, and coordinate multisectoral efforts to combat the rising epidemic of obesity and diabetes in India.
Background retinopathy refers to non-proliferative changes in the retina associated with diabetes, including microaneurysms, hemorrhages, exudates, and venous abnormalities, which can progress to more severe vision-threatening stages if blood glucose and blood pressure are not adequately controlled.
Hyperglycemia occurs in up to approximately 50% of patients with pheochromocytoma, and the prevalence of diabetes is approximately 35%. The presence of diabetes in a young hypertensive person of normal body weight should raise suspicion of pheochromocytoma. The predominant mechanism of diabetes in this context is catecholamine-mediated reduction in insulin sensitivity and insulin secretion, predominantly caused by epinephrine rather than norepinephrine. Epinephrine inhibits beta-cell insulin secretion via stimulation of alpha-2 adrenergic receptors. In the liver, epinephrine activates beta-2 adrenoceptors to enhance glycogenolysis transiently and gluconeogenesis more sustainably, with the latter fueled by precursors such as lactate, alanine, and glycerol generated by beta-2 adrenergic stimulation of muscle glycolysis and adipose tissue lipolysis. Lipolysis in adipose tissue is also stimulated via beta-1 and beta-3 adrenoceptors. Additionally, epinephrine impairs glucose utilization in muscle through direct beta-2 adrenergic effects. Due to its higher affinity for beta-2 receptors, epinephrine is more potent than norepinephrine in producing hyperglycemia, and these combined effects represent potent mechanisms that raise blood glucose.
Dipeptidyl peptidase 4 (DPP-4) inhibitors are a class of incretin-based therapies used in the management of diabetes. These medications work by inhibiting the enzyme DPP-4, which breaks down incretin hormones such as glucagon-like peptide 1 (GLP-1), thereby enhancing the effects of GLP-1 on insulin secretion and blood glucose regulation. Cardiovascular outcome trials have evaluated their safety, including the SAVOR-TIMI 53 trial, which involved 16,492 individuals with diabetes who were at high risk for or had established cardiovascular disease. In this trial, saxagliptin, a DPP-4 inhibitor, did not significantly increase the risk of a composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal ischaemic stroke. However, saxagliptin was associated with an increased risk of hospitalization for heart failure compared to placebo, with this excess risk becoming apparent as early as six months after treatment initiation and persisting throughout follow-up. A similar cardiovascular profile was observed with another DPP-4 inhibitor, alogliptin.
Gene therapy approaches for treating type 1 diabetes focus on increasing regulatory T cell (Treg) numbers or activity and reducing autoreactive T cells. Adeno-associated viruses (AAVs) are commonly used vectors for delivering immunomodulatory genes in mouse models. AAV-mediated overexpression of cytokines such as IL-2, IL-4, IL-10, IL-35, or the chemokine CCL22 has shown therapeutic effects in NOD mice. IL-2 supports Treg survival and function, and while low-dose recombinant IL-2 improves clinical conditions in humans with type 1 diabetes, repeated administrations are required. In contrast, a single AAV-mediated delivery of the IL-2 gene, either systemically, muscularly, or β cell–specifically, increases Treg frequency and activation and prevents diabetes in mice. IL-4 induces expression of Foxp3, a key marker of Tregs, in precursor cells, and AAV-mediated IL-4 expression in β cells prevents islet destruction and diabetes onset in NOD mice.
Serum urate concentrations and gout are strongly associated with abdominal adiposity and have been shown to predict the development of type 2 diabetes mellitus (T2DM). Patients with gout have high rates of metabolic syndrome and T2DM compared to individuals without gout. Promotion of renal tubular reabsorption of uric acid by insulin is thought to mediate this relationship, and recent identification of the glucose and fructose transporter SLC2A9 as a key regulator of serum urate concentrations suggests a further etiologic link between hyperuricemia and hyperglycemia. A study reported a prevalence of gout of 22% in patients with T2DM treated in secondary care, with key risk factors including male sex, renal impairment, and diuretic use. Severe hypertriglyceridemia may reduce urate concentrations as glycosuria has a uricosuric effect, and as glycemic control improves in patients initiating treatment for diabetes, there is a potential risk of worsening gout attacks.
Annual screening for eye and foot complications is an important aspect of diabetes care, and in the 1999-2002 survey, 60% achieved LDL cholesterol concentrations of <3.4 mmol/L; however, levels of care were noted to be suboptimal, especially in females and in those under the age of 45 years.
Increased skeletal fragility is observed in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), though the mechanisms may differ. In T1DM, most cross-sectional studies report decreased bone mineral density (BMD) throughout the skeleton, with evidence suggesting that this deficit occurs early in the disease course, possibly before clinical diagnosis. Studies in children and young adults show lower than normal BMD at the hip and spine at the time of diagnosis, and longitudinal data indicate that BMD does not progressively decline in T1DM. Markers of bone turnover in middle-aged individuals with T1DM are reported to be at normal levels, supporting the idea that the BMD deficit is established early. Insulin deficiency, along with reduced levels of other pancreatic β-cell hormones such as amylin and preptin, which are involved in skeletal homeostasis, likely contributes to the decreased BMD in T1DM. Additionally, low levels of IGF-I have been linked to cortical bone loss in T1DM. Insulin therapy does not normalize BMD, suggesting that other factors, such as lower body weight, which has a positive correlation with BMD, also play a role in the reduced bone density observed in T1DM.
Hypoglycemia unawareness and the reduced epinephrine response in defective glucose counter-regulation are reversible within 2-3 weeks through strict avoidance of hypoglycemia in most affected individuals. Risk factors for hypoglycemia include both relative and absolute therapeutic insulin excess, as well as factors associated with HAAF, such as absolute endogenous insulin deficiency, a history of severe hypoglycemia, hypoglycemia unawareness, prior exercise or sleep, and aggressive glycemic therapy. The pathophysiology explains the increasing incidence of iatrogenic hypoglycemia over time in type 2 diabetes mellitus (T2DM), approaching the rates seen in type 1 diabetes mellitus (T1DM), with most hypoglycemic episodes occurring in people with T2DM. To minimize the risk of iatrogenic hypoglycemia, it is essential to recognize the problem and apply principles of aggressive glycemic therapy while considering risk factors for insulin excess and HAAF. Achieving the highest possible glycemic control safely for each individual at their specific diabetes stage is crucial, and concerns about hypoglycemia should not justify poor glycemic control.
The ADOPT trial assessed the durability of glycemic efficacy of glyburide, metformin, and rosiglitazone as monotherapies in diabetes, using the primary endpoint of maintaining fasting plasma glucose (FPG) less than 180 mg/dL, and secondary outcomes including time to FPG exceeding 140 mg/dL. Other prespecified outcomes were levels of FPG and glycated hemoglobin (HbA1c), weight changes, and measures of insulin sensitivity and β-cell function determined by the HOMA 2 method. The proportion of patients failing to maintain FPG below 180 mg/dL was lowest with rosiglitazone (2.9 per 100 patient-years), followed by metformin (4.3 per 100 patient-years), and highest with glyburide (7.5 per 100 patient-years). At study end, the percentages of patients achieving HbA1c < 7.0% (< 53 mmol/mol) were 26% for glyburide, 36% for metformin, and 40% for rosiglitazone. Weight gain was greater with rosiglitazone compared to glyburide and even more so compared to metformin, hypoglycemia was more common with glyburide, and gastrointestinal side effects were more frequent with metformin. Cardiovascular events were reduced with glyburide but not with rosiglitazone or metformin.
In early experimental diabetes, activation of PKC-β isoforms contributes to diabetes-related decreases in retinal and renal blood flow, potentially by reducing nitric oxide production and increasing endothelin-1, a potent vasoconstrictor. PKC overactivity is linked to reduced nitric oxide production in the glomerulus and smooth muscle cells under high glucose conditions, and it inhibits insulin-stimulated expression of endothelial nitric oxide synthase in cultured endothelial cells. Hyperglycaemia enhances endothelin-1's ability to activate MAPK in glomerular mesangial cells via PKC isoforms, and high glucose-induced PKC-α activation increases endothelial cell permeability. PKC activation also leads to increased expression of VEGF in smooth muscle cells, contributing to permeability changes. Additionally, PKC activation promotes the accumulation of microvascular matrix proteins such as TGF-β1, fibronectin, and type IV collagen, an effect mediated through nitric oxide inhibition. Hyperglycaemia-induced PKC activation is also associated with overexpression of PAI-1 and activation of NFκB in endothelial and vascular smooth muscle cells.
SGLT-2 inhibitors lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule, leading to glucosuria. These drugs have been studied in cardiovascular outcome trials, showing that empagliflozin and canagliflozin significantly reduce three-point MACE in patients with type 2 diabetes. Additionally, canagliflozin showed benefits in those with diabetic nephropathy. Dapagliflozin did not significantly reduce three-point MACE, likely due to studying a lower-risk population. However, all SGLT-2 inhibitors demonstrated a reduction in hospitalization for heart failure or cardiovascular death, indicating a protective effect against heart failure-related events. This benefit was confirmed in the DAPA-HF trial, which included patients with heart failure with reduced ejection fraction, both with and without diabetes. Empagliflozin also significantly reduced all-cause mortality compared to placebo in these patients.
Hyperglycaemia and ketonaemia in diabetes can lead to osmotic diuresis, causing dehydration, hypovolaemia, and electrolyte loss. Hypovolaemia reduces glomerular filtration rate and increases counter-regulatory hormones, worsening hyperglycaemia and potentially leading to hypoperfusion and elevated lactic acid levels. Dehydration may become severe due to osmotic diuresis, vomiting from ketosis, and inability to maintain fluid intake. Acidosis, insulin deficiency, and hypertonicity cause potassium to shift from intracellular to extracellular spaces, where it can be lost through urine or vomiting. Hypovolaemia also increases aldosterone, promoting sodium reabsorption and further potassium excretion, often resulting in hyperkalaemia despite overall potassium deficiency. Treatment with fluids and insulin can reveal this potassium deficit. Phosphate and magnesium depletion are also common in diabetic ketoacidemia, potentially worsening arrhythmias associated with potassium imbalances.
Many drugs can cause hyperglycemia and diabetes or worsen blood glucose control in patients with diabetes, and their possible contribution should be considered in newly diagnosed patients or in those with previously well-controlled diabetes who develop hyperglycemia. These drug effects are often reversible, and alternative treatments may be available. When diabetogenic drugs are necessary, careful monitoring of glycemic control and appropriate use of antidiabetic treatments can help mitigate their effects.
The 2022 consensus group expanded the definition of diabetes remission, particularly in relation to timing and intervention, though the criteria have limitations, including a glucocentric focus on type 2 diabetes. Normal HbA1c levels do not always indicate true normoglycaemia, as seen after bariatric surgery where patients may experience significant glucose fluctuations, including hypoglycaemia, which affects over 50% of individuals post-surgery and increases over time. Hypoglycaemia risk is similarly present after gastric bypass and sleeve gastrectomy, with gastric bypass leading to a nearly threefold increase in hospitalization for hypoglycaemia. Bariatric surgery introduces persistent gastrointestinal alterations affecting gut hormones, microbiota, and bile acids, meaning patients have not truly stopped treatment. Even with lifestyle and diet interventions, remission may depend on continued adherence to these changes. There is limited data on whether remission impacts the progression or reversal of micro- and macrovascular complications in type 2 diabetes.
HHS (Hyperosmolar Hyperglycemic State) typically develops gradually over days to weeks, in contrast to DKA which progresses over hours, and is most commonly seen in older individuals with type 2 diabetes though it can occur in younger adults and even those with type 1 diabetes, especially given the rising prevalence of obesity leading to earlier onset of type 2 diabetes; HHS may present as the initial manifestation of type 2 diabetes in up to 20% of cases, with infection being the most frequent trigger, particularly urosepsis and pneumonia accounting for up to half of cases, while other precipitating factors include acute conditions that elevate counterregulatory stress hormones like surgery, trauma, acute coronary syndromes, or stroke, and certain medications such as glucocorticoids, second-generation antipsychotics (clozapine, olanzapine), phenytoin, thiazide diuretics, protease inhibitors, and beta-blockers can also induce HHS by increasing insulin resistance, especially if glucose monitoring or screening for new-onset diabetes is not conducted.
Sleep duration and variability have been linked to type 2 diabetes, with longer sleep duration showing an inverse association and greater sleep variability showing a positive association. Long-term shift work, particularly rotating night shifts for over 20 years, has been associated with an increased risk of type 2 diabetes, as observed in the Nurses' Health Study. Additionally, greater bedtime variability has been linked to insulin resistance, independent of sleep duration. Research suggests that disruptions in sleep timing and consistency, rather than shift work alone, may contribute to metabolic disturbances that increase diabetes risk, although findings in this area remain inconsistent and require further investigation.
In patients with diabetes and one other cardiovascular disease (CVD) risk factor, treatment has been shown to reduce the risk of combined CVD events by 25%, CVD mortality by 37%, myocardial infarction (MI) by 22%, and stroke by 33%. Hypertensive patients with type 2 diabetes mellitus (T2DM) treated with fosinopril experienced fewer CVD events compared to those treated with amlodipine. ACE inhibition has demonstrated reductions in cardiovascular mortality and morbidity in patients with stable coronary artery disease. Meta-analysis including over 31,000 patients found that ACE inhibitors reduced all-cause mortality and MI by 14%, stroke by 23%, and revascularization procedures by 7% compared to placebo. In high-risk patients with T2DM, the combination of perindopril and indapamide led to a reduction in macrovascular outcomes when compared to placebo.
Patients with type 1 diabetes mellitus (T1DM) typically require exogenous insulin for 24-hour background and mealtime coverage, often delivered through a basal bolus regimen. This regimen offers a more physiologic insulin replacement and greater flexibility throughout the day compared to less frequent premixed insulin approaches. However, it involves more daily injections and frequent self-blood glucose monitoring, which can be challenging for some patients, especially young children and teenagers. The basal bolus method allows adjustment of mealtime insulin doses at up to three different times to adapt to varying daily activities and meal sizes, providing significant freedom. For some individuals, this flexibility is less important, and they may prefer a regimen involving only two daily injections using premixed insulin instead.
Hyperglycaemia following acute stroke is associated with poorer outcomes, particularly in individuals without a history of diabetes. Those without diabetes but with admission plasma glucose levels above 6–8 mmol/l have a significantly increased unadjusted relative risk of in-hospital or 30-day mortality at 3.07 (95% CI 2.50 to 3.79), compared to a smaller and less statistically certain increase of 1.30 (95% CI 0.49 to 3.43) in those with known diabetes. Additionally, hyperglycaemic individuals without diabetes have a 1.41 relative risk (95% CI 1.16 to 1.73) of poor functional outcomes. Sudden increases in plasma glucose levels appear to impair tissue function more severely in individuals who are not accustomed to hyperglycaemia.
People with HNF1A and HNF4A variants are sensitive to sulfonylurea therapy, which is recommended as first-line treatment, often resulting in better glycaemic control compared to insulin, with a fasting glucose-lowering effect four times greater than that seen in type 2 diabetes. Most individuals successfully transition to sulfonylurea treatment, although insulin may be needed as diabetes duration progresses. Hypoglycaemia can occur even with very low sulfonylurea doses, so starting doses should be low, such as 20–40 mg/day gliclazide or 2.5 mg/day glibenclamide in adults, with short-acting agents like nateglinide being an alternative if hypoglycaemia occurs. Those with shorter diabetes duration, lower HbA1c, and lower BMI are more likely to be successfully managed on sulfonylurea alone, while those with longer diabetes duration, especially with overweight or obesity and high HbA1c, are more likely to require insulin in addition to sulfonylureas. Glucagon-like peptide 1 (GLP-1) receptor agonists effectively reduce glycaemia, and when sulfonylureas are insufficient, sodium-glucose cotransporter-2 (SGLT-2) inhibitors may improve glycaemic levels but can cause hypovolaemia due to excessive urinary glucose loss, with safety and efficacy in HNF1A MODY needing further research. The DPP-4 inhibitor linagliptin has shown effectiveness as an add-on to glimepiride in improving glycaemic variability and HbA1c without increasing hypoglycaemia risk in individuals with HNF1A variants. Due to the increased cardiovascular disease risk in HNF1A, statin therapy is recommended for those over 40 years of age.
Autoimmune type 1 diabetes mellitus (T1DM) was once thought to be the primary form of diabetes in children and young adults, but current understanding recognizes that genetic or acquired factors affecting pancreatic beta-cell structure and function, along with mechanisms like amylin deposition and mitochondrial damage, can lead to a wide range of clinical presentations with significant overlap between type 1 and type 2 diabetes phenotypes. Accurate diagnosis can be aided by detailed medical history, including family history, presentation mode, and infection exposure, as well as physical examination for body leanness, microvascular complications, metabolic syndrome, and cardiovascular risk factors. Laboratory tests such as autoantibody detection and genetic markers also assist in refining the diagnosis, which is crucial for guiding treatment in young patients who are at high risk for long-term chronic complications due to the early onset and prolonged duration of their condition.
GLP-1 signaling in the islet, particularly from alpha cells, plays a role in the recovery from injury, as observed in rats treated with the beta-cell toxin streptozotocin. This signaling is mediated by interleukin (IL)-6, which is released in response to conditions such as obesity, diabetes, and critical illness. Given the involvement of GLP-1 in adaptations to metabolic stress, understanding the regulation of alpha-cell GLP-1 and glucagon production may offer potential for therapeutic development in diabetes.
Patients with type 2 diabetes mellitus (T2DM) and conditions such as left ventricular hypertrophy (LVH) or nephropathy can benefit from treatment with angiotensin receptor blockers (ARBs) like losartan, which have been shown to reduce cardiovascular risk and mortality to levels similar to those in patients without LVH. The ONTARGET study demonstrated that the ARB telmisartan offers cardiovascular benefits comparable to the ACE inhibitor ramipril in high-risk patients with diabetes and end-organ damage, although combining ramipril with telmisartan did not further reduce cardiovascular events and was associated with more adverse effects such as hypotension and renal dysfunction. ACE inhibitors and possibly ARBs are recommended as initial antihypertensive agents in diabetes due to their ability to prevent or slow the progression of macrovascular complications, leading to reduced cardiovascular mortality and morbidity.
Many drugs can cause or worsen pre-existing hyperglycemia, leading to drug-induced diabetes, a condition recognized by the World Health Organization (WHO) and the American Diabetes Association (ADA) as a separate etiologic category. Drug-induced diabetes is significant for two reasons: it can complicate glycemic control in patients already managing diabetes through polypharmacy, and it can induce hyperglycemia in previously normoglycemic individuals, though this state is often reversible and not insulin-dependent, but may become permanent.
Infections have been linked to type 1 diabetes through various studies, including in vitro research, animal models, analyses of pancreatic tissue, and epidemiological investigations, though a definitive causal relationship in humans remains unproven. Congenital rubella syndrome is associated with an increased incidence of type 1 diabetes, and while rubella vaccination has reduced its current impact, this connection serves as evidence that intrauterine factors and viral infections may influence type 1 diabetes risk. However, the strength and consistency of the evidence supporting this association, as well as the actual risk magnitude, may have been exaggerated.
Proteomic studies of gastric antrum biopsies from individuals with diabetic gastroparesis identified several underexpressed proteins including trefoil factor 2 (TFF2), fatty acid-binding protein (FABP3 heart), glycerol-3-phosphate dehydrogenase (GPD1 [NAD(+)]), trypsin-1 (PRSS1), interleukin-1 receptor type 2 (IL-1R2), granulocyte colony-stimulating factor 3 (CSF3), carbonic anhydrase 3 (CA3), α-2-HS-glycoprotein (AHSG), and carbonic anhydrase 1 (CA1), with only calcium/calmodulin-dependent protein kinase type II subunit-β (CAMK2B) being overexpressed. These proteins are primarily involved in tissue repair, cellular metabolism, or translation of ligand-receptor interaction to cellular function, and downregulation of IL-1/IL-1R2 and IL-6/CSF3 pathways suggests reduced cytokine response without consistent immune or inflammation-related changes.
Effective contraception should be used until optimal glycated hemoglobin (HbA1c) levels are achieved, with glucose levels optimized as close to normal as possible without significant hypoglycemia. Blood glucose monitoring is advised before meals, 1 hour post-prandial, and occasionally during the night, targeting pre-meal glucose below 5.3 mmol/L and post-meal glucose below 7.8 mmol/L. Oral anti-diabetes agents should be stopped if glucose levels are suboptimal, initiating insulin therapy, though metformin may be considered if benefits outweigh risks. Management of hypoglycemia, structured education, dietary adjustments with low glycemic index carbohydrates, weight loss for those with BMI ≥27 kg/m², regular exercise, and smoking and alcohol cessation are recommended. Folic acid supplementation at 5 mg/day is advised, and other medications like ACE inhibitors, angiotensin receptor antagonists, statins, and diuretics should be discontinued. Hypertension should be treated with methyldopa or labetalol. Regular screening for diabetes-related complications is necessary, including retinopathy assessment at the initial visit and annually thereafter, with referral to specialists for existing complications such as retinopathy, proteinuria, reduced glomerular filtration rate, or cardiac issues. Patients should be counseled on the risks of pregnancy including miscarriage, malformation, stillbirth, neonatal death, macrosomia, eclampsia, premature delivery, and cesarean delivery, along with the progression of diabetes-related complications. Referral to an obstetrician or diabetes specialist midwife and further education and support are recommended.
DPP-4 inhibitors are primarily excreted through the kidneys, and several genetic factors influence their effectiveness. Variants such as rs7202877 near CTRB1 and CTRB2, which encode chymotrypsin, are linked to a low response to DPP-4 inhibitors. The SNP rs6923761 in the GLP-1 receptor gene is associated with a reduced response to sitagliptin or vildagliptin, while variation in rs3765467 of the same gene correlates with better drug response. Polymorphisms in KCNQ1 and KCNJ11, genes involved in incretin secretion, are associated with increased effectiveness of DPP-4 inhibitors. Other genetic variants including PRKD1, CDKAL1, IL-6, TGF7L2, DPP-4, and PNPLA3 also show associations with variable responses to these medications.
Islet transplantation offers therapeutic benefits for individuals with type 1 diabetes, especially through the Edmonton Protocol, but its widespread use is limited by the shortage of cadaveric donors and the significant number of functional islets needed per patient. Additionally, islet function is compromised and apoptosis is promoted due to the processes of isolation, purification, transplantation, and the host's immune response, which hinder long-term graft survival. To address these challenges, gene therapy strategies involving ex vivo genetic engineering of islets before transplantation have been investigated, with adenoviral vectors being frequently used due to their high efficiency in transducing islets across species, including humans, and more recently, a chimeric AAV vector with improved transduction efficiency has been developed.
Most cases of type 2 diabetes can be prevented or delayed through lifestyle changes and the use of metformin, particularly in high-risk groups such as women with a history of gestational diabetes mellitus (GDM) and pre-diabetes, where treating five to six women can prevent one case of diabetes over three years. Weight loss plays a crucial role in reducing the risk of type 2 diabetes and may contribute to its remission. Women with prior GDM and their families represent a key high-risk group for targeted interventions. Studies have shown promise in modifying risk factors postpartum to improve metabolic outcomes and reduce the future risk of type 2 diabetes; however, challenges such as time constraints, emotional stress, and lack of social support hinder lifestyle implementation and lead to high attrition rates. While interventions during pregnancy for GDM have not been shown to prevent long-term complications in offspring based on findings from the ACHOIS study and the MFMU trials, addressing postpartum obstacles remains essential for effective diabetes prevention strategies.
Canagliflozin was assessed in the CREDENCE trial for its effects on kidney outcomes in individuals with type 2 diabetes and albuminuric chronic kidney disease, defined as an eGFR of 30 to $< 90\mathrm{ml / min} / 1.73\mathrm{m}^2$ and a urinary albumin-to-creatinine ratio of $> 300$. The trial included 4401 participants who were randomized to receive either canagliflozin $100\mathrm{mg}$ or placebo, with a median follow-up of 2.6 years. All participants were required to be on stable treatment with an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker for at least four weeks before randomization. Canagliflozin significantly reduced the risk of the primary composite outcome of end-stage kidney disease, doubling of serum creatinine level, or death from renal or cardiovascular causes with a hazard ratio of 0.70 (95% CI 0.59 to 0.82). It also reduced the risk of MACE by 20% and the composite of cardiovascular death or hospitalization for heart failure by 31%.
Higher HbA1c levels increase the likelihood of diagnosing gestational diabetes mellitus (GDM), though there is significant overlap between HbA1c values in women with and without GDM, which limits its diagnostic accuracy. Studies using HbA1c thresholds of 5.4–5.7% (35–48 mmol/mol) show varying sensitivities (26–86%) and specificities (21–92%) for detecting GDM. In a large study of 8497 women, 82% of those diagnosed with GDM had HbA1c levels below 5.9% (41 mmol/mol) at their first prenatal visit, and only 5% of all women screened with HbA1c went on to perform an oral glucose tolerance test (OGTT), with 23% of GDM cases identified before 20 weeks and the remaining 77% detected through initial or repeat OGTT after 20 weeks.
Supervised exercise, including aerobic exercise, resistance training, or a combination of both, has been shown to improve glycemic control in individuals with type 2 diabetes. In the DARE trial, 251 sedentary individuals with type 2 diabetes were assigned to aerobic exercise, resistance exercise, combined exercise, or a control group. Compared to the control group, HbA1c levels decreased significantly in those performing aerobic exercise by 0.5% (5 mmol/mol) and in those doing resistance exercise by 0.4% (4 mmol/mol). The combined exercise group showed even greater improvements, with an additional HbA1c reduction of 0.5% compared to aerobic exercise and 0.6% compared to resistance exercise alone. Among individuals with baseline HbA1c ≤ 7.5% (48 mmol/mol), only those in the combined exercise group experienced a significant decrease in HbA1c.
Certain antidepressants interact with oral anti-diabetes medications through inhibition of cytochrome P450 enzymes, potentially affecting blood glucose control; for instance, fluoxetine may enhance the effects of sulfonylureas, leading to hypoglycaemia. Some antidepressants, such as mirtazapine and paroxetine, can cause weight gain, which may be不利 for diabetes management, whereas bupropion is associated with weight loss and does not appear to worsen sexual function, making it potentially more suitable for people with diabetes. Newer antidepressants like vilazodone, vortioxetine, and levomilnacipran have a more favorable side effect profile regarding weight and sexual functioning, though none have been specifically tested in individuals with diabetes.
Rashes are less common with oral anti-diabetes agents other than sulfonylureas, though metformin may cause transient erythema, urticaria, psoriasiform drug eruption, erythema multiforme, photosensitivity, and leucocytoclastic vasculitis. Acarbose can lead to generalized erythema multiforme and acute generalized exanthematous pustulosis, possibly due to its degradation products since it is minimally absorbed from the gut. Thiazolidinediones and glinides like repaglinide may cause oedema, transient erythema, and urticaria.
Improving glucose management significantly reduces the risk of development and progression of all stages of diabetic nephropathy in type 1 diabetes, with beneficial effects extending beyond the actual period of optimal glucose management, a phenomenon termed 'metabolic memory'. In the open follow-up of the DCCT cohort, despite similar $\mathrm{HbA_{1c}}$ levels (~64 mmol/mol, ~8.0%) between previously intensively and conventionally managed groups, the incidence of moderately and severely increased albuminuria, eGFR < 60 ml/min/1.73 m², and ESKD was significantly reduced in those who had received prior intensive management. Observational studies also show that individuals with type 1 diabetes and CKD stages 1–3 with severely increased albuminuria have a lower cumulative risk of ESKD after 15 years if their $\mathrm{HbA_{1c}}$ improves compared to those whose $\mathrm{HbA_{1c}}$ remains stable or worsens. Prolonged periods of normoglycaemia are necessary to reverse kidney structural changes, as serial kidney biopsies in selected individuals after successful pancreas transplantation showed regression of kidney structural changes after 10 but not 5 years. Additionally, not only mean glycaemic levels as reflected by $\mathrm{HbA_{1c}}$ but also time in target glycaemic range is important for the development of renal complications. Insulin pump therapy, associated with less variability and improved time in range compared to multiple daily insulin injections, has been shown to contribute to a decline in albuminuria in type 1 diabetes with increased albuminuria, beyond changes in $\mathrm{HbA_{1c}}$.
In diabetes, insulin secretion is impaired, leading to insufficient opposition of glucagon effects, which can amplify fasting hepatic glucose production. Both insulin and glucagon secretion are abnormal in people with diabetes, with plasma glucagon levels often elevated in cases of severe insulin deficiency or ketoacidosis. In type 1 diabetes, reducing plasma glucagon through somatostatin inhibition has been shown to improve hyperglycemia and ketogenesis. Some individuals with type 2 diabetes exhibit fasting hyperglucagonemia even without metabolic decompensation, contributing to elevated hepatic glucose production. Suppressing islet hormone secretion with somatostatin in type 2 diabetes leads to reduced basal hepatic glucose production, an effect enhanced by basal insulin administration. These findings indicate that glucagon action plays a role in the pathogenic elevation of fasting glucose in a subset of individuals with type 2 diabetes.
In individuals who no longer produce sufficient endogenous insulin, such as those with type 1 diabetes or after total pancreatectomy, exogenous insulin administration is necessary to provide 24-hour background and mealtime coverage unless they are in the early stages of type 1 diabetes, have residual beta-cell function, or have become insulin-independent following a pancreas or islet cell transplant. Many individuals use a basal bolus regimen, combining short- and long-acting insulin preparations, which offers a more physiological insulin replacement with greater 24-hour flexibility compared to premix insulins injected once or twice daily. This approach, however, requires more daily injections and more frequent blood glucose monitoring. The basal bolus regimen allows individuals to adjust mealtime insulin doses based on varying daily activities and meal sizes, although some prioritize simplicity over flexibility and opt for twice-daily premixed insulin injections.
Administration of second-generation antipsychotics (SGAs) can lead to hyperglycaemia, weight gain, and dyslipidaemia, which contribute to cardiovascular risks, and these drug-related effects along with lifestyle factors such as overweight, obesity, physical inactivity, and smoking, highlight the importance of monitoring and prompt treatment. A meta-analysis found high prevalence rates of metabolic syndrome among individuals with schizophrenia, particularly those taking SGAs like clozapine (52%), olanzapine (28%), and risperidone (28%), compared to unmedicated individuals (20%).
In diabetes, the regulation of glucagon secretion by ambient glucose concentrations is altered, as low glucose levels increase and high concentrations inhibit glucagon release, partly through changes in α-cell electrical activity involving KATP channels. Despite similarities in glucose transport, metabolism, and KATP channel activity between α and β cells, their secretory responses to glucose are opposite, with differences in resting electrical characteristics and ion channel function contributing to the reciprocal secretion of glucagon and insulin during hypo- and hyperglycaemia. Additionally, α cells express sodium glucose transporters SGLT1 and SGLT2, and reduced SGLT2 activity increases glucagon secretion, suggesting that SGLT-2 inhibitors may influence glucagon levels in humans. Beyond glucose, amino acids such as alanine, glutamine, proline, and glycine stimulate glucagon release, highlighting the role of nutrient signaling in α-cell function relevant to diabetes.
DPP-4 inhibitors function by blocking the enzyme DPP-4, which normally deactivates glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, thereby enhancing glucose-dependent insulin secretion from pancreatic β cells. These medications carry a low risk of hypoglycemia, making them a favorable treatment option. However, their effectiveness, measured by the change in HbA1c levels from baseline to six months post-treatment, is influenced by several factors. Markers of insulin resistance, including high BMI, elevated serum triglycerides, increased C-peptide levels, and a higher homeostatic model assessment (HOMA) index, are associated with a reduced response to DPP-4 inhibitors. Additionally, lipotoxicity further diminishes the therapeutic response to these drugs.
Previous higher blood glucose levels in people with diabetes can lead to increased susceptibility to damage from subsequent lower blood glucose exposure, a phenomenon known as "hyperglycemic memory." This was observed in the Diabetes Control and Complications Trial (DCCT), where individuals who had been poorly controlled on conventional insulin therapy continued to experience a higher incidence of diabetic retinopathy compared to those receiving intensive therapy, despite similar post-trial HbA1c levels. The long-term follow-up of the DCCT, known as the Epidemiology of Diabetes Interventions and Complications (EDIC) study, further supports the lasting benefits of early intensive glucose control in reducing the risk of complications.
Hyperglycaemia and ketoacidosis in individuals with suboptimal metabolic management of diabetes can lead to infections from organisms that are typically nonpathogenic, particularly in traumatized skin. Deep phycomyces infections, such as rhinocerebral mucormycosis, are rare but life-threatening complications of diabetes, presenting initially with facial or ocular pain and nasal stuffiness, which may progress to fever, facial cellulitis, periorbital oedema, proptosis, and potentially blindness. The infection can spread through the nasal structures and sinuses into the brain or major blood vessels. It should be suspected in diabetic patients with sinusitis, purulent nasal discharge, altered mentation, and tissue infarction in the nose or palate. Treatment requires correcting acid-base imbalances, aggressive debridement of dead tissue, and intravenous antifungal therapy.
In diabetes management, certain drug classes such as incretin mimetics and α-glucosidase inhibitors are used, while thiazolidinediones may cause fluid retention or weight gain. The effectiveness of oral diabetes medications in lowering glucose is often not linear with increasing dose, meaning higher doses may lead to more side effects with minimal improvement in blood sugar control. An alternative approach involves using lower doses of two complementary drugs, such as glyburide and metformin, which can reduce side effects and provide equal or better glycemic control.
Inositol derivatives such as D-chiro-inositol (INS-1) and pinitol enhance muscle glucose uptake and lower hyperglycemia in diabetic animal models and individuals with type 2 diabetes mellitus (T2DM), while D-chiro-inositol-galactosamine (INS-2) improves insulin action in diabetic rats, potentially through direct activation of pyruvate dehydrogenase phosphatase, also known as protein phosphatase 2C (PP2C).
Ad-36 improves metabolic profiles by enhancing insulin sensitivity and increasing glucose uptake in adipose tissue and skeletal muscle cells, both in individuals with and without diabetes, through mechanisms involving upregulation of pro-adipogenic genes, adiponectin, and fatty acid synthetase, as well as reduced expression of inflammatory cytokines via phosphotidylinositol 3-kinase pathway activation.
GLP-1 has been shown to normalize plasma glucose in patients with long-standing severe type 2 diabetes mellitus (T2DM) when administered intravenously, and near-normalize glucose levels in those with moderate disease over a period covering nighttime and the following day, including meals. However, continuous intravenous infusion is not practical clinically, and subcutaneous injections of GLP-1 have only short-lasting effects on glucose and insulin concentrations due to rapid and extensive metabolism. The intact GLP-1 peptide has an intravenous half-life of 1–2 minutes and is quickly cleared from plasma, with degradation primarily caused by the enzyme DPP-4, which removes the two N-terminal amino acids, inactivating its insulin-secretion effect, though it may still exert cardiovascular effects.
Self-monitoring of blood glucose (SMBG) is a standard of care for patients with type 1 diabetes mellitus (T1DM) and is necessary for insulin-treated patients with type 2 diabetes mellitus (T2DM), though its optimal use in the latter group is not well established. SMBG may benefit some non-insulin-treated patients with T2DM but is unlikely to be useful for those who are well-controlled. Effective SMBG requires high motivation and proper understanding of how to interpret results and take appropriate actions, as lack of knowledge can make the procedure clinically and cost-ineffective. Patients must be educated on accurate testing techniques and how to use the data to adjust therapy based on food intake and physical activity. Correct technique involves obtaining a blood sample from the side of the finger pulp, using the second drop of blood after wiping away the first, using the meter correctly, and disposing of the lancet properly. Alternative sampling sites such as the base of the thumb, forearm, and thigh can be used, though fingertip readings are more accurate during periods of rapid glucose change, such as after meals or during hypoglycemia.
DPP-4 inhibitors prevent the enzymatic activity of DPP-4, which breaks down incretins such as GLP-1 and GIP, thereby increasing their circulating concentrations. This enhancement of endogenous incretins promotes nutrient-induced insulin secretion, suppresses excessive glucagon secretion, and has a low risk of causing hypoglycemia due to its glucose-dependent mechanism, making it preferable over sulfonylureas. While animal studies suggest DPP-4 inhibitors may increase insulin biosynthesis and β-cell mass, these findings have not been confirmed in clinical trials. The increased GLP-1 levels from DPP-4 inhibition do not significantly affect satiety or gastric emptying, resulting in minimal nausea and little to no change in body weight.
Adolescents with type 1 diabetes from 13 to 17 years old had a mean HbA1c of 9.2% (77 mmol/mol) in a 2019 T1D Exchange study, with only 17% achieving HbA1c levels below 7.5% (<58 mmol/mol), and 79% reported missing insulin bolus doses, while 40% of those on injection-based therapy missed basal insulin. A 2013 study by Hilliard et al. found that approximately two-thirds of 150 adolescents with type 1 diabetes did not check blood glucose more than four times daily nor achieved the target HbA1c of <7.5% (58 mmol/mol), with both modifiable and non-modifiable factors influencing outcomes—non-modifiable factors included ethnic minority status and unmarried caregiver status, while modifiable factors included injection-based insulin regimens and diabetes-specific family conflict. Additionally, adolescents using diabetes devices like pumps and CGMs were more likely to have better psychosocial, sociodemographic, and diabetes self-care characteristics compared to non-device users, as found by Chen et al.
In obese individuals with type 2 diabetes mellitus (T2DM) not adequately controlled by metformin alone, adding orlistat to the treatment regimen reduces HbA1c levels by 0.35% (4 mmol/mol) and enhances lipid and blood pressure management. Additionally, in patients treated with insulin, the inclusion of orlistat for one year leads to greater improvements in glycemic control, with a reduction in HbA1c of -0.62±0.08% compared to -0.27±0.08% with placebo (P<0.002), as well as better lipid profiles even when diabetes medication doses are reduced.
The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study examined the impact of mild hyperglycaemia during pregnancy, below the threshold for diabetes, on maternal and fetal outcomes. The study involved 23,000 pregnant women who underwent a 75g oral glucose tolerance test (OGTT) at 24–32 weeks’ gestation, with clinicians blinded to results unless specific glucose thresholds were exceeded (fasting glucose >5.8 mmol/l; two-hour glucose >11.1 mmol/l; or random glucose >8.9 mmol/l later in gestation), at which point women were excluded. The study found continuous independent relationships between untreated maternal glucose levels (measured fasting, one hour, and two hours post-glucose load) and several primary outcomes including birth weight above the 90th centile, clinical neonatal hypoglycaemia, primary caesarean section, and cord C-peptide levels indicating fetal hyperinsulinaemia, with the strongest associations observed for birth weight and cord C-peptide. Mean birth weight differences between the highest and lowest glucose categories ranged from 242g to 305g. Among secondary outcomes, shoulder dystocia and pre-eclampsia were linked to both fasting and post-challenge glucose levels, whereas preterm delivery, hyperbilirubinaemia, and NICU admission were associated only with post-challenge glucose levels. There was no observed association between maternal glucose levels and perinatal mortality, potentially due to the exclusion of 2.9% of women with elevated glucose levels (1.7% with elevated two-hour glucose and 1.2% with elevated random glucose later in pregnancy).
Autoimmune type 1 diabetes is characterized by increasing prevalence and incidence worldwide, with clinical onset peaking in childhood though it can occur at any age. Its aetiology involves the appearance of a first β-cell autoantibody, typically against insulin or glutamic acid decarboxylase 65 (GAD65), with some children presenting both autoantibodies. The disease progresses through three stages: the initial development of multiple β-cell autoimmunity (Stage 1), followed by asymptomatic loss of β-cell secretory capacity (Stage 2), and finally, loss of β-cell function accompanied by diabetes symptoms (Stage 3). The condition results from a loss of immunological tolerance to specific β-cell autoantigens, with human leucocyte antigen (HLA) genes being the strongest genetic determinants for the risk of β-cell autoimmunity, although they may not influence progression to type 1 diabetes.
Islet transplantation is indicated for hypoglycemia unawareness in diabetes patients. While pancreas transplantation restores counter-regulatory responses to hypoglycemia and improves hypoglycemia awareness, the effects of islet transplantation on these responses are inconsistent. Some studies show that islet transplantation does not restore counter-regulatory responses or symptom recognition, whereas others report improvements in hormonal and symptom responses to hypoglycemia after the procedure. Variations in outcomes may depend on patient subsets or the timing of post-transplant testing. In one cohort, 85% of islet transplant recipients reported return of hypoglycemia symptoms, though 62% later lost hypoglycemia awareness.
In older individuals with diabetes, studies have shown that targeting systolic blood pressure below 140 mmHg does not consistently reduce myocardial infarction or mortality rates. In very old patients (over 80 years), such as those in the Hypertension in the Very Elderly Trial (HYVET), a target of 150/80 mmHg resulted in a significant 33.7% reduction in cardiovascular events, although these findings may not apply broadly due to the healthier baseline status of participants. A separate community study in those aged over 85 found a U-shaped relationship between systolic blood pressure and mortality, with the lowest risk around 164.2 mmHg, suggesting that optimal blood pressure targets in this age group may be higher than 140 mmHg. For antihypertensive treatment, thiazide diuretics, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers are commonly used first-line agents, though higher doses of diuretics may negatively affect blood glucose and lipid levels, and most patients require combination therapy.
Patients with autonomic neuropathy may experience hypoglycemia without awareness due to impaired autonomic nervous system function, which can affect the body's ability to detect and respond to low blood sugar levels.
Patients with type 2 diabetes mellitus (T2DM) eventually require a progression of therapy from combination oral medications to injectable treatments such as basal bolus insulin regimens or incretin insulin combinations. Early initiation of combination therapy helps reduce side effects, enhances clinical effectiveness, lowers pill burden and cost, and improves adherence. According to new ACCE guidelines, treatment strategies are individualized based on baseline HbA1c levels, incorporating various medications and determining the appropriate number and type of insulin to start.
More women with diabetic nephropathy may undergo a combined pancreas-kidney transplant before planned pregnancy, though the benefit and risk of this approach compared to single kidney transplant for pregnancy outcomes have not yet been evaluated.
Alefacept may influence immune responses relevant to type 1 diabetes by increasing the ratio of regulatory T cells (Tregs) to effector memory T cells (Tem cells), particularly among CD4+ and CD8+ Tem cells, which are implicated in β-cell destruction. This effect might be mediated through increased expression of the programmed death-1 (PD-1) receptor on CD4+ cells, leading to downregulation of their effector functions.
GLP-1 and PYY are co-secreted from enteroendocrine cells in the colonic mucosa in response to nutrient sensing, with some similar effects including slowing gastrointestinal motility, reducing gastric acid secretion, and promoting satiety through central mechanisms. However, they have opposing effects on insulin secretion: GLP-1 enhances glucose-stimulated insulin secretion, while PYY inhibits it. Both GLP-1 and PYY are enzymatically cleaved by dipeptidyl peptidase (DPP)-4, which has implications in type 2 diabetes pathogenesis due to their roles in regulating insulin secretion and glucose homeostasis.
Hyperglycaemia has complex effects on the gastrointestinal system, including inducing apoptosis of enteric neurons, which can be reversed by overexpression of glial cell line-derived neurotrophic factor, a trophic factor for enteric neurons, as shown in transgenic mice where it also improved gastric emptying and intestinal transit. While insulin and insulin-like growth factors have been shown to prevent the loss of interstitial cells of Cajal (ICC) in cultures, ICC do not express receptors for these hormones, suggesting the effects may be mediated indirectly through smooth muscle secretion of stem cell factor, which is critical for ICC survival. In obese, leptin receptor knockout mice, hyperglycaemia is associated with increased kit expression in ICC and enhanced cholinergic responses, indicating that hyperglycaemia may have both detrimental and compensatory effects on gastrointestinal function.
Different organizations have proposed varying glycaemic targets for managing blood glucose levels in critically ill patients. A joint statement from the ADA and the AACE in 2014 recommended initiating insulin when glucose concentrations are persistently above 10.0 mmol/l (180 mg/dl), aiming for a target range of 7.8 to 10.0 mmol/l (140 to 180 mg/dl), with a lower target of 6.1 to 7.8 mmol/l (110 to 140 mg/dl) considered appropriate in experienced centers if severe hypoglycaemia does not increase. In contrast, the Society of Critical Care Medicine in the USA advises initiating glucose-lowering therapy when levels exceed 8.3 mmol/l (150 mg/dl), maintaining glucose below 10.0 mmol/l (180 mg/dl) and above 3.9 mmol/l (70 mg/dl). Some suggest that glycaemic targets should vary based on whether a patient has a known or unknown diagnosis of diabetes, and concerns have been raised that tight glycaemic control in critically ill individuals may cause more harm than benefit.
In patients inadequately controlled by metformin and sulfonylurea, adding insulin glargine once daily or exenatide twice daily both reduced HbA1c by 1.1% (12 mmol/mol) from a baseline mean of 8.2% (66 mmol/mol). Body weight increased by 1.8 kg with insulin glargine, whereas exenatide resulted in a 2.3 kg weight loss. Hypoglycemia occurred at similar frequencies between the two treatments, though nocturnal hypoglycemia was less common with exenatide. Withdrawal rates were higher in the exenatide group (19%) compared to the insulin glargine group (10%).
Dipeptidyl-peptidase 4 (DPP-4) inhibitors, also known as gliptins, are oral anti-diabetes medications that work by inhibiting the enzyme DPP-4, which deactivates endogenous incretins such as GIP and GLP-1. Incretins are gut-derived hormones that stimulate glucose-dependent insulin release from pancreatic islets and suppress glucagon secretion. These hormones are responsible for the incretin effect, which is the enhanced insulin secretion observed after oral glucose intake compared to intravenous glucose administration. In individuals with type 2 diabetes, the incretin effect is significantly diminished or may be completely absent.
Neonatal diabetes can result from various genetic mutations affecting pancreatic β-cell function or development, with differing inheritance patterns and associated clinical features. Mutations in the KATP channel genes (KCNJ11 and ABCC8) are the most common cause of permanent neonatal diabetes and can also cause transient neonatal diabetes, often presenting with developmental delay and epilepsy that is responsive to sulfonylurea treatment. Transient neonatal diabetes is frequently linked to abnormalities in chromosome 6q24 and may be associated with macroglossia and umbilical hernia. Homozygous glucokinase mutations cause rare cases of neonatal diabetes with autosomal recessive inheritance, and both parents typically have hyperglycemia due to heterozygous glucokinase mutations. Mutations in SLC2A2 and CLIS3 are also rare causes of neonatal diabetes, with the former associated with hypergalactosemia and hepatic failure and the latter with congenital hypothyroidism, glaucoma, liver fibrosis, and cystic kidney disease. Reduced pancreatic mass due to mutations in PTF1A, POX1, or HNF1B can lead to neonatal diabetes, with PTF1A and POX1 mutations causing pancreatic agenesis, sometimes with cerebellar involvement, and HNF1B mutations associated with exocrine pancreatic insufficiency and renal cysts. Increased β-cell destruction due to mutations in EF2AK3, FOXP3, or INS can also lead to neonatal diabetes, with EF2AK3 mutations linked to spondyloepiphyseal dysplasia, renal failure, recurrent hepatitis, and mental retardation; FOXP3 mutations associated with immune dysregulation, intractable diarrhea, eczematous rash, and elevated IgE; and INS mutations accounting for a significant proportion of permanent neonatal diabetes without additional features.
Certain medications can contribute to hyperglycaemia or trigger diabetes in susceptible individuals. Glucocorticoids reduce insulin sensitivity in the liver, skeletal muscle, and adipose tissue, with the effect being dose-dependent. Second-generation antipsychotics require regular monitoring of glucose levels, among other metabolic parameters. Combined oral contraceptives, despite being linked to metabolic issues, are still considered safe for women with type 1 or type 2 diabetes without vascular complications, as well as those with a history of gestational diabetes. Menopause hormone therapy has little impact on glucose homeostasis and can be used safely in postmenopausal women with diabetes, though ongoing glycaemic monitoring and adjustments to diabetes medications are advisable. Thiazide diuretics may affect glucose metabolism in a dose-dependent way, but the impact is generally mild, and maintaining normal potassium levels helps mitigate this effect. The role of beta-blockers in influencing glucose homeostasis or causing diabetes remains unclear, but those with vasodilating properties like carvedilol and nebivolol are preferred for people with or at risk for diabetes, unless contraindicated.
In diabetic pregnancies, the fetal metabolic intrauterine environment significantly influences birth weight, often resulting in "growth promoted" infants, with over half exceeding the 90th percentile for gestational age. Studies show that babies born to mothers with type 1 diabetes mellitus (T1DM) have a mean birth weight 1.41 standard deviations above the population norm, and this increased birth weight has remained consistent over time. Accelerated fetal growth in diabetic pregnancies is associated with higher risks of emergency cesarean section, birth trauma, birth asphyxia, and future obesity in childhood and adulthood.
SGLT-2 inhibitors, a class of medications used in diabetes management, are associated with several adverse effects related to their mechanism of action. The most common are genital mycotic infections due to glucosuria, including balanoposthitis in men and vulvovaginal candidiasis in women, which are usually mild to moderate and responsive to standard treatment. Urinary tract infections are less frequent, while serious complications such as pyelonephritis, urosepsis, or Fournier's gangrene are extremely rare. A numerical imbalance in bladder cancer cases was observed with dapagliflozin, but causality is unlikely due to early detection and potential detection bias. Volume depletion-related adverse events like dizziness, orthostatic hypotension, and syncope may occur, especially in older individuals, those with renal impairment, or those on concomitant diuretic therapy. Although acute kidney injury risk does not appear increased, thrombosis due to haemoconcentration is a theoretical concern. Canagliflozin has been linked to a higher incidence of fractures, likely due to falls from volume depletion, and an increased risk of amputations, prompting recommendations to discontinue treatment if pre-amputation events occur. Additionally, individuals on SGLT-2 inhibitors may develop diabetic euglycemic ketoacidosis during intercurrent illness, which can be difficult to recognize due to the absence of marked hyperglycemia, necessitating drug discontinuation during acute illness or surgery and avoidance in those predisposed to ketoacidosis.
The prevalence of diabetes in Australians aged ≥25 years was 7.5% in 2000, with higher rates in men (8%) than women (7%), and increased significantly with age, rising from 2.5% in those aged 25–44 years to 24% in those aged ≥75 years, more than doubling since 1981; about 50% of cases were previously undiagnosed. The combined prevalence of impaired fasting glucose and impaired glucose tolerance was 16%, with 17% in men and 15% in women, indicating that nearly 25% of Australians aged ≥25 years have abnormal glucose metabolism. Type 2 diabetes accounts for over 85% of cases, while type 1 diabetes accounts for 10%, and projections based on the AusDiab study suggest the prevalence of diabetes could rise from 7.6% in 2000 to 11.4% by 2025, with an annual incidence of 0.8% for men and 0.6% for women reported in the 2012 report.
Healthy eating is an important aspect of managing diabetes, as it can influence body weight, blood glucose levels, and overall metabolic control. Maintaining an appropriate energy intake helps achieve or sustain a desirable body weight, which is crucial for metabolic health. Alcohol consumption should be moderate, as excessive intake may negatively affect hyperlipidemia, hypertension, or increase the risk of hypoglycemia. The use of unnecessary special diabetic food products should be avoided, as they may not provide additional benefits over regular foods. Meal selection and distribution should align with glucose-lowering medications to optimize blood sugar control. Additionally, if hypertension is present, salt restriction may be beneficial to manage blood pressure.
Neonatal diabetes caused by heterozygous KCNJ11 or ABCC8 variants can be inherited with a 50% chance from an affected parent, while the risk for unaffected parents with one affected child is low at 5–10% due to possible germline mosaicism. In cases where neonatal diabetes is caused by a recessive ABCC8 variant, there is a 25% chance of each subsequent child being affected. Fetal inheritance of a KATP variant from the mother leads to reduced insulin secretion in utero, resulting in decreased fetal growth by approximately 900g. If both the fetus and mother have KATP neonatal diabetes, maternal glibenclamide treatment is advised as it crosses the placenta and can normalize fetal growth, whereas glibenclamide is not recommended in the third trimester if the fetus is unaffected due to the risk of neonatal hypoglycaemia and excessive fetal growth. Cell-free fetal DNA testing is valuable in managing pregnancies affected by KATP neonatal diabetes by providing fetal genotype information to guide treatment decisions.
Selective inhibitors of SGLT2, known as "flozins," have been developed to reduce hyperglycemia in diabetic animals and are now in clinical trials. These inhibitors partially prevent glucose reabsorption, allowing the elimination of up to about 100g/day of glucose, which helps improve glycemic control in patients with type 2 diabetes mellitus (T2DM). SGLT2 inhibitors can be used alongside other antidiabetic treatments and may aid in weight loss by eliminating glucose. Lowering glucotoxicity through these inhibitors may improve insulin sensitivity. Since SGLT2 inhibition does not stimulate insulin secretion or interfere with the counter-regulatory system, serious hypoglycemia can likely be avoided with appropriate dosing. However, potential adverse effects include osmotic diuresis leading to dehydration, electrolyte imbalance, and increased risk of urinary tract and genital infections.
Regular physical activity and structured exercise programs can lead to improvements in HbA1c levels among individuals with diabetes, as indicated by several studies. Aerobic exercises such as treadmill training, swimming, cycling, and circuit training, performed multiple times per week over periods ranging from 2 to 14 weeks, generally result in a reduction in HbA1c values. For example, engaging in aerobic exercise for 45 minutes three times a week or swimming twice a week for 14 weeks has been associated with decreased HbA1c levels. Additionally, more frequent physical activity, such as exercising three or more times per week, tends to correlate with lower HbA1c compared to sedentary behavior or less frequent activity. However, the beneficial effects of exercise on HbA1c may diminish if the exercise program is not maintained consistently over time.
Low self-efficacy and high outcome expectancy are associated with poorer metabolic control in individuals with diabetes. An internal locus of control can be particularly beneficial for those with low confidence in following medical recommendations or believing in their effectiveness. Coping styles, such as emotion-focused and problem-focused strategies, influence how individuals handle stress related to diabetes management. Emotion-focused coping involves reinterpreting stressful situations, while problem-focused coping aims to change the environment to eliminate threats, such as reducing carbohydrate intake by removing unhealthy snacks. Some coping strategies, like those that increase emotional arousal (e.g., anger or anxiety), can worsen stress, which in turn negatively affects metabolic control. In adults with type 1 diabetes mellitus (T1DM), higher stress levels are linked to poorer metabolic control when ineffective coping styles are used. In adolescents, emotion-focused coping methods like disengagement or aggression are associated with worse metabolic control and lower diabetes-related quality of life, whereas active coping strategies that directly address the source of distress are linked to better metabolic outcomes. A meta-analysis of 21 studies found that approach coping is associated with improved psychological adjustment and slightly better metabolic control in individuals with diabetes.
Abnormal glucose tolerance and diabetes occur in approximately 40–50% of chronic pancreatitis cases, developing insidiously and typically emerging several years after the onset of pain, with a prevalence reaching 60% after 20 years. This form of diabetes arises due to damage to β-cells caused by loss of trophic signals from exocrine tissue, and while about half of patients require insulin for optimal glycemic control, ketoacidosis is rare even upon insulin withdrawal, possibly due to better preservation of β-cell function compared to type 1 diabetes, reduced glucagon secretion, and lower triglyceride stores. These patients are also susceptible to severe and prolonged hypoglycemia and often experience difficulty in diabetes management due to significant fluctuations in blood glucose levels.
Bariatric surgery is an effective treatment for patients with type 2 diabetes mellitus (T2DM) and a BMI ≥ 35 kg/m², leading to significant and sustained weight loss along with high rates of diabetes remission, particularly when combined restrictive and malabsorptive techniques are used. In the Swedish Obese Subjects study, surgical treatment resulted in substantial weight loss and reduced the incidence of T2DM compared to conventional dietary treatment, while a meta-analysis found that 78% of obese T2DM patients experienced complete remission of diabetes after surgery. Insulin treatment can typically be discontinued within months post-surgery, and other diabetes medications as well as treatments for cardiovascular risk factors can often be reduced or stopped. Additionally, circulating adipokines normalize rapidly in relation to the degree of weight loss achieved.
In vitro experiments suggest that active insulin-secreting beta cells hyperexpress islet autoantigens such as GAD and are more susceptible to the toxic effects of the cytokine interleukin-1β. Factors that increase stress on beta cells may non-specifically contribute to the onset of clinical type 1 diabetes, including insulin resistance or mechanisms involved in infections, puberty, and growth spurts. Insulin resistance, though difficult to measure reliably in children, can be assessed relative to first-phase insulin response during an intravenous glucose tolerance test, which has shown predictive value for progression to type 1 diabetes. A 2020 review indicated that no single aetiological factor has been strongly linked to the risk of type 1 diabetes with sufficient magnitude and changing exposure patterns to explain the disease's evolving epidemiology, suggesting that multiple or yet unknown factors are likely involved. Methodological challenges such as measurement errors, confounding, and selection bias should also be considered in aetiological studies of type 1 diabetes.
The Effect of sotagliflozin on cardiovascular and renal events in patients with type 2 diabetes and moderate renal impairment who are at cardiovascular risk (SCORED) trial evaluated the dual SGLT-2 and SGLT-1 inhibitor sotagliflozin in individuals with type 2 diabetes and chronic kidney disease, regardless of albuminuria status. The trial initially focused on MACE and a composite of cardiovascular mortality or hospitalization for heart failure as primary outcomes, but due to early cessation and fewer than planned events, the primary outcome was modified to include cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure. Over a median follow-up of 16 months, sotagliflozin demonstrated a reduced occurrence of the primary outcome compared to placebo (HR 0.74; 95% CI 0.63 to 0.88). However, sotagliflozin has not received marketing approval for the treatment of type 2 diabetes.
Hypoglycemia-associated autonomic failure (HAAF) in diabetes is influenced by several risk factors, including absolute endogenous insulin deficiency, a history of severe iatrogenic hypoglycemia, hypoglycemia unawareness, recent antecedent hypoglycemia, prior exercise or sleep, and aggressive glycemic therapy such as lower HbA1c levels or glycemic goals. The extent of endogenous insulin deficiency determines the inability of insulin levels to decrease and glucagon levels to increase during falling plasma glucose concentrations due to therapeutic hyperinsulinemia. A history of severe hypoglycemia or hypoglycemia unawareness suggests recent hypoglycemic events, which lead to attenuated sympathoadrenal and symptomatic responses to subsequent hypoglycemia, a key feature of HAAF. Additionally, prior exercise and sleep contribute to this attenuated response. Intensive glycemic therapy studies in both type 1 and type 2 diabetes consistently show higher hypoglycemia rates in groups aiming for lower HbA1c levels compared to those with higher targets. However, improving glycemic control while minimizing hypoglycemia risk remains achievable.
Diabetes management has evolved significantly over time, beginning with early lifestyle modifications such as avoiding wine, sex, and salty cereals as recommended by Li Hsuan in 7th century China, and progressing to food restriction advised by Thomas Willis in 17th century England. In 1797, John Rollo introduced an animal-based diet, while Apollinaire Bouchardat in 1875 advocated food restriction and increased exercise. By 1903, Carl von Noorden promoted the "oatmeal" diet, and in 1913 Frederick Allen introduced a starvation diet for early-onset diabetes, followed by Karl Petren's high-fat, low-carbohydrate diet in 1915. The discovery of insulin began with Georg Zuelzer and Nicolas Paulesco isolating pancreatic extracts with hypoglycemic activity in 1907 and 1921, respectively, culminating in the isolation and first clinical use of insulin by Frederick Banting, Charles Best, J.J.R. Macleod, and James Collip in 1922–1923. Hans Christian Hagedorn developed the first long-acting insulin using protamine in 1936, and in 1979 David Goeddel produced synthetic human-sequence insulin through recombinant DNA technology. Insulin delivery methods advanced with the description of continuous subcutaneous insulin infusion by John Pickup in 1978 and the invention of the pen injection device by John Ireland in 1981. Oral hypoglycemic agents have roots in Avicenna's use of lupin, fenugreek, and zedoary seeds in the 10th century, and later in the 19th and 20th centuries, treatments included sodium salicylate, biguanide derivatives like Synthalin, and sulfonamides noted by Celestino Ruiz in 1930. The discovery of sulfonylureas by Auguste Loubatières in 1942 led to the introduction of carbutamide in 1950, and phenformin was introduced by G. Ungar in 1957. Diabetic monitoring advanced with the first randomized trial in diabetes conducted by the University Group Diabetes Program in 1969, followed by the introduction of home blood glucose monitoring in 1978 by Peter Sönksen and Robert Tattersall. In 1975, R. Flückiger and K.H. Winterhalter identified HbA1c as glycated hemoglobin, and the St Vincent Declaration by the World Health Organization in 1991 set targets for diabetes care. Clinical trials such as the Diabetes Control and Complications Trial in 1993 and the UK Prospective Diabetes Study in 1998 demonstrated the benefits of improved glycemic control in preventing complications in type 1 and type 2 diabetes, respectively. Management of complications included the use of a xenon arc lamp to treat diabetic retinopathy by Gerd Meyer-Schwickerath in 1964, the first combined kidney-pancreas transplant in 1966, and evidence from Carl-Erik Mogensen and Hans-Henrik Parving in the 1980s that strict blood pressure control slows the progression of diabetic neuropathy.
In individuals with classic symptoms of hyperglycaemia, a single measurement of glucose or HbA₁c above the diagnostic threshold is sufficient for diagnosing diabetes, whereas in the absence of clear symptoms, two abnormal test results from the same or separate samples are required. When uncertainty exists, the World Health Organization (WHO) and American Diabetes Association (ADA) recommend using a standard 75g oral glucose tolerance test (OGTT), preferably alongside HbA₁c measurement. However, in many high-income countries where accurate HbA₁c testing is widely available, clinical practice is shifting away from routine OGTT use, favoring instead the use of a single blood sample to measure fasting or random glucose along with HbA₁c for diagnosis.
In genetically predisposed children, the early detection of islet autoantibodies, such as IAA and GAD65Ab, often precedes the appearance of ICA and IA-2Ab, which typically occurs last, with additional autoantibodies usually emerging within a year of the first detection. While a single autoantibody may indicate non-progressive β-cell autoimmunity, the presence of multiple autoantibodies generally signifies a progressive process leading to type 1 diabetes mellitus (T1DM). The number of detectable autoantibodies correlates with the risk of developing T1DM, with 60–100% of individuals having three or more autoantibodies progressing to clinical T1DM within 5–6 years, a risk pattern observed in both family members of T1DM patients and the general population. GAD65Ab is considered a marker of general non-specific autoimmunity, whereas IA-2Ab and IAA are more specific indicators of β-cell death, and the recently identified ZnT8Ab tends to appear after three years of age, increasing in frequency with age up to adolescence.
Increased macrophage infiltration in adipose tissue, particularly surrounding dead adipocytes, is associated with obesity and may contribute to systemic insulin resistance, including in the liver, potentially playing a role in the development of diabetes. This inflammation-related insulin resistance may be mediated by increased NEFA levels and reduced adiponectin concentrations, and macrophage accumulation in adipose tissue can be partially reversed by weight loss, which also reduces the expression of genes involved in macrophage recruitment.
Low-dose ATG therapy, with or without GCSF, has been studied in individuals with newly diagnosed type 1 diabetes, showing that ATG alone can slow the decline of C-peptide and reduce HbA1c levels. In a clinical trial involving 89 participants, those treated with ATG alone had higher AUC C-peptide levels (0.646 nmol/l/min) compared to placebo (0.406 nmol/l/min), and this effect was maintained over 24 months, with sustained reductions in HbA1c. However, no significant difference was observed between the ATG/GCSF group and placebo in terms of C-peptide preservation.
Glucokinase MODY and transcription factor MODY are forms of maturity-onset diabetes of the young with distinct clinical features. Glucokinase MODY typically presents with mild hyperglycaemia from birth, often asymptomatic and detected through screening, while transcription factor MODY presents during adolescence or early adulthood with more noticeable symptoms and progressive deterioration of glycaemic control. In Glucokinase MODY, fasting plasma glucose (FPG) is usually between 5.4–8.3 mmol/l and HbA1c ranges from 40–60 mmol/mol (5.8–7.6%), with minimal increase in glycaemia over time, whereas transcription factor MODY can involve fasting glucose levels frequently exceeding 14 mmol/l off treatment, and HbA1c levels may be high depending on age and treatment. During an oral glucose tolerance test, Glucokinase MODY shows a fasting plasma glucose above 5.5 mmol/l and a 2-hour increment usually below 5.5 mmol/l, whereas transcription factor MODY often has a fasting glucose below 5.5 mmol/l with a 2-hour increment exceeding 5.5 mmol/l. Microvascular complications are rare in Glucokinase MODY but frequent in transcription factor MODY. The underlying pathophysiology of Glucokinase MODY involves a β-cell defect affecting glucose sensing, while transcription factor MODY involves a β-cell defect where insulin secretion is initially normal at euglycaemic levels but fails to increase during hyperglycaemia. Glucokinase MODY is rarely in need of pharmacological treatment, whereas transcription factor MODY is sensitive to sulfonylurea treatment and may eventually require insulin.
Infections, including tuberculosis, can cause unpredictable changes in glycaemic levels and complicate diabetes management through inflammatory processes, altered appetite and body weight, and drug-drug interactions. Rifampicin, a key tuberculosis medication, increases the hepatic metabolism of sulfonylureas and may enhance the glucose-lowering effect of metformin. For individuals with both diabetes and tuberculosis, insulin therapy is recommended due to its lack of pharmacokinetic interactions with anti-tuberculous agents. Close monitoring of glycaemic levels, renal and hepatic function, as well as patient education, is essential in managing these comorbid conditions. Integrated care and policy development are important for addressing the bidirectional screening of diabetes in tuberculosis patients and vice versa.
Suppressing glucagon action can reduce hyperglycemia, and various peptide antagonists of the glucagon receptor have been developed, including hybrid peptides that also act as GLP-1 receptor agonists. Small molecule glucagon receptor antagonists such as Cpd1, NNC 25-0926, and MB09975N are under investigation, while other approaches include using compounds like skyrin to uncouple the glucagon receptor from adenylate cyclase activation. Inhibitors of glucagon secretion, such as MB39890A and somatostatin analogs, have also been developed but lack sufficient selectivity. Octreotide, a somatostatin analog, suppresses glucagon secretion and delays intestinal glucose absorption but also inhibits insulin secretion, making it unsuitable for type 2 diabetes mellitus (T2DM), though it may aid glycemic control with insulin in type 1 diabetes mellitus (T1DM).
Good glycemic control can reduce the risks of pregnancy-induced hypertension, pre-eclampsia, and preterm birth in women with microalbuminuria.
Intraportal islet cell transplantation has been explored as a treatment for insulin-dependent diabetes mellitus, with various immunosuppressive regimens influencing outcomes. In 1997, Secchi et al. reported a 35% insulin independence rate using induction immunosuppression with steroids and ATG, along with maintenance immunosuppression involving azathioprine, cyclosporine A, and steroids, plus peri-transplant insulin use. A different approach using OKT3 as the induction agent showed graft survival up to six years in some cases. However, by 2000, the global experience was largely disappointing, with the Islet Transplant Registry reporting only an 11% one-year insulin independence rate across 237 transplants. That same year marked a breakthrough with the Edmonton Protocol, which utilized a steroid-free immunosuppressive regimen including daclizumab, sirolimus, and tacrolimus, together with more than 11,000 islet equivalents per kilogram, achieving 100% one-year insulin independence in seven consecutive non-uraemic individuals with type 1 diabetes. This protocol revitalized research and initiated new clinical programs in islet cell transplantation worldwide.
Recent studies have examined the optimal initiation of insulin treatment in patients with type 2 diabetes, comparing basal insulin alone to combinations of basal and prandial insulin. The 4-T Study, a multicenter trial, evaluated 708 patients with HbA1c levels between 7–10% (53–86 mmol/mol) who were on maximal tolerated doses of metformin and sulfonylureas, randomizing them to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once or twice daily. After one year, mean HbA1c levels were similar in the biphasic (7.3%, 56 mmol/mol) and prandial groups (7.2%, 55 mmol/mol), but higher in the basal group (7.6%, 60 mmol/mol). Proportions of patients achieving HbA1c ≤6.5% (48 mmol/mol) were highest in the prandial group (23.9%), followed by the biphasic group (17.0%), and lowest in the basal group (8.1%). Hypoglycemia rates were lowest in the basal group (2.3 events per patient-year) and highest in the prandial group (12.0 events), while weight gain was greatest in the prandial group (5.7 kg) and least in the basal group (1.9 kg). After three years, median HbA1c levels ranged from 6.8–7.1% (51–54 mmol/mol) without significant differences between groups, though fewer participants on biphasic insulin reached HbA1c targets of 6.5% or 7.0% (48 or 53 mmol/mol). The study supported initiating insulin with basal insulin added to oral therapy, with possible intensification to a basal-bolus regimen, though biphasic insulin may offer a less intensive alternative for some patients.
GLP-1 receptor agonists in development for diabetes include CJC1134, an exendin-4 molecule linked to serum albumin with a half-life of approximately 10–15 days, and NN9535, a once-weekly GLP-1 receptor agonist from Novo Nordisk Pharmaceutical. Additionally, oral, intranasal, and pulmonary administration methods for GLP-1 receptor agonists are being investigated.
In individuals with diabetes, $\alpha$ cells exhibit abnormal sensitivity to glucose, leading to higher plasma glucagon levels after mixed-nutrient meals in type 2 diabetes, and reduced glucagon responses to hypoglycaemia. This dysfunction suggests a form of $\alpha$-cell glucose insensitivity, potentially with a genetic origin. A common polymorphism in the KCNJ11 gene, which encodes the KIR6.2 component of the $\mathrm{K}_{\mathrm{ATP}}$ channel, is associated with type 2 diabetes and linked to impaired glucose-induced suppression of glucagon.
Type 1 diabetes mellitus (T1DM) develops in genetically susceptible individuals following immune-mediated destruction of pancreatic beta-cells, requiring lifelong insulin treatment, and can occur at any age, with peak incidence around puberty. The classification between T1DM and type 2 diabetes becomes more challenging with increasing age. In childhood, T1DM incidence is similar in males and females, but after 15 years of age, males show a 1.3- to 2.0-fold higher incidence in most populations. Childhood incidence varies widely between countries, with low rates in some Asian and South American regions (0.1–8 per 100,000/year) and high rates in Finland (>40 per 100,000/year), Sardinia (~38 per 100,000/year), and Sweden (~30 per 100,000/year). Moderate to high incidences are seen in North America (15–25 per 100,000/year) and Australia (~15 per 100,000/year), while Eastern European countries have lower rates (4–10 per 100,000/year). About 10–20% of new childhood T1DM cases have a family history of the disease, and those with an affected first-degree relative have a cumulative risk of 3–7% by age 20, compared to 0.2–0.8% in the general population. Monozygotic twins of individuals with T1DM have less than 50% cumulative incidence even after more than 30 years of follow-up. Geographic and familial clustering may be influenced by human leukocyte antigen haplotypes. The incidence of childhood-onset T1DM has increased by 3–4% annually, with a trend toward younger onset over time, which cannot be explained by genetic changes alone. Potential causes for the rise remain unknown, though virus infections and nutrition have been suggested. Despite improved insulin therapy and disease management, mortality in T1DM patients remains 2 to 10 times higher than in the general population, primarily due to acute and chronic complications such as cardiovascular disease after age 30.
Orally active glucose-lowering drugs began with synthalin, a guanidine derivative developed in 1926, but it was withdrawn due to toxicity. Sulfonylureas emerged in the 1940s from research on sulfonamide derivatives, with carbutamide entering clinical practice in 1955, followed by tolbutamide in 1957. Phenformin, the first biguanide, was introduced in 1959, and metformin became available in Europe in 1960 but only reached the US market in 1994. Troglitazone, the first glitazone, was released in 1994 but withdrawn due to liver damage, later succeeded by rosiglitazone and pioglitazone. In 2005, a new class targeting the incretin system was introduced, including GLP-1 agonists like exenatide and DPP-4 inhibitors known as gliptins.
Sulfonylureas carry an increased risk of hypoglycaemia and weight gain, especially long-acting formulations, though some are suitable for those with renal impairment or low risk of hypoglycaemia. Metformin has a low risk of hypoglycaemia, offers cardiovascular benefits, and is weight neutral, but it should be avoided in those with renal impairment due to an increased risk of lactic acidosis, particularly in cases of heart failure or sepsis. Meglitinides are short-acting with a lower risk of hypoglycaemia and weight gain compared to sulfonylureas, making them suitable for individuals with erratic eating patterns. Alpha-glucosidase inhibitors and pioglitazone have a low risk of weight gain and hypoglycaemia and are suitable for those with renal impairment, but they may cause gastrointestinal side effects, fluid retention, and can worsen heart failure. Dipeptidyl peptidase 4 (DPP-4) inhibitors have a low risk of hypoglycaemia but may increase fracture risk and possibly bladder cancer, along with gastrointestinal side effects, and often require dose adjustments in renal impairment. Glucagon-like peptide 1 (GLP-1) receptor agonists promote weight loss with a low risk of hypoglycaemia, but they are injectable, may not be suitable for frail individuals or those with renal failure, and require dose adjustment in renal impairment. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are associated with weight loss and a low risk of hypoglycaemia but may cause nausea, carry a possible risk of pancreatitis, are not suitable for frail older people with weight loss, and increase the risk of urinary tract infections, candidiasis, and dehydration. Insulin is effective, can be tailored rapidly to changes in need, and improves quality of life, but it carries a high risk of hypoglycaemia and weight gain, along with risks of infections, candidiasis, dehydration, and hypotension.
GLP-1 stimulates insulin secretion and is involved in normalizing post-prandial glycemia, but its short half-life limits its use as a diabetes therapy. Exenatide, a GLP-1 analogue with 50% amino acid homology to GLP-1, has a longer half-life due to resistance to DPP-4 degradation, making it effective for regulating blood glucose in type 2 diabetes. Liraglutide, another GLP-1 analogue modified with palmitate, has an extended half-life of over 12 hours by binding to plasma albumin and reducing DPP-4 exposure. DPP-4 inhibitors like sitagliptin are also used clinically to prolong the activity of endogenous GLP-1, thereby improving blood glucose control in individuals with type 2 diabetes.
Morning administration of intermediate-acting basal human insulin may closely fit the glucose excursion induced by a single morning dose of oral steroid, while basal insulin analogues may be appropriate for prolonged hyperglycaemia. Care should be taken to identify and protect against hypoglycaemia overnight and in the early morning when using long-acting insulin analogues. For individuals taking multiple steroid doses per day, a basal bolus regimen may be considered the best option.
rtCGM systems are utilized in diabetes management either as standalone devices for individuals on multiple daily insulin injections or in conjunction with insulin pumps. These systems enable automated insulin dosing by communicating with the pump to suspend insulin delivery at specific glucose thresholds or during predicted low glucose events. They also help prevent hyperglycaemia through automated adjustments of basal insulin rates or correction boluses. Most rtCGM systems allow for cloud-based data transmission, enabling sharing of glucose readings with family members or diabetes care teams.
In type 2 diabetes, the disease often goes undiagnosed for years, during which time retinopathy can develop and may already be vision-threatening by the time of diagnosis. A significant proportion of individuals diagnosed with type 2 diabetes show signs of retinopathy, with some having advanced forms such as proliferative diabetic retinopathy or diabetic maculopathy. After diagnosis, the annual incidence of vision-threatening retinopathy remains steady, though less than 10% progress to treatment-requiring stages. Despite type 1 diabetes having a higher risk per individual, the larger population of type 2 diabetes results in a comparable absolute number of cases with vision-threatening retinopathy.
Repaglinide, a non-sulfonylurea insulin secretagogue of the meglitinide class, is used to lower post-prandial hyperglycemia in diabetes management. It has a rapid onset of action and is associated with a lower risk of hypoglycemia compared to sulfonylureas, resulting in improved post-prandial glucose control.
Basal insulin analogues such as glargine, detemir, and degludec have varying durations of action, with glargine lasting 20–24 hours, detemir between 6 and 23 hours (often administered twice daily), and degludec up to 72 hours. Rapid-acting insulin analogues like aspart, lispro, and glulisine are used before meals and to manage hyperglycaemia, while faster acting insulin aspart (Fiasp) has a quicker onset and shorter duration. Regular human insulin, a short-acting type, has a longer onset and peak action and is still widely used. Intermediate-acting insulins such as NPH are often combined with short-acting or rapid-acting insulins; when mixing, clear insulin should be drawn up before cloudy insulin to prevent contamination. Glargine and detemir should not be mixed with other insulins according to manufacturer instructions.
Statin therapy in individuals with diabetes has been shown to significantly reduce LDL cholesterol and cardiovascular disease (CVD) risk. In the Collaborative Atorvastatin Diabetes Study (CARDS), atorvastatin 10 mg/day led to a 40% reduction in LDL cholesterol and a 37% reduction in combined CVD endpoints among people with type 2 diabetes and additional risk factors. Similarly, the Heart Protection Study (HPS) demonstrated that simvastatin 40 mg/day resulted in a 33% reduction in LDL cholesterol and a 31% reduction in CVD endpoints, with a pre-specified subgroup of 5963 individuals with diabetes, including 600 with type 1 diabetes. A meta-analysis of 18,686 individuals with diabetes (1466 type 1, 17,220 type 2) showed that over 4.3 years, statin therapy reduced mortality by 9% per 1 mmol/L LDL cholesterol reduction, and CVD events by 13% per 1 mmol/L reduction, similar to effects seen in non-diabetic populations.
Patients with HNF1A mutations exhibit elevated HDL cholesterol levels, unlike those with type 2 diabetes mellitus (T2DM) who typically have reduced HDL levels. Despite this difference, individuals with HNF1A mutations have a higher risk of coronary heart disease compared to those with type 1 diabetes mellitus (T1DM). The frequency of microvascular complications in HNF1A mutation carriers is similar to that observed in both T1DM and T2DM and is associated with the degree of glycemic control. These patients also have a reduced renal threshold for glucose, meaning that mutation carriers without diabetes can develop glycosuria following a glucose challenge even when blood glucose levels remain within the normal range.
Continuous IV insulin infusion, typically using diluted regular insulin at a dose of 0.05–0.1 units/kg/h, should start after initial volume expansion in the management of diabetes-related conditions. An IV bolus of insulin is not recommended due to the increased risk of cerebral edema. The insulin infusion should aim for a gradual decrease in blood glucose levels by 50–100 mg/dl/h (2.8–5.6 mmol/l/h). If blood glucose levels drop too quickly or become excessively low before resolving acidosis, the IV dextrose concentration can be increased to 12.5% to prevent hypoglycemia while continuing insulin therapy to correct metabolic acidosis. Reducing the infusion rate below 0.05 units/kg/h is cautioned as it may prolong ketogenesis suppression, although it might be necessary in cases of severe or persistent hypoglycemia. Monitoring blood ketones, specifically β-hydroxybutyrate, is more effective than blood gases in adjusting insulin and glucose infusion rates.
GLP-1 receptor agonists (GLP-1RAs) are used in the treatment of type 2 diabetes, with seven currently approved for clinical use. These medications were developed to overcome the rapid degradation of native GLP-1 by the enzyme DPP-4, which results in a very short half-life of 1–2 minutes. To address this, GLP-1RAs resistant to DPP-4 degradation have been developed using two strategies: one based on exendin-4, a naturally occurring DPP-4 resistant polypeptide isolated from lizard saliva that activates the GLP-1 receptor with equal efficacy to native GLP-1, and another based on modifying the native GLP-1 structure with amino acid alterations to prevent DPP-4 degradation. The GLP-1RAs differ in pharmacokinetic profiles, dividing them into short-acting and long-acting formulations, and these differences in molecular structure, size, and similarity to native GLP-1 impact their efficacy and tolerability.
H-ficolin levels are associated with an increased risk of worsening urinary albumin excretion in individuals with type 1 diabetes, with those in the highest quartile having a twofold greater risk compared to those in the lowest quartile, even after adjusting for factors such as HbA1c, systolic blood pressure, smoking status, and baseline urinary albumin excretion. Elevated H-ficolin levels are also linked to progression to micro- or macroalbuminuria and correlate with diabetic kidney disease, mortality, and cardiovascular events in people with type 1 diabetes. No studies have yet explored the relationship between L-ficolin or M-ficolin and nephropathy risk in humans.
GLP-1/glucagon receptor co-agonists studied in individuals with type 2 diabetes are based mostly on oxyntomodulin, which exerts relatively weak agonist effects at both GLP-1 and glucagon receptors, and these molecules are vulnerable to degradation by DPP-4, leading to modifications in engineered co-agonists to improve stability.
α-Glucosidase inhibitors are used in the management of diabetes and should be taken with meals, starting at a low dose such as 50 mg/day of acarbose, with gradual dose escalation over several weeks. Patients should maintain a diet containing complex digestible carbohydrates. These medications primarily target postprandial glycemia, making monitoring of blood glucose after meals helpful. Hypoglycemia is not a common occurrence when α-glucosidase inhibitors are used alone, but gastrointestinal side effects are frequent, often limiting initial tolerability and affecting dose titration. The gastrointestinal symptoms typically improve over time or with slow dose adjustment, likely due to adaptation of the intestinal tract, though overall tolerability can remain poor.
Albiglutide was effective in preventing heart failure in people without a prior history of diabetes, but its effects on prevalent heart failure were less clear. The cardiovascular effects of albiglutide were evaluated in a trial of people with HFrEF and no history of diabetes, showing mainly neutral effects on left ventricular ejection fraction and myocardial glucose uptake. Liraglutide also showed a neutral effect on left ventricular ejection fraction in people with HFrEF, both with and without diabetes, though safety concerns arose due to increased heart rate and serious adverse cardiac events. Evidence from the FIGHT trial further supported safety concerns regarding GLP-1 receptor agonists in HFrEF, showing a higher, though not statistically significant, rate of heart failure rehospitalization with liraglutide. Despite these concerns, GLP-1 receptor agonists may have a potential role in HFpEF due to their non-cardiac effects, particularly weight loss, which warrants further study.
Many women with diabetes are postmenopausal, and diabetes professionals need to be aware of the potential risks and benefits associated with hormone replacement therapy (HRT), which is considered a short-term treatment for menopausal symptoms and does not increase cardiovascular risk, though it carries other risks such as cardiovascular disease, stroke, thromboembolism, and breast cancer.
MODY (Maturity-Onset Diabetes of the Young) includes several subtypes caused by mutations in transcription factors, such as MODY 1 (HNF-4α), MODY 3 (HNF-1α or TCF1), MODY 4 (IPF-1), MODY 5 (HNF-1β or TCF-2), MODY 6 (NeuroD1), MODY 7 (CEL), and MODY 2 (glucokinase), which play critical roles in pancreatic development and β-cell function. Genetic mutations in these transcription factors lead to insulin insufficiency and hyperglycemia, while common polymorphisms in HNF-1α, HNF-4α, and HNF-1β are associated with increased diabetes risk, potentially interacting with other genetic, environmental, or lifestyle factors to result in overt diabetes.
Patients with type 1 diabetes mellitus (T1DM) who have microalbuminuria tend to have higher blood pressure (BP) than those with normal urinary albumin excretion, even though their BP may not reach the threshold for hypertension. When proteinuria develops, untreated BP exceeds 140/90 mmHg in more than 80% of T1DM patients, and hypertension becomes nearly universal once end-stage renal disease (ESRD) is present.
Chronic exposure to high insulin concentrations leads to downregulation of cell-surface insulin receptors, contributing to impaired insulin responsiveness, and this receptor loss is observed in hyperinsulinemic insulin-resistant humans. Genetic ablation of the insulin receptor in mice results in lethality at 4–5 days after birth due to severe diabetic ketoacidosis. Muscle-specific insulin receptor knockout mice exhibit impaired insulin-stimulated glucose uptake and activation of glycogen synthase, along with features of metabolic syndrome such as increased fat mass, serum triglycerides, and serum free fatty acids, although basal and contraction-stimulated glucose transport remain normal. Transgenic mice expressing dominant-negative insulin receptors develop obesity, hyperinsulinemia, glucose intolerance, and hypertriglyceridemia, phenotypes similar to those in insulin-resistant humans. Patients with genetic mutations in the insulin receptor gene (type B insulin resistance) or circulating antibodies blocking insulin receptor binding (type A insulin resistance) develop severe insulin resistance, acanthosis nigricans, and glucose intolerance. In addition to receptor downregulation, impaired intrinsic activity of the insulin receptor tyrosine kinase contributes to insulin resistance in humans and patients with type 2 diabetes mellitus (T2DM), through various regulatory and pathophysiologic processes. The number and functional activity of insulin receptors are essential for effective insulin action.
Patient self-titration of insulin is more effective than waiting for a physician visit and involves the patient in their own care. When patients can no longer maintain adequate glycemic control despite having fasting glycemia in a desirable range, or if their fasting control is erratic, meal insulin may be added at dinner or the largest meal based on weight (0.1 units/kg) or an arbitrary low dose, with upward titration based on 2-hour post-prandial glucose levels. Overuse of basal insulin alone can cause serious overnight hypoglycemia, and when there is a history of overnight or early morning hypoglycemia, testing post-prandial control becomes important. A unit-for-unit trade-off between meal insulin and basal insulin is often necessary to minimize nocturnal hypoglycemia by decreasing basal insulin as meal insulin increases.
Classic symptoms of diabetes include polyuria, thirst, blurred vision, paresthesia, and fatigue, which result from hyperglycemia and osmotic diuresis. However, many individuals with Type 2 diabetes experience an insidious onset and may initially be asymptomatic, especially obese patients, in whom diabetes may be detected through routine laboratory tests. Chronic skin infections are common, and women may present with generalized pruritus or symptoms of vaginitis as initial complaints.
Patients with type 2 diabetes mellitus (T2DM) and advanced nephropathy experience reduced renal outcomes when treated with angiotensin receptor blockers (ARBs). In the RENAAL study, losartan reduced the risk of doubling serum creatinine, end-stage renal disease (ESRD), or death by 16% compared to placebo. Similarly, irbesartan showed a 20% reduction in these outcomes compared to placebo and a 23% reduction compared to amlodipine, highlighting the protective effects of ARBs in managing nephropathy in T2DM patients.
High glucose levels in mouse kidney endothelial cells increase methylglyoxal modification of the corepressor mSin3A, leading to greater recruitment of O-GlcNAc-transferase and subsequent O-linked N-acetylglucosamine modification of Sp3. This modification reduces Sp3's ability to bind to a glucose-responsive GC-box in the Ang-2 promoter, resulting in elevated Ang-2 expression. Increased Ang-2 expression under high glucose conditions raises the levels of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in both cells and kidneys of diabetic mice, making microvascular endothelial cells more susceptible to the pro-inflammatory effects of tumor necrosis factor α (TNF-α).
Thiazide-induced dysglycaemia has been associated with hypokalaemia, as potassium loss may impair insulin release from pancreatic beta cells, leading to hyperglycaemia. Analysis of intervention trials using thiazides showed an inverse relationship between potassium balance and blood glucose levels, with a modest average increase in glucose of 7.07±7.38 mg/dl (0.4±0.4 mmol/l). In the SHEP trial, a 0.5 mEq/l (0.5 mmol/l) decrease in serum potassium was linked to a 45% increased risk of incident diabetes (95% CI 24% to 70%, p<0.001), though this association was only observed during the first year of treatment with chlortalidone. A more recent subgroup analysis found no correlation between fasting serum glucose and potassium levels in individuals with hypertension receiving hydrochlorothiazide alone or in combination with atenolol.
Increased vascular superoxide production, mediated by elevated NAD(P)H oxidase activity and expression of its subunits, contributes to oxidative stress in diabetes, particularly in atherosclerotic conditions. This oxidative stress is further indicated by increased nitrotyrosine staining in diabetic plaques. Reductions in vascular superoxide through interventions like PPAR-α and PPAR-γ agonists correlate with decreased plaque formation, highlighting the role of oxidative stress in diabetic atherosclerosis. Deletion of the antioxidant enzyme Gpx1 in the vascular wall exacerbates plaque development in diabetes through increased inflammation, while treatment with a Gpx1 analog, ebselen, reduces oxidative stress and atherosclerosis in diabetic mice. Additionally, upregulation of RAGE in Gpx1-deficient diabetic mice links vascular RAGE expression to heightened oxidative stress and accelerated atherosclerosis in diabetes.
In patients with overt type 2 diabetes, a possible practical algorithm for the diagnosis and monitoring of non-alcoholic fatty liver disease (NAFLD) involves assessing alanine transaminase levels, using the Enhanced Liver Fibrosis (ELF) score, and applying the Fibrosis-4 (FIB-4) index.
Technology and innovations can significantly impact diabetes care in low- and middle-income countries (LMICs) by improving data collection, education, and service delivery. Implementing new information technologies allows LMICs to make evidence-based decisions, provided data collection, analysis, and interpretation are systematic and ideally automated. Digital health strategies, such as decision support tools, text message reminders with health education, and automated monitoring with self-care support calls, are accessible through mobile phones, which are widely available even in resource-limited settings. These technologies enhance diabetes outcomes, including improved HbA1c levels, and provide patients with a sense of support. Telehealth has also proven valuable, particularly during the COVID-19 pandemic, in managing diabetes and addressing healthcare specialist shortages. Electronic records further support health systems in LMICs by facilitating data collection and improving the use of that data to enhance care quality.
LADA is considered an intermediary form between type 1 diabetes and type 2 diabetes, sharing genetic similarities with both. The HLA locus, which accounts for 50% of the genetic susceptibility to type 1 diabetes, shows similar associations with LADA, though with some differences. The type 1 diabetes variant PTPN22 has a weak association with LADA, while data on INS class I VNTRs have been inconclusive, with associations reported for both type 1 diabetes and type 2 diabetes—short tandem repeats linked to type 1 diabetes and long repeats to type 2 diabetes. The TCF7L2 gene variant, strongly associated with type 2 diabetes, is clearly linked to LADA but not to type 1 diabetes, indicating that LADA is a genetic admixture of both types. Understanding the genetic differences and heterogeneity among diabetes types can help clarify the underlying mechanisms of phenotypic variation and support the development of individualized therapies.
Amylin inhibits glucagon secretion in rats following an arginine infusion in a dose-dependent manner, but it does not suppress glucagon release in the isolated perfused pancreas, suggesting that its ability to inhibit glucagon secretion depends on extrapancreatic pathways. Amylin also delays gastric emptying, and dose-response studies have demonstrated that amylin is more potent in this respect than other gastrointestinal hormones. However, the ability of amylin to slow gastric emptying is overridden by hypoglycemia. Additionally, amylin reduces food intake and body weight in rodents, with the inhibitory effect on food intake present after both intracerebral and peripheral administration, appearing to be mediated mainly via central pathways that include high affinity binding sites in the area postrema in the hindbrain.
α-Glucosidase inhibitors delay carbohydrate digestion by competitively inhibiting α-glucosidase enzymes in the intestinal brush border, preventing the breakdown of disaccharides and oligosaccharides into monosaccharides, which leads to a delayed and more distal glucose absorption. Different inhibitors have varying affinities for specific α-glucosidase enzymes, resulting in slightly different activity profiles, such as acarbose having the highest affinity for glycoamylase, sucrase, maltase, and dextrinases, while miglitol is a stronger inhibitor of sucrase. These agents are only effective when complex digestible carbohydrates are consumed and do not significantly affect the absorption of glucose itself. By shifting glucose absorption more distally in the intestine, α-glucosidase inhibitors may alter the release of glucose-dependent intestinal hormones like GIP and GLP-1, with GIP release being reduced and GLP-1 secretion increased. These effects likely contribute to the reduced postprandial insulin concentrations observed with the use of α-glucosidase inhibitors due to the attenuated rise in postprandial glucose levels.
Diabetes is associated with an increased risk of infections due to multiple disturbances in innate immunity, including impaired phagocytosis by neutrophils, macrophages, and monocytes, as well as impaired neutrophil chemotaxis and bactericidal activity, and compromised innate cell-mediated immunity, while humoral immunity remains largely unaffected. Vascular disease in diabetes can hinder immune response expression and microcirculation function, contributing to severe infections such as malignant otitis externa, emphysematous pyelonephritis, and necrotizing fasciitis. Other predisposing factors include obesity, impaired kidney function, congestive heart failure, stroke, peripheral artery disease, and sensory neuropathy, and better blood glucose regulation generally improves cellular immunity and reduces severe infection incidence. Certain life-threatening infections like rhinocerebral mucormycosis, Fournier gangrene, and emphysematous cystitis occur almost exclusively in people with diabetes. Increased skin and mucosal carriage of Staphylococcus aureus and Candida spp. raises infection risk, and some microorganisms, such as certain Klebsiella serotypes and Burkholderia pseudomallei, become more virulent in high-glucose environments. Diabetes increases the risk of tuberculosis approximately threefold, leads to more frequent urinary tract infections and asymptomatic bacteriuria due to autonomic neuropathy, and makes skin and soft tissue infections more common, particularly in the diabetic foot, which is influenced by peripheral artery disease and neuropathy. Skin infections or genital infections can be initial presentations of diabetes, and diabetes predicts worse outcomes from coronavirus infections like Covid-19, with patients being 2–3 times more likely to experience adverse outcomes including death. Viral infections such as hepatitis C are linked to a higher prevalence of diabetes, and highly active antiretroviral therapy for HIV/AIDS may also precipitate diabetes.
Improved control of hypertension is likely to reduce the risk of renal disease in patients with type 1 diabetes mellitus (T1DM), although no trials have directly addressed this. Trials have explored the use of renin angiotensin system (RAS) inhibitors in T1DM patients with normal urine albumin excretion and blood pressure. The EUCLID study found that lisinopril reduced urine albumin excretion over 2 years compared to placebo, but the clinical significance of the small difference (1 μg/min) is uncertain. The DIRECT study showed that candesartan at 32 mg/day for 4.7 years did not prevent microalbuminuria in patients with T1DM.
Metformin, sulfonylureas, pioglitazone, gliptins, GLP-1 receptor agonists, and SGLT-2 inhibitors are classes of non-insulin therapies used in diabetes management, each with varying risks of hypoglycaemia when used as monotherapy, where sulfonylureas carry a moderate risk, and gliptins, GLP-1 receptor agonists, and SGLT-2 inhibitors have a low or no risk. Metformin should be withdrawn if creatinine exceeds 150 mmol/l or eGFR falls below 30 ml/1.73 m², and its use should be reviewed in the presence of gastrointestinal disease or symptoms. Sulfonylureas require dose review if renal or liver function deteriorates, with a potential switch to tolbutamide, and tolbutamide dose should also be adjusted if liver function declines. Pioglitazone should only be prescribed when benefits clearly outweigh risks, especially in individuals with terminal disease, and it should be avoided in those with or at risk of bladder tumour or heart failure. Gliptins require dose adjustment according to renal function, some can be used across all stages of renal disease, and their combination with sulfonylureas increases the risk of hypoglycaemia. GLP-1 receptor agonists need dose review with significant weight loss or development of abdominal pain or pancreatitis. SGLT-2 inhibitors should be stopped in cases of clinical dehydration, peripheral vascular disease, foot ulceration, acute illness, or pre-surgery, with ketone testing recommended during acute illness and individual product guidelines should be followed for renal considerations.
Selective inhibitors of $11\beta$-hydroxysteroid dehydrogenase-1 ($11\beta$-HSD1) have been shown to improve insulin sensitivity, glycemic control, and plasma lipids in obese-diabetic rodents, suggesting a potential therapeutic role in diabetes management. Since $11\beta$-HSD1 is expressed by pancreatic $\beta$-cells and excess glucocorticoids are linked to islet hypertrophy, the effects of these inhibitors on $\beta$-cell function require further evaluation.
In chronic kidney disease (CKD), red blood cell turnover abnormalities can make HbA1c results misleading, as one study showed a decrease in HbA1c by approximately 1% (11 mmol/mol) when hemoglobin levels increased from 10.6 to 11.8 g/dL with erythropoietin treatment. Due to these inaccuracies, diabetes management in CKD should prioritize self-monitoring of blood glucose and continuous glucose monitoring. Additionally, albumin turnover abnormalities complicate the interpretation of fructosamine levels.
GLP-1 receptor agonists (GLP-1RAs) have demonstrated a protective effect on renal outcomes in diabetes, including a reduction in a composite renal outcome encompassing macroalbuminuria, doubling of serum creatinine, a decline in estimated glomerular filtration rate (eGFR), kidney replacement therapy, or kidney disease-related death. This effect appears primarily driven by a decrease in macroalbuminuria, although their role in delaying worsening kidney function and progression to dialysis remains uncertain. A sensitivity analysis excluding the ELIXA trial showed a significant 18% reduction in worsening kidney function, defined as doubling of serum creatinine or a ≥40% decline in eGFR, with GLP-1RA treatment.
Gliptins are DPP-4 inhibitors that enhance incretin levels by preventing the degradation of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), thereby enhancing endogenous incretin activity. Incretin hormones, secreted from the intestine during meal digestion, increase glucose-induced insulin secretion by pancreatic islet β-cells, reducing prandial glucose excursions. GLP-1 also suppresses glucagon secretion from islet α-cells. Incretin mimetics like exenatide and liraglutide are used therapeutically in diabetes management.
Adherence to diabetes management components varies, with 69% following a diet, less than half engaging in regular exercise, and self-monitoring of blood glucose ranging from 53% to 70%. Only 7% of patients adhere to all aspects of the treatment regimen, over half make errors with insulin dosage, and three-quarters are judged to be in an "unacceptable" category regarding meal quality, quantity, and timing.
Elevated circulating MBL levels are associated with increased urinary albumin excretion in individuals with type 1 diabetes, even within the normal range of excretion, and are higher in those with microalbuminuria or macroalbuminuria compared to those with normoalbuminuria. Certain MBL genotypes linked to high circulating MBL are associated with a 50% increased risk of developing diabetic nephropathy and higher mortality over 10 years in people with type 1 diabetes. Serum MBL measured soon after diabetes onset can predict the development of microalbuminuria over 18 years. While some studies support a role for MBL in the progression of renal disease to end-stage renal disease in type 1 diabetes, one study found no association between 19 MBL SNPs and the presence of type 1 diabetes or nephropathy, and the reason for this discrepancy remains unclear.
The diagnostic criteria for diabetes and impaired glucose tolerance are based on epidemiological evidence linking microvascular complications to specific levels of hyperglycaemia, with adjustments made to fasting glucose thresholds as new data emerged. In 1999, the fasting glucose threshold for diagnosing diabetes was lowered from 7.8 mmol/l (140 mg/dl) to 7.0 mmol/l (126 mg/dl), and a fasting glucose level between 6.1 and 6.9 mmol/l (111–125 mg/dl) was classified as pre-diabetic, termed impaired fasting glucose. Further reductions in the normal fasting glucose level to 5.6 mmol/l (100 mg/dl) increased the number of individuals categorized as having pre-diabetes. Impaired glucose tolerance, another pre-diabetic state identified through oral glucose tolerance testing, is defined by post-load glucose levels of 7.8–11.0 mmol/l (140–199 mg/dl), and it is estimated that approximately 541 million people or 10.6% of those aged 20–79 years have this condition.
In young people with type 1 diabetes, hypertension is strongly associated with renal damage and even minor degrees of proteinuria, with blood pressure rising as urinary albumin excretion (UAE) reaches the microalbuminuric range (>30 mg/24h) and typically exceeding the WHO threshold during the macroalbuminuric stage (>300 mg/24h). This association may be partly genetic, as individuals with diabetes and microalbuminuria often have parents with hypertension and may inherit increased activity of the cell membrane Na⁺–H⁺ pump, indicated by elevated Na⁺–Li⁺ countertransport in red blood cells, leading to higher intracellular Na⁺ levels and increased vascular smooth muscle tone.
Close surveillance by an experienced obstetrician is necessary for women with diabetes during pregnancy due to increased risks of preterm delivery, large-for-gestational-age (LGA) infants, and perinatal mortality. The timing and mode of birth should be discussed during antenatal appointments, with an individualized approach considering fetal well-being, estimated size, glycaemic management, diabetes complications, and past obstetric history. According to NICE guidelines, women with type 1 diabetes should be offered elective delivery between 37 weeks and 38 weeks plus 6 days gestation, unless significant complications arise earlier, in which case delivery before 37 weeks should be considered.
Pentamidine, a drug used to treat Pneumocystis jirovecii infection in patients with AIDS, is related to the diabetogenic drug alloxan and can cause destruction of beta cells, leading to initial insulin release and transient hypoglycemia followed by diabetes. This effect is more common with intravenous administration but can also occur with inhaled aerosol. In a study of 128 AIDS patients treated with pentamidine, nearly 40% developed glucose homeostasis abnormalities, including hypoglycemia alone (5%), hypoglycemia followed by diabetes (15%), and diabetes alone (18%). Risk factors for these abnormalities included higher pentamidine doses, elevated plasma creatinine, and severe anoxia.
In healthy individuals, pancreatic-derived insulin acts directly on the liver via the portal circulation, where it suppresses hepatic glucose production, particularly in the fasting state. Between 50% and 80% of insulin is metabolized by the liver, resulting in lower insulin levels entering the systemic circulation. Peripheral tissues like muscle take up glucose at higher insulin concentrations, which typically occur postprandially. However, subcutaneous insulin administration delivers insulin into the systemic circulation, leading to relatively lower levels reaching the liver. This reduced hepatic exposure results in less suppression of glucose production by the liver and preferential glucose uptake by muscle and adipose tissue, complicating the management of blood glucose and body weight in diabetes.
Mental health professionals trained in diabetes should be involved in patient and family care to assess psychosocial functioning and support the diabetes team in managing mental health issues. Access to psychiatrists should be available for cases involving severe mental health conditions and the possible use of psychotropic medications. Consistent contact between diabetes care providers and patients is important, and overall quality of life, including emotional and social development, should be regularly monitored. Assessments should evaluate a patient's ability to manage diabetes, particularly during late childhood and before adolescence, including their knowledge, insulin adjustment, goal-setting, problem-solving, adherence, and self-care skills. Patients who struggle with HbA1c targets or experience frequent severe hypoglycemia or diabetic ketoacidosis (DKA) should be evaluated for depression, eating disorders, or other psychiatric conditions, which should be addressed if present. Family dynamics, including communication and shared responsibilities for diabetes care, should be assessed, especially when cultural or language barriers exist. Parents should receive training in behavior management, particularly around diagnosis and prior to adolescence, focusing on support, problem-solving, and realistic expectations. Motivational interviewing may help when discussing intensified insulin regimens, aiding in goal clarification and resolving reluctance. Adolescents should gradually take on more diabetes care responsibilities while maintaining agreed-upon parental support, and the transition to adult diabetes care should be planned well in advance through collaboration between the adolescent, parents, and the diabetes team.
In type 2 diabetes mellitus (T2DM), experimental studies suggest that RAS inhibitors reduce atherosclerosis, with possible superiority of ACE inhibitors over ARBs; however, human studies have not conclusively demonstrated clear superiority of one antihypertensive class over another. The ONTARGET study found no difference in cardiovascular outcomes between ACE inhibitors and ARBs, and dual RAS blockade did not provide additional cardiovascular benefit, instead leading to more adverse events. Only 30% of participants in the ONTARGET study had diabetes, and no specific subgroup analysis has been reported, leaving uncertainty about the optimal RAS-blocking strategy for microvascular and macrovascular outcomes in diabetes.
Gabapentin and pregabalin are used to treat painful diabetic neuropathy, a complication of diabetes. Gabapentin, an anticonvulsant structurally related to GABA, provides at least moderate pain relief in 60% of patients with diabetes at a dose of 3600 mg/day, compared to 33% on placebo, though common adverse effects include dizziness and somnolence. Pregabalin, which has a sixfold higher binding affinity to the α2-δ subunit of voltage-activated calcium channels, shows response rates of 46%, 39%, and 27% for 600 mg/day, 300 mg/day, and 150 mg/day doses respectively, with a number needed to treat of 4.2, 5.9, and 20.0. Common side effects of pregabalin include dizziness, somnolence, peripheral edema, headache, and weight gain. Pregabalin has more solid evidence of efficacy and easier dose titration compared to gabapentin in managing painful diabetic neuropathy.
Sulfonylureas and non-SU rapid secretagogues lower HbA1c by 1.0–2.0%, have a strong pre-prandial and mild post-prandial effect, act as direct or indirect insulin secretagogues, and are associated with hypoglycemia and weight gain. Biguanides reduce HbA1c by 1.0–2.0%, primarily lower pre-prandial glucose, decrease hepatic glucose output, and may cause gastrointestinal side effects, lactic acidosis, and are weight neutral. Thiazolidinediones lower HbA1c by 0.5–1.6%, mainly affect pre-prandial glucose, increase muscle insulin sensitivity, and can lead to edema and congestive heart failure. Incretin agonists reduce HbA1c by 0.9–1.1%, have mild pre-prandial and stronger post-prandial effects, exert strong GLP-1 effects, stimulate insulin, suppress glucagon, and commonly cause nausea, vomiting, and weight loss. DPP-4 inhibitors lower HbA1c by 0.6–0.8%, have mild pre-prandial and moderate post-prandial effects, provide moderate GLP-1 activity, increase insulin and decrease glucagon, and are associated with nausea and neutral weight effects. Insulin lowers HbA1c by 1.5–2.5%, strongly affects pre-prandial glucose, reduces hepatic glucose output, and is linked to weight gain and hypoglycemia.
In individuals with type 1 diabetes and renal failure, preoperative serum MBL levels predict graft and patient survival, with lower MBL levels linked to better outcomes. In those with type 1 diabetes and diabetic nephropathy, successful simultaneous pancreas-kidney transplantation leads to normalization of circulating MBL, particularly in individuals with a polymorphism in the MBL2 gene, whereas kidney transplantation alone does not normalize MBL levels. This suggests that glycaemia, rather than the reversal of end-stage renal disease, is associated with decreased MBL, a finding supported by the correlation between MBL levels and glucose and HbA1c, but not serum creatinine or eGFR.
Diuretics can be effective antihypertensive agents for people with diabetes who have increased total body sodium and expanded extracellular fluid volume, but certain diuretics that cause potassium and magnesium loss may worsen hyperglycemia by impairing insulin secretion and reducing insulin sensitivity. High-dose thiazide diuretics, such as ≥5 mg/day bendroflumethiazide, are associated with up to a threefold increased risk of developing diabetes in hypertensive patients, an effect not seen with lower doses (up to 2.5 mg/day). Potassium depletion varies among diuretics, being most severe with chlortalidone and less so with furosemide and bendroflumethiazide, while indapamide has negligible effects. This mechanism is not relevant in individuals with type 1 diabetes who are C-peptide negative and dependent on exogenous insulin. Thiazides may also aggravate dyslipidemia, though low doses likely pose minimal risk, and they are linked to gout and impotence, leading to their avoidance in middle-aged men with diabetes and hyperuricemia or erectile dysfunction. Diuretics should be used cautiously or at the lowest effective dose in patients with a history of hyperosmolar hyperglycemic syndrome as they may precipitate this condition.
In the UKPDS, intensive glucose management leading to a mean $\mathrm{HbA_{1c}}$ of 7.0% (53 mmol/mol) compared to 7.9% (63 mmol/mol) in less strictly managed patients reduced the relative risk of microalbuminuria and proteinuria by approximately 30% over 9–12 years, with no significant differences between specific glucose-lowering therapies. Similar to the DCCT, no threshold for $\mathrm{HbA_{1c}}$ and complication risk was observed, indicating that lower $\mathrm{HbA_{1c}}$ levels correspond to lower nephropathy risk, with a 1% (11 mmol/mol) reduction in $\mathrm{HbA_{1c}}$ associated with a 37% decrease in microvascular complication risk. Long-term follow-up of the UKPDS cohort showed that despite $\mathrm{HbA_{1c}}$ levels becoming similar between previously intensively and conventionally managed groups after one year, the risk of microvascular complications remained lower, supporting the concept of "metabolic memory" as seen in the DCCT/EDIC study.
In diabetes, elevated glucose levels contribute to the formation of advanced glycation end products (AGEs), which originate from early glycation products known as Schiff bases that convert into more stable Amadori products such as 1-amino-1-deoxyfructose derivatives. These Amadori products undergo further enzymatic changes, producing reactive intermediates like 3-deoxyglucosone and methylglyoxal. Methylglyoxal reacts with amino, sulfhydryl, and guanidine groups in proteins, leading to protein damage through browning, denaturation, and redox-active cross-linking between lysine residues. It also generates hydroimidazolones, $N^{\epsilon}$ (carboxyethyl)lysine, a homologue of carboxymethyllysine (CML), and methylglyoxal-lysine dimer. AGE-based cross-links are resistant to enzymatic breakdown, making them highly stable. The rate of AGE formation is influenced by glucose concentration, oxidative stress levels, and the duration of exposure to these conditions.
Treatment of mild hyperglycaemia reduces fetal growth and the proportion of infants born large for gestational age (LGA), although it is uncertain if infants who are small or appropriate for gestational age benefit from such treatment. A study involving Hispanic women with mild hyperglycaemia, defined as fasting glucose less than 5.8 mmol/l, and fetal abdominal circumference above the 75th centile compared diet therapy alone to diet combined with twice-daily insulin, aiming for a fasting glucose target of 4.4 mmol/l and a two-hour post-prandial glucose below 6.1 mmol/l. The study found that the LGA rate was significantly higher in the diet-only group at 45%, compared to 13% in the insulin-treated group. Additionally, the diet-treated group experienced a reduction in initial abdominal circumference below the 75th centile in 14% of cases. Concerns remain that overtreatment might lead to growth-retarded babies.
Elevated very low-density lipoproteins (VLDLs), triglycerides (TAGs), and fatty acids predict type 2 diabetes and cardiovascular mortality. Excess lipid storage, especially in the form of obesity, is linked to insulin resistance, though intramuscular and intramyocellular TAG content shows an even stronger association with muscle insulin resistance than overall body fat. Increased intramyocellular TAG concentrations, measurable non-invasively by 1H NMR spectroscopy, are referred to as ectopic lipid accumulation or metabolic obesity, and their presence in insulin-resistant states suggests that intracellular TAGs or lipid metabolites may mediate the effects of circulating lipids on insulin action. Randle's glucose-fatty acid cycle hypothesis proposed that fatty acid oxidation impairs glucose metabolism by inhibiting the pyruvate dehydrogenase complex, leading to reduced glucose utilization. However, more recent studies using 13C/31P NMR spectroscopy show that lipid-induced muscle insulin resistance in humans primarily results from reduced insulin-stimulated glucose transport into muscle cells, followed by impaired glucose phosphorylation and decreased glycogen synthesis, rather than inhibition of the pyruvate dehydrogenase complex. Some studies suggest that lipid-induced insulin resistance may be more pronounced in men than in women, potentially explaining the higher diabetes risk observed in men.
GLP-1 is a key incretin hormone that enhances the insulin response to enteral glucose and plays a role in glucose homeostasis through several mechanisms, including potentiation of insulin release, reduced glucagon release, increased satiety, and delayed gastric emptying, all of which are relevant to diabetes. GLP-1 is rapidly inactivated by DPP-4, and this process can be inhibited by DPP-4 inhibitors, which prolong the activity of endogenous GLP-1. GLP-1 receptor agonists, which are modified analogues of native GLP-1 to resist DPP-4 degradation, are used in the treatment of type 2 diabetes.
Rosiglitazone has been evaluated for cardiovascular safety in two studies: the RECORD trial and the BARI 2D trial. In the BARI 2D trial, 2368 patients with type 2 diabetes mellitus (T2DM) and heart disease were assigned to either prompt revascularization with intensive medical therapy or intensive medical therapy alone, and also to either insulin-sensitization or insulin-provision therapy. Over 5 years, survival rates were similar between revascularization (88.3%) and medical therapy (87.8%), as well as between insulin-sensitization (88.2%) and insulin-provision (87.9%). Freedom from major cardiovascular events, including death, myocardial infarction, or stroke, also did not differ significantly between groups. Severe hypoglycemia occurred more frequently with insulin-provision (9.2%) compared to insulin-sensitization (5.9%).
Various oral agents are used in diabetes management, each acting through distinct mechanisms: metformin and thiazolidinediones improve insulin resistance, sulfonylureas, meglitinides, and DPP-4 inhibitors enhance insulin secretion with differing time courses and mechanisms, SGLT-2 inhibitors promote renal glucose excretion, and α-glucosidase inhibitors delay carbohydrate digestion. GLP-1 receptor agonists also increase insulin secretion and reduce glucagon levels. When glycemic targets are not met or maintained, timely progression to the next therapeutic step is crucial to prevent prolonged hyperglycemia, with insulin being an option when other treatments are ineffective or inappropriate. Effective diabetes care requires integrated management of cardiovascular risk and comorbidities, along with continuous glucose monitoring and careful therapeutic adjustments to ensure efficacy, safety, and avoidance of hypoglycemia. Early and sustained glycemic control is vital to reduce the risk of long-term complications.
GLP-1 receptor agonists (GLP-1RAs) improve glycemic control with varying potencies, with subcutaneous semaglutide being the most effective in lowering HbA1c levels, while shorter-acting agents like lixisenatide have lesser glycemic benefits. These medications carry a low risk of hypoglycemia due to their glucose-dependent insulin secretion and preservation of glucagon response during low blood glucose. When initiating GLP-1RAs, dose adjustments of other hypoglycemia-inducing diabetes medications such as insulin, sulfonylureas, or meglitinides may be needed. In addition to glycemic control, GLP-1RAs promote weight loss, partly by slowing gastric emptying and acting on hypothalamic appetite centers to increase satiety. Notably, liraglutide 3.0 mg daily and semaglutide 2.4 mg once weekly are approved for weight management in adults with obesity or overweight, regardless of type 2 diabetes status.
MODY (Maturity-Onset Diabetes of the Young) is a form of diabetes often characterized by mild fasting hyperglycaemia, with certain types, such as GCK-MODY, not necessarily requiring treatment. MODY caused by HNF4α and HNF1α mutations shows sensitivity to sulfonylureas and also responds well to incretin-based therapies, including dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists. However, many individuals with transcription factor MODY may eventually need insulin due to progressive β-cell failure, which can result from delayed diagnosis, long disease duration, and ongoing glucolipotoxicity and inflammation leading to suboptimal glycaemic control.
Higher blood glucose ranges, such as 180–270 mg/dL (10–15 mmol/L) or up to 360 mg/dL (20 mmol/L), have been proposed for certain situations, but the latter may increase the risk of ketoacidosis in type 1 diabetes and hyperosmolar states in type 2 diabetes. A recommended glycaemic target range of 6–15 mmol/L (108–270 mg/dL) is suggested to avoid both hypoglycaemia and hyperglycaemia, particularly in individuals in their last year of life. For those with type 2 diabetes nearing the end of life, the frequency of daily capillary blood glucose tests should decrease along with reduction or discontinuation of diabetes medications. However, individuals with type 1 diabetes must continue insulin use until death to prevent diabetic ketoacidosis, and blood glucose testing should continue at least daily to monitor for significant hypoglycaemia or hyperglycaemia. Continuous glucose monitoring systems may be beneficial in some cases due to their less invasive nature.
Adipose tissue produces various autocrine, paracrine, and endocrine factors such as free fatty acids (FFA), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP1), plasminogen activator inhibitor 1 (PAI-1), prostaglandin E2 (PGE2), retinol-binding protein 4 (RBP4), and C-reactive protein (CRP), which influence insulin action, metabolic control, and vascular, inflammatory, and immune processes that can affect diabetic control.
Antiretroviral therapy, particularly regimens containing protease inhibitors (PI), is associated with an increased risk of diabetes due to a direct inhibitory effect on cellular glucose transport. Even in individuals receiving PI-sparing regimens, diabetes prevalence is elevated, possibly due to nucleoside analogue-induced mitochondrial toxicity. Discontinuation of PI has limited benefit in reversing lipodystrophy but may improve glucose levels in diabetes, and altering thymidine analogue nucleoside reverse transcriptase inhibitors may help with lipodystrophy. In HIV-infected individuals starting antiretroviral therapy, higher levels of inflammatory markers such as high-sensitivity C-reactive protein, soluble tumor necrosis factor receptor (sTNFR)-1, and sTNFR2 are linked to an increased diabetes risk, suggesting that HIV-related inflammation contributes to insulin resistance.
In type 2 diabetes mellitus (T2DM), the ability of glucose to regulate its own metabolism is impaired, a defect referred to as reduced "glucose effectiveness." Normally, an increase in plasma glucose stimulates glucose uptake and suppresses glucose production, especially in the presence of basal insulin concentrations. However, in individuals with T2DM, an intravenous infusion of 35g of glucose results in severe hyperglycemia compared to those without diabetes, despite insulin concentrations being clamped at basal levels. This excessive rise in blood glucose is primarily due to impaired glucose-induced stimulation of glucose uptake, while glucose-induced suppression of glucose production remains normal.
The CEMACH audit evaluated 3808 pregnancies among women with type 1 diabetes (T1DM) and type 2 diabetes (T2DM), finding similar rates of perinatal mortality, stillbirth, neonatal mortality, and congenital anomalies between the two groups. However, notable differences were observed in pre-pregnancy planning, obesity, social deprivation, risks of recurrent and severe hypoglycemia, and retinopathy, which can influence clinical care before and after pregnancy. A very small percentage (0.73%) of the pregnancies involved women with maturity-onset diabetes of the young (MODY) or other or unknown causes of diabetes.
The introduction of PD-1 and PDL-1 inhibitors as immune checkpoint inhibitors for treating cancer has been associated with autoimmune reactions, including the development of type 1 diabetes. A systematic review and meta-analysis reported 71 cases of type 1 diabetes onset following immune checkpoint inhibitor therapy. The average age of affected individuals was 61.7 years, with 55% being men and melanoma as the most common underlying cancer (53.5%), followed by lung, head and neck, renal cell, and urothelial carcinomas. The median time to diabetes onset was 49 days, with 76% presenting with diabetic ketoacidosis (DKA). At diagnosis, the mean HbA1c was 7.8% (62 mmol/mol), all individuals had insulin deficiency requiring permanent exogenous insulin, and half of them tested positive for autoantibodies linked to type 1 diabetes. Those with autoantibodies experienced a more rapid onset and higher incidence of DKA compared to those without.
Psychologic problems in patients with diabetes can be effectively addressed through direct questioning and timely referral to mental health professionals experienced in diabetes-related issues. While some argue that physicians should diagnose and treat emotional disorders in diabetes patients, this approach is often impractical due to limited expertise and time. Integrating mental health specialists such as psychologists, psychiatrists, or social workers into the diabetes treatment team offers a more effective solution, as demonstrated by the success of the DCCT in maintaining low levels of psychopathology and high quality of life among patients.
DPP-4 inhibitors such as sitagliptin are predominantly renally excreted, requiring possible dose reduction, whereas vildagliptin is considered safe as it is not renally excreted. GLP-1 analogs like exenatide are renally excreted and contraindicated in end-stage renal disease (ESRD), while liraglutide is likely safe due to its non-renal excretion pathway.
Brain structure anomalies detected via MRI have been documented in children with diabetes, particularly those with early onset, showing elevated rates of mesial temporal sclerosis—a rare brain anomaly. In one study, 16% of children with early-onset diabetes exhibited this anomaly compared to less than 1% in the general pediatric population, with the anomalies developing within a short timeframe, on average within 7 years of diabetes onset, and without a link to prior hypoglycemia.
Norepinephrine, the major sympathetic neurotransmitter, influences hormone secretion in the islets through interactions with adrenoreceptors on $\beta$-cells and $\alpha$-cells, potentially affecting diabetes-related processes. It can stimulate insulin secretion via $\beta_2$-adrenoreceptors or inhibit it via $\alpha_2$-adrenoreceptors, with the net effect depending on the relative expression of these receptor subtypes. In human islets, $\beta$-adrenergic agonists are stimulatory, whereas in rodent islets they are ineffective, likely due to species differences in receptor expression. The stimulatory effects of $\beta_2$-receptors involve activation of adenylate cyclase and increased intracellular cyclic AMP, while $\alpha_2$-receptor activation inhibits secretion by reducing cyclic AMP, cytosolic calcium, and through an unidentified mechanism in the stimulus-secretion coupling. Additionally, norepinephrine stimulates glucagon secretion from $\alpha$-cells via both $\beta_2$ and $\alpha_2$-receptors. Circulating catecholamines like epinephrine can also modulate islet hormone secretion through these receptors, potentially influencing glucose homeostasis and diabetes pathophysiology.
Lifestyle intervention and metformin have been shown to slow the progression to type 2 diabetes mellitus (T2DM) in women with a history of gestational diabetes mellitus (GDM). A subanalysis of the Diabetes Prevention Program (DPP) found that among women with prior GDM, those receiving intensive lifestyle or metformin treatment had a 55% and 51% lower risk, respectively, of progressing to diabetes within 3 years compared to those on placebo. In parous women without a history of GDM, the risk reductions were 49% for lifestyle intervention and 14% for metformin. These findings suggest that women with a history of GDM are particularly responsive to the protective effects of metformin. Additionally, it was estimated that treating five to six women with a history of GDM and impaired glucose tolerance (IGT) with metformin or lifestyle intervention for 3 years could prevent one case of diabetes.
Sleep deprivation and fragmentation are associated with metabolic hormone dysregulation, reduced GLP-1 levels, lower satiety, higher energy intake, and reduced insulin sensitivity, all of which can contribute to weight gain and potentially influence diabetes risk.
DPP-4 (dipeptidyl peptidase 4) is an enzyme that degrades GLP-1 (glucagon-like peptide-1), a hormone involved in glucose regulation by stimulating insulin secretion and suppressing glucagon release. SGLT (sodium-dependent glucose cotransporters), particularly SGLT2, play a role in glucose reabsorption in the kidneys, and their inhibition is a therapeutic target in diabetes management.
Ageing is associated with increased insulin resistance due to loss of skeletal muscle mass, which can be improved by combining protein intake with exercise training, leading to muscle hypertrophy and increased muscle strength and mass. A diet high in fibre and potassium and low in saturated fats, refined carbohydrates, and salt can help achieve ideal body weight, improve lipid profiles, lower blood pressure, and reduce cardiovascular risk. The Mediterranean diet, particularly with high intake of vegetables and fruits, is linked to reduced risk of frailty syndrome in older women with type 2 diabetes. Lifestyle interventions including modest weight reduction, a healthy low-fat diet, and regular exercise can prevent diabetes development, with long-lasting benefits especially in older individuals. Exercise also improves muscle strength and walking balance, while intensive lifestyle interventions, as shown in the Look AHEAD study, increase the likelihood of diabetes remission and enhance clinical outcomes. Additionally, combined exercise and nutrition interventions, as demonstrated in the FINGER study, positively affect cognitive function in older people with diabetes.
Environmental factors may trigger β-cell autoimmunity and accelerate the pathogenic process, leading to β-cell destruction mediated by cytotoxic CD8+ T cells. β-cell destruction may occur before β-cell autoimmunity, although the exact mechanism is unclear. The presence of multiple β-cell autoantibodies (≥2), especially when appearing within 6–12 months of the first autoantibody, significantly increases the risk of progressing to type 1 diabetes. In children with insulin or GAD autoantibodies, the appearance of autoantibodies against IA-2 or ZnT8 serves as a strong marker for accelerated progression to clinical type 1 diabetes. The rate and duration of β-cell destruction vary, influencing the time between the initial detection of autoantibodies and the clinical diagnosis of diabetes.
Higher blood glucose levels in the past can increase the risk of complications in individuals with diabetes, even if blood glucose is later controlled, as seen in the Diabetes Control and Complications Trial (DCCT), where conventional insulin therapy led to a higher incidence of diabetic retinopathy compared to intensive management, despite similar glycated haemoglobin (HbA1c) levels after the trial.
When basal insulin doses exceed 0.5 units/kg or when fasting glucose targets are met but HbA1c remains uncontrolled, insulin therapy should be intensified by adding prandial insulin to basal insulin. A starting prandial insulin dose of 4 units or 0.1 units/kg, equivalent to 10% of the basal insulin dose, is typically given at the largest meal of the day and can be increased by 1–2 units or 10–15% to achieve postprandial glucose targets. If HbA1c remains elevated, a transition to a basal-bolus regimen with multiple mealtime insulin injections may be necessary, often requiring a reduction in basal insulin to prevent hypoglycemia. Regular human insulin should be taken approximately 30 minutes before meals to align with postprandial glucose rises, whereas rapid-acting insulin analogues such as aspart, glulisine, and lispro have a faster onset within 15 minutes and quicker return to baseline levels. Newly approved faster-acting insulin aspart and ultra-rapid lispro offer even quicker absorption, earlier onset, and offset of action, more closely mimicking natural mealtime insulin secretion and potentially improving postprandial glucose control while reducing the risk of hypoglycemia.
Many older people with diabetes and critical or worsening limb ischemia, or ischemic ulcers that are slow to heal, will benefit from surgical revascularization such as angioplasty or arterial reconstruction. Appropriate cases should be referred early for surgery, ideally through joint protocols developed by the diabetes specialist and the vascular surgeon. A reasonable life expectancy is considered important by surgeons, as concomitant cardiac and cerebrovascular disease kill 50% of patients within 5 years. Following proximal arterial reconstruction, the 5-year patency averages 70% and may exceed life expectancy in patients with major co-morbidities; for distal reconstruction surgery, 5-year limb salvage rates approach 85%.
Exogenous glucagon has been used for nearly 50 years to treat hypoglycaemia in individuals with diabetes, while attempts to block glucagon action to lower blood glucose have also been explored for a similar duration. Mouse models with disrupted glucagon receptor function or absence of α-cell secretion show lower fasting glucose and improved glucose tolerance, indicating that long-term glucagon signaling blockade could effectively reduce diabetic hyperglycaemia. However, no drug that selectively blocks glucagon effects has been approved due to safety concerns and findings in pre-clinical models. These models show α-cell hyperplasia and elevated proglucagon-related peptides, along with increased pancreatic weight and reduced hepatic lipid oxidation, raising concerns about potential hepatic toxicity. In human trials, some GCGR antagonists have lowered fasting and post-prandial glucose in individuals with diabetes in a dose-responsive manner, making them promising candidates for diabetes treatment. Despite this, concerns about adverse effects such as α-cell hyperplasia, hepatic steatosis, and increased susceptibility to liver toxicity have prevented these compounds from advancing beyond the trial stage. Additionally, the impact of these agents on glucose counter-regulation requires further evaluation.
Different organizations provide specific target glucose levels for managing diabetes, focusing on fasting and post-prandial blood sugar levels; for instance, NICE recommends fasting glucose below 5.3 mmol/l, 1-hour post-prandial below 7.8 mmol/l, and 2-hour post-prandial below 6.4 mmol/l, while ADA and Diabetes Canada suggest similar but slightly varying targets, and ADIPS sets slightly stricter thresholds with fasting glucose at or below 5.0 mmol/l, 1-hour post-prandial at or below 7.4 mmol/l, and 2-hour post-prandial at or below 6.7 mmol/l.
Inflammatory processes are implicated in the development of type 2 diabetes mellitus (T2DM), with prospective studies showing that elevated plasma interleukin 6 (IL-6) levels increase T2DM risk, although findings on the association between the IL6 G174C promoter polymorphism and T2DM are conflicting. A large case-control study involving over 20,000 participants found that the IL6 promoter variant was linked to a reduced T2DM risk (OR 0.91, P = 0.037), and additional associations between T2DM and genetic variants such as IL6R-D358A in Danish white individuals and TNF G-308A promoter SNP in the Finnish Diabetes Prevention Study have also been reported. Furthermore, interactions between IL6 and IL6R variants and age in influencing T2DM risk were observed in a prospective study of a general French population.
Vitreous haemorrhage can be a presenting sign of retinopathy in individuals with diabetes, especially those not regularly followed in screening programs or those in whom retinal neovascularization has not regressed after photocoagulation. Sudden reduction in visual acuity due to vitreous haemorrhage necessitates referral to an ophthalmologist, and in cases where photocoagulation has not been performed, ultrasound B-scan is important to rule out retinal detachment and other conditions requiring surgery. Simple vitreous haemorrhages may resolve spontaneously over a few weeks, allowing subsequent photocoagulation, while non-resolving haemorrhages are treated with vitrectomy to remove vitreous opacities and enable retinal treatment. Vitrectomy may also benefit diabetic maculopathy by improving diffusion and facilitating oxygen and metabolite exchange. Both retinal photocoagulation and vitrectomy can lead to regression of new vessels in the iris and anterior chamber angle, though insufficient regression may necessitate treatment for neovascular glaucoma. The visual prognosis depends on the extent of retinal damage caused by the underlying retinopathy.
Acute hyperglycaemia delays gastric emptying in both healthy individuals and those with type 1 diabetes, potentially due to suppression of antral motility and migrating motor activity, although the effect is modest. Severe acute hyperglycaemia in type 1 diabetes prolongs gastric emptying half-time by only 17 minutes. Modulating blood glucose within the physiological postprandial range (4–8 mmol/l) can also delay gastric emptying to a lesser extent. Higher HbA1c levels are associated with more gastrointestinal symptoms and slower gastric emptying in people with diabetes. While strict glycaemic control improves neural, renal, and retinal functions, its effect on gastric emptying remains unclear, as studies show no improvement in gastric emptying following short-term or sustained glycaemic improvement in type 2 diabetes or suboptimally managed diabetes. Additionally, electrolyte imbalances from diabetic ketoacidosis, such as hypokalaemia, and uraemia may worsen motor dysfunction in diabetes.
SGLT-2 inhibitors, which are used in the management of diabetes, exert a glucosuric effect that increases the risk of genital infections, particularly vulvovaginal mycotic infections in women, especially during the initial months of therapy. There is also a small increased risk of urinary tract infections associated with these medications. The occurrence and severity of such infections can be mitigated with appropriate patient education at the start of therapy, and most infections respond to standard treatments, often managed by the patient themselves. The osmotic diuresis caused by glucosuria, typically less than 500 ml/day, necessitates patient attention to adequate hydration, particularly in hot climates, and this should be emphasized when initiating treatment. Additionally, a temporary decline in eGFR may occur after starting SGLT-2 inhibitors, so extra caution is advised for individuals on diuretic therapy, although clinical trials have not shown electrolyte imbalances with these drugs.
Rituximab was evaluated in a randomized, double-blind study involving 87 individuals with newly diagnosed type 1 diabetes, administered via infusions on days 1, 8, 15, and 22 within three months post-diagnosis. At one-year follow-up, rituximab demonstrated a higher baseline-adjusted 2-hour C-peptide AUC during a mixed-meal tolerance test compared to placebo, with values of 0.56 nmol/l and 0.47 nmol/l, respectively (p=0.03). The rituximab group also showed lower HbA1c levels (6.8% vs 7.0%, p<0.001) and reduced exogenous insulin use (0.39 IU/kg vs 0.48 IU/kg, p<0.001). However, at the two-year follow-up, while the 2-hour C-peptide AUC remained higher in the rituximab group, the difference was no longer statistically significant, and no differences in HbA1c or insulin dose were observed. B lymphocyte levels in rituximab-treated participants returned to baseline at 18 months.
DPP-4 inhibitors are a class of medications used in the management of diabetes that increase serum levels of native GLP-1 by inhibiting the DPP-4 enzyme. Several large cardiovascular outcome trials, including SAVOR-TIMI 53, EXAMINE, TECOS, and CARMELINA, evaluated the cardiovascular safety of DPP-4 inhibitors compared to placebo. These trials confirmed the cardiovascular safety of DPP-4 inhibitors, but none demonstrated a reduction in cardiovascular events, including three-point or four-point MACE. Additionally, the SAVOR-TIMI 53 trial noted an increased risk for hospitalization due to heart failure with saxagliptin, though this effect was not observed with other DPP-4 inhibitors, suggesting it may be specific to saxagliptin or a chance finding.
Lifestyle interventions during pregnancy, particularly in women with obesity, may help limit gestational weight gain and reduce postpartum weight retention, which is relevant for lowering the risk of complications in subsequent pregnancies, including gestational diabetes mellitus (GDM). The Finnish Gestational Diabetes Prevention Study (RADIEL) demonstrated that such interventions can reduce the incidence of GDM in high-risk women, although other studies have not consistently shown improvements in maternal or neonatal outcomes like GDM, pre-eclampsia, macrosomia, or preterm birth. Pregestational BMI is a significant predictor of pregnancy outcomes, with higher BMI associated with increased insulin resistance and elevated plasma triglycerides early in pregnancy. Additionally, interpregnancy weight changes influence the risk of complications in future pregnancies, and mild to moderate weight loss in women with obesity has been linked to a reduced risk of large-for-gestational-age (LGA) infants without increasing the risk of small-for-gestational-age (SGA) infants.
Variants of the KCNJ11 gene can lead to impaired depolarization of the β-cell membrane and altered insulin release, particularly under stress conditions such as glucotoxicity. Many other genes, including HHEX/IDE, GIPR, PROX1, DGKB, CDKAL1, SLC30A8, CGK, and CDKN2A/2B, have also been linked to abnormal insulin secretion. Most gene variants associated with type 2 diabetes primarily affect insulin secretion, with the impairment becoming more pronounced as two-hour plasma glucose levels rise, even in individuals with normal glucose tolerance. In both lean and obese individuals with two-hour plasma glucose levels between 120–140 mg/dl, β-cell function is already reduced by 60% compared to those with levels below 100 mg/dl. When insulin secretion is analyzed in relation to plasma glucose levels, it becomes evident that β-cells in people predisposed to diabetes release less insulin in response to the same glucose stimulus, a condition known as impaired glucose sensitivity, which is more precisely defined using mathematical modeling.
Antibody testing and genetic analysis aid in diagnosing diabetes, especially in children with mild or early symptoms, and help differentiate type 1 diabetes from type 2 diabetes as body habitus becomes less reliable for distinction. Over 80–90% of individuals with new-onset type 1 diabetes have one or more anti-islet cell autoantibodies, including islet cell antibodies, insulin autoantibodies, GAD65 antibodies, IA-2 antibodies, and ZnT8 antibodies, with the presence of multiple autoantibodies strongly predicting progression to overt diabetes. Although most type 1 diabetes cases occur without a family history, those with a first-degree relative affected have a 5% lifetime risk, significantly higher than the 0.3% risk in the general population, and monozygotic twins show a concordance rate of over 50%, compared to 6–10% in dizygotic twins. Genetic risk scores (GRS) are increasingly used to predict type 1 diabetes development and distinguish it from other diabetes types, including monogenic and type 2 diabetes, and when combined with environmental and autoantibody data into a combined risk score (CRS), predictive accuracy improves beyond that of individual components alone, enhancing early detection and potential preventive interventions.
Insulin glargine, a long-acting analog, has theoretical concerns due to its higher binding affinity for the IGF-I receptor and potential mitogenic potency compared to human insulin. Its safety during pregnancy has not been conclusively established due to a lack of large, adequately controlled studies. An audit involving 115 women with type 1 diabetes mellitus (T1DM) and 109 babies across 20 diabetic obstetric units in the UK found no unexpected or adverse maternal or fetal outcomes when insulin glargine was used, with 69% of women using it prior to pregnancy and only one discontinuing its use at booking. The majority of women used rapid-acting insulin analogs like insulin aspart (45%) or lispro (42%) as bolus insulin, while 8% used human soluble insulin. These findings align with earlier smaller studies showing similar safety profiles during pregnancy.
Other oral hypoglycemic agents can cause various skin-related adverse reactions, though such occurrences are less common compared to sulfonylureas. Metformin, a biguanide, may lead to transient erythema, urticaria, a psoriasisiform drug eruption, erythema multiforme, photosensitivity, and leukocytoclastic vasculitis. Acarbose, which is minimally absorbed from the gut, can cause generalized erythema multiforme, likely due to its degradation products triggering an allergic reaction. Thiazolidinediones like rosiglitazone and pioglitazone, as well as glinides such as repaglinide, may result in edema, transient erythema, and urticaria, although these reactions are uncommon.
Iatrogenic hypoglycemia is a critical limitation in managing diabetes, occurring when treated with insulin secretagogues or insulin. Hypoglycemia arises from therapeutic hyperinsulinemia, and in type 1 diabetes and advanced type 2 diabetes, the body's normal defenses—reduced insulin and increased glucagon—are impaired due to β-cell failure. This leads to defective glucose counter-regulation, worsened by reduced epinephrine response, and hypoglycemia unawareness, primarily due to diminished sympathetic neural activity. The concept of hypoglycemia-associated autonomic failure (HAAF) explains that prior episodes of hypoglycemia, along with factors like exercise or sleep, can further blunt the sympathoadrenal response to subsequent hypoglycemia, exacerbating both defective glucose counter-regulation and hypoglycemia unawareness.
Supporting individuals with diabetes to achieve optimal glycaemic control involves both short-term and long-term assessment methods, such as self-monitoring of blood glucose and measuring $\mathrm{HbA_{1c}}$, which reflects longer-term glycaemic management. Not all individuals require self-monitoring, but when they do, healthcare professionals should discuss the results and their implications for future care. Discrepancies between $\mathrm{HbA_{1c}}$ and self-monitored blood glucose may arise due to biological factors, timing of readings, or fabricated results, which can sometimes be identified by a pristine testing sheet and use of a single pen colour. Exploring such discrepancies non-judgmentally is important, as they may indicate issues in the patient–professional relationship or psychosocial difficulties. Technological tools like computers and online platforms can help identify patterns of hypo- and hyperglycaemia, provided the glucose meter has not been shared.
Sleep impairments are both influenced by and contribute to diabetes and its complications, acting as barriers to effective diabetes self-management. Screening for sleep problems in individuals with diabetes can help prevent negative impacts on behaviour, physiology, and mental health. Sleep disorders are highly prevalent in type 1 diabetes and are linked to markers of glucose metabolism, suggesting that identifying and evaluating these disorders may improve diabetes management and glycaemic control. The relationship between sleep disorders and glycaemic indices in type 1 diabetes requires further study. Research should also focus on distinguishing the effects of individual sleep disorders in type 2 diabetes from sleep duration, as well as understanding sleep consistency and timing. The roles of obesity and depression in the sleep-diabetes connection need further clarification, and longitudinal studies using objective sleep assessments are necessary to better understand how sleep affects diabetes complications and interacts with behavioural and mental health comorbidities.
Abatacept treatment in individuals with newly diagnosed type 1 diabetes was associated with higher C-peptide levels compared to placebo, indicating a slower decline in beta-cell function. Administered intravenously over two years, abatacept resulted in a 59% higher adjusted C-peptide area under the curve after two years, representing a 9.6-month delay in functional decline compared to placebo. Additionally, a greater proportion of abatacept-treated individuals had HbA1c levels below 7% at 24 months, although insulin requirements remained similar between groups. These effects were partially sustained one year post-treatment, with the abatacept group still showing lower HbA1c levels compared to placebo.
Suboptimal diabetes management in ambulatory individuals with type 1 or type 2 diabetes is associated with worse outcomes, and improving glycaemic levels over many years leads to better results as demonstrated by the Diabetes Control and Complications Trial and UK Prospective Diabetes Study. In hospitalized individuals, hyperglycaemia is linked to higher in-hospital morbidity and mortality, longer hospital stays, poor post-discharge outcomes, and increased healthcare costs. New-onset hyperglycaemia is associated with an 18-fold increase in in-hospital mortality, while known diabetes leads to a 2.7-fold increase compared to normoglycaemic individuals. Guidelines from the American College of Endocrinology and AACE emphasize early detection and aggressive management of hyperglycaemia to improve outcomes, and the JBDS in the UK also recommends aggressive glucose management during hospital admissions.
Young, lean, insulin-resistant first-degree relatives of people with type 2 diabetes exhibit 30% lower basal rates of muscle ATP synthase and TCA cycle fluxes compared to insulin-sensitive individuals, along with 38% lower mitochondrial density, suggesting that reduced mitochondrial function may stem from lower mitochondrial content rather than reduced PGC1α expression. In another cohort of first-degree relatives, the effect of exercise training on insulin sensitivity and ATP synthesis was influenced by a G/G-SNP in the NDUFB6 gene, part of complex I of the mitochondrial respiratory chain, but not by PGC1α polymorphisms. The insulin resistance observed in these relatives, similar to those with overt type 2 diabetes, highlights the role of inherited factors in the pathogenesis of insulin resistance and type 2 diabetes. Reduced mitochondrial content due to impaired biogenesis may be an acquired abnormality contributing to reduced mitochondrial oxidative and phosphorylation activity. Given the role of mitochondria in muscle fat metabolism, this dysfunction may predispose to plasma membrane sn-1,2-DAG accumulation in muscle cells, promoting insulin resistance in individuals whose parents have type 2 diabetes.
GLP-1 receptor agonists, used to treat type 2 diabetes, and dual agonists combining GLP-1 and GIP are transforming anti-obesity medications by promoting significant weight loss and potentially preventing and reversing type 2 diabetes. GLP-1 regulates food intake by affecting appetite and reward-related brain areas, while GIP activates distinct neurons to inhibit food intake in a way that adds to GLP-1's effects. Common side effects of these drugs include mild to moderate gastrointestinal issues like nausea and vomiting, which can be reduced by gradually increasing the dosage, and an increased risk of gallstones that may occasionally lead to pancreatitis.
Dipeptidyl-peptidase 4 (RPP-4) and glucagon-like peptide 1 (GLP-1) are involved in glucose metabolism, with GLP-1 being a target for diabetes therapies such as lixisenatide. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are another class of diabetes medications. Long-acting release (LAR) formulations are used in diabetes treatment, as seen in trials comparing insulin degludec with glargine U-100. Clinical trials such as TOSCA-IT, CAROLINA, and DEVOTE compare different diabetes treatments, including pioglitazone versus sulfonylureas, linagliptin versus glimepiride, and insulin degludec versus glargine U-100, focusing on cardiovascular outcomes such as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina.
Many drugs can interfere with glucose homeostasis or interact with antidiabetic agents, thereby disturbing glycemic control in individuals with diabetes. Certain drugs, such as glucocorticoids, some oral contraceptives, antipsychotics, HIV protease inhibitors, gatifloxacin, and β-adrenoceptor antagonists, induce insulin resistance and can worsen hyperglycemia. Others, like pentamidine and cyclosporine, damage β-cells and contribute to diabetogenesis. Sulfonylureas and related agents may cause hypoglycemia through interactions that block their metabolism in the liver or impair renal elimination; for instance, ciprofloxacin inhibits CYP2C9, which degrades glyburide, while non-steroidal anti-inflammatory agents reduce renal clearance. Hypoglycemia can also be triggered by drugs such as quinine, sulfamethoxazole, and pentamidine, with the latter initially causing transient hypoglycemia via insulin loss from β-cells before potentially leading to permanent diabetes. Specific diabetic complications like nephropathy and neuropathy necessitate cautious use of certain medications.
Diabetes management involves monitoring and maintaining blood glucose levels within specific target ranges, as indicated by HbA1c and self-monitoring blood glucose (SMBG) measurements. Optimal HbA1c levels are below 7.5% according to DCCT standards or below 58 mmol/mol according to IFCC standards, while high-risk levels are 9.0% or higher (DCCT) or 75 mmol/mol or higher (IFCC). For SMBG, fasting or preprandial blood glucose should ideally be between 5–8.3 mmol/L (90–150 mg/dL), with high-risk levels exceeding 11.1 mmol/L (200 mg/dL). Post-prandial glucose should optimally remain between 5–10 mmol/L (90–180 mg/dL), with high-risk levels above 13.9 mmol/L (250 mg/dL). At bedtime, optimal glucose levels range from 6.7–10 mmol/L (120–180 mg/dL), and high-risk levels are either below 4.4 mmol/L (80 mg/dL) or above 11.1 mmol/L (200 mg/dL). During nocturnal periods, optimal levels range from 4.4–9 mmol/L (80–160 mg/dL), with high-risk levels either below 3.9 mmol/L (70 mg/dL) or above 11.1 mmol/L (200 mg/dL).
Acute hyperglycemia delays gastric emptying in healthy individuals and those with type 1 diabetes mellitus (T1DM), potentially due to suppression of antral motility and migrating motor activity. Even severe hyperglycemia in T1DM, ranging from 16 to 20 mmol/L, only modestly prolongs gastric emptying half-time by about 17 minutes. Modulating blood glucose within the normal postprandial range of 4–8 mmol/L can also delay gastric emptying, albeit to a lesser extent. Higher glycated hemoglobin levels are associated with more gastrointestinal symptoms and slower gastric emptying in people with diabetes. While strict glycemic control benefits neural, renal, and retinal functions in diabetes, its effect on gastric emptying remains uncertain, as one study showed no improvement in gastric emptying after a week of better control in patients with type 2 diabetes mellitus (T2DM). Additionally, electrolyte disturbances from diabetic ketoacidosis, such as hypokalemia, and uremia can further impair gastrointestinal motility in diabetes, and gastroparesis may also be induced by treatments involving amylin or GLP-1 analogs.
Genome-wide scans have identified chromosomal regions associated with type 2 diabetes mellitus (T2DM), but each region spans 10-20 million nucleotides, making it difficult to pinpoint the specific diabetes-related genes among hundreds that may be present. One approach to identifying the true gene variants that increase T2DM risk involves refining these regions using dense maps of single nucleotide polymorphisms (SNPs) to detect linkage disequilibrium (LD). However, DNA polymorphisms not directly linked to the functional variant can still show association with the disease or related traits. The extent of LD varies across the genome, ranging from 10 to 300 kilobases or more. While studying isolated populations like Finns or Icelanders is thought to improve LD mapping, this approach has not fully resolved the challenges in identifying causative variants.
Improved glucose control appears to have a more significant long-term cardiovascular benefit in individuals with type 1 diabetes mellitus (T1DM), as evidenced by the EDIC study showing reduced cardiovascular complications years after initial glucose-lowering interventions. In type 2 diabetes mellitus (T2DM), intensive glucose therapy demonstrated some long-term benefits on macrovascular outcomes based on 10-year follow-up data from the UKPDS, though these benefits, particularly for myocardial infarction and all-cause mortality, only became evident during extended post-trial follow-up. However, more recent large-scale trials such as ADVANCE and ACCORD, which aimed for near-normal glucose levels in T2DM patients using a target HbA1c of less than 6.5% (48 mmol/mol), did not show significant cardiovascular benefits and, in the case of ACCORD, raised concerns due to adverse findings. These results suggest that while glucose control is important, its impact on cardiovascular outcomes may differ between T1DM and T2DM and may not always lead to improved cardiovascular health when targeted in isolation.
In diabetic maculopathy, retinal photocoagulation is the first-line treatment when exudates or retinal edema are present outside the foveal area and do not threaten central vision, as it helps improve oxygen and nutrient diffusion from the choroid while reducing retinal vessel dilation. However, focal treatment of microaneurysms is not effective due to their spontaneous resolution regardless of intervention. Retinal photocoagulation can decrease retinal vessel permeability and lead to regression of hard exudates around leakage points, but treatment should avoid the papillomacular bundle and areas within 500μm of the fovea to preserve vision. In cases of ischaemic maculopathy with occluded perifoveal capillaries and an enlarged foveal avascular zone, photocoagulation is not recommended as it may worsen central vision.
Malnutrition in utero and during early childhood, as well as exposure to hyperglycemia in utero, is associated with an increased risk of developing type 2 diabetes mellitus (T2DM) later in life. Research by Hales et al. showed an inverse relationship between weight at birth and at one year of age and the likelihood of developing T2DM in adulthood. It is suggested that early malnutrition may impair beta-cell development or program beta-cells in a way that limits their ability to adapt to later overnutrition, particularly in individuals who were born thin and subsequently become obese. A key feature of those at risk for T2DM is their inability to appropriately increase insulin release in response to insulin resistance, although early life malnutrition is only one of many factors that contribute to disease susceptibility.
ACE inhibitor use is associated with hospitalization for severe hypoglycemia in patients with diabetes, and there is evidence evaluating the efficacy, safety, and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure. Additionally, studies have examined the impact of diabetes on outcomes in patients with heart failure and the effects of various treatments such as candesartan, carvedilol, spironolactone, and rosuvastatin in diabetic populations. Research also includes a meta-analysis of glycemic control and macrovascular disease in type 1 and type 2 diabetes mellitus.
Statin medications, including pravastatin, atorvastatin, and rosuvastatin, are associated with an increased risk of new-onset diabetes, with varying degrees of risk among the different statins. Statins appear to increase insulin resistance and decrease insulin secretion, leading to small increases in HbA1c and fasting glucose levels. A meta-analysis found a 9% increased risk of incident diabetes with statin use, and rosuvastatin in particular was linked to a 28% increase in diabetes risk in the JUPITER trial, although it also prevented a significant number of cardiovascular events. Despite this risk, guidelines from the American Diabetes Association recommend statin therapy for most people with diabetes who have cardiovascular disease or risk factors, noting the absolute risk of rosuvastatin-induced diabetes is small (1.5% over five years compared to 1.2% with placebo).
MODY, or maturity-onset diabetes of the young, is a form of monogenic diabetes with multiple subtypes, each linked to a specific gene mutation. MODY1 is associated with the HNF4A gene on chromosome 20q, presents in adolescence or early adulthood, and is characterized by a severe form of diabetes with frequent complications. MODY2 results from mutations in the GCK gene on chromosome 7p, has a mild phenotype with lifelong, early childhood onset, and rarely causes complications. MODY3, caused by mutations in the TCF1 (HNF1A) gene on chromosome 12q, manifests during adolescence or early adulthood and is a severe form with frequent complications. MODY4, due to mutations in the IPF-1 gene on chromosome 13q, appears in early adulthood and is a severe form with unknown complications, although pancreas agenesis and neonatal diabetes mellitus (NDM) may occur in rare homozygotes. MODY5 arises from mutations in the TCF2 (HNF1B) gene on chromosome 17q, presents in early adulthood, and is associated with kidney disease (RCAD), with pancreas agenesis and NDM in rare homozygotes. MODY6 involves the NEUROD1 gene on chromosome 2q32, begins in early adulthood, and is a severe form with unknown complications, though NDM may occur in rare homozygotes. MODY7 is linked to the INS gene on chromosome 11p15.5, can present in early childhood or early adulthood, and varies from mild to severe diabetes with rare complications.
Lifestyle modification (LSM), including diet changes and increased physical activity, as well as metformin (MET) treatment, have been shown to reduce the incidence of type 2 diabetes in individuals with impaired glucose tolerance (IGT). LSM typically involves weight reduction, increasing physical activity to at least 30 minutes daily, reducing total calories, refined carbohydrates, and fats, avoiding sugar, and consuming fibre-rich foods. Supervised exercise programs, including aerobic training (AT), resistance training (RT), or a combination of both, also significantly lower diabetes risk. Studies indicate that LSM alone can reduce diabetes incidence by 28.5% to 55%, while metformin alone reduces it by about 26.4%. When LSM is combined with metformin or with exercise, the risk reduction is slightly lower or similar, suggesting that lifestyle changes are a key factor in diabetes prevention. These interventions were shown to be effective over study durations ranging from 2 to 3.1 years.
Gestational diabetes is defined as carbohydrate intolerance resulting in hyperglycemia of variable severity, with onset or first recognition during pregnancy, though it may have existed undiagnosed before pregnancy. It can develop at any stage of pregnancy, but diabetes detected in the first trimester is often considered pre-existing and undiagnosed, with the term gestational diabetes reserved for cases diagnosed in the second or third trimester. Women who have diabetes before pregnancy are classified as having diabetes mellitus and pregnancy and should be managed accordingly. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) has established diagnostic criteria for gestational diabetes, which have been adopted by major national guidelines.
Various oral anti-diabetes drugs have been developed in the last decades, including dipeptidyl-peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, which significantly improve glycemic levels when added to traditionally used drugs such as metformin, sulfonylurea derivatives, and insulin. GLP-1 receptor agonists and SGLT-2 inhibitors also reduce body weight and blood pressure and improve cardiovascular outcomes, with SGLT-2 inhibitors having additional favorable effects beyond glucose control.
Increased activation of protein kinase C theta (PKCθ) leads to elevated serine phosphorylation of insulin receptor substrate 1 (IRS-1) at specific sites such as Ser-1101, which interferes with insulin-stimulated tyrosine phosphorylation of IRS-1 and the subsequent binding and activation of phosphatidylinositol 3-kinase (PI3K). This disruption results in reduced recruitment of glucose transporter type 4 (GLUT4) to the cell membrane, impairing insulin-stimulated glucose uptake and its phosphorylation to glucose-6-phosphate, ultimately leading to decreased insulin-stimulated glycogen synthesis.
Metoclopramide, a peripheral cholinergic and antidopaminergic agent, is used in the USA to treat diabetic gastroparesis, initially enhancing gastric emptying of liquids and providing symptomatic relief through central antiemetic effects, though long-term use is limited by declining efficacy and central nervous system side effects. A recommended short-term regimen is 10 mg three times daily, taken 30 minutes before meals, with a higher dose of 20 mg three times a day. Domperidone, another dopaminergic antagonist not approved in the USA, has limited evidence supporting its use. Botulinum toxin injection into the pylorus has shown no effectiveness in controlled studies, primarily involving idiopathic gastroparesis. Aprepitant, an NK1 antagonist at 125 mg/day, improved secondary outcomes but not nausea severity in a four-week trial involving individuals with nausea and vomiting, including those with delayed gastric emptying. Emerging treatments for diabetic gastroparesis include relamorelin, a pentapeptide ghrelin agonist, and tradipitant, an NK1 antagonist.
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated significant risk reduction in major adverse cardiovascular events (MACE), heart failure, and kidney outcomes in patients with diabetes. MACE is defined as a composite of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. Heart failure outcome is primarily defined as hospitalization for heart failure. Kidney outcomes across various trials include a range of markers such as doubling of serum creatinine level, a reduction in estimated glomerular filtration rate (eGFR), initiation of renal replacement therapy, or death from renal disease, with specific thresholds varying by trial. SGLT-2 inhibitors showed significant risk reduction in kidney outcomes including a sustained decrease in eGFR, end-stage kidney disease (ESKD), or renal death. GLP-1 RAs also demonstrated risk reduction in kidney outcomes, including new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, and sustained decline in eGFR.
Interleukin-1β (IL-1β), a proinflammatory cytokine, plays a significant role in the pathogenesis of both type 1 and type 2 diabetes mellitus (T2DM). It is involved in cytokine-mediated β-cell destruction in type 1 diabetes and has been found to influence β-cell function in T2DM. In vitro studies show that β-cells produce IL-1β in response to high glucose and leptin levels, and IL-1β-expressing β-cells have been observed in pancreatic sections of T2DM patients but not in healthy individuals. At low concentrations, IL-1β enhances β-cell proliferation and reduces apoptosis, while at higher concentrations, it impairs insulin release and increases apoptosis. This apoptosis is mediated by Fas, a member of the tumor necrosis factor receptor family, which is upregulated by IL-1β within β-cells, promoting Fas-induced apoptotic cell death. An IL-1 receptor antagonist (IL-1Ra) has been shown to protect β-cells from the adverse effects of IL-1β in vitro and improve glycemic control in T2DM patients by enhancing β-cell secretory function.
In type 1 diabetes, eGFR may decline before the onset of albuminuria, with a median annual fall of 1.5% in those with normoalbuminuria and 2.2% in those with moderately increased albuminuria. This suggests that albuminuria may not be a reliable indicator of diabetic nephropathy. Alternative explanations include suppression of albuminuria by renin-angiotensin system inhibitors or distinct pathological processes underlying kidney disease with and without albuminuria. Some individuals with type 1 diabetes experience a rapid, malignant-like decline in kidney function, necessitating identification through novel biomarkers.
In patients with type 2 diabetes mellitus (T2DM) and microalbuminuria, inhibition of the renin-angiotensin system (RAS) plays a key role in therapy. Clinical studies demonstrate that treatment with the angiotensin receptor blocker (ARB) irbesartan at doses of 150 or 300 mg/day significantly reduces the progression to persistent proteinuria compared to placebo, with high-dose irbesartan showing a greater effect. Additionally, a smaller study showed that ACE inhibition helps reduce the rise in urinary albumin excretion (UAE) and stabilizes serum creatinine over several years. The HOPE study further supported these findings, showing that ramipril significantly lowers the risk of developing proteinuria in T2DM patients with microalbuminuria, an effect independent of blood pressure reduction.
First-line antihypertensive drugs suitable for use in patients with diabetes include diuretics such as low-dose bendroflumethiazide, cardioselective beta-blockers, calcium-channel antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II type 1 (AT1) receptor blockers. Subjects of African descent may have low renin hypertension and may not respond well to beta-blockers or ACE inhibitors. Drug selection can be guided by coexistent conditions such as angina or arrhythmia, where beta-blockers or calcium-channel antagonists may be beneficial; heart failure, where ACE inhibitors and certain beta-blockers are preferred; previous myocardial infarction, where ACE inhibitors and beta-blockers are indicated; or nephropathy, where ACE inhibitors and ARBs are particularly useful.
Lipolysis in adipose tissue is highly sensitive to insulin, with normal subjects showing half-maximal suppression of glycerol production at a plasma insulin concentration of 13 mU/L. In patients with type 2 diabetes mellitus (T2DM), triglyceride breakdown is increased and plasma non-esterified fatty acid (NEFA) concentrations are higher compared to normal subjects at similar insulin levels, indicating insulin resistance in adipose tissue. However, unrestrained lipolysis leading to ketoacidosis does not typically occur in T2DM due to insufficient insulin deficiency.
A widely varying prevalence of moderately elevated albuminuria, from 10% to 42%, has been reported in diabetes. Longitudinal studies suggest that the rate of progression from normo- to moderately elevated albuminuria is 3–4% per annum. One older study demonstrated equivalent cumulative incidence of severely increased albuminuria in type 1 diabetes and type 2 diabetes after 25 years' duration. National US survey data reported a prevalence of CKD, defined as eGFR < 60 ml/min/1.73 m² or UAE > 30 mg/g, of 44% in the overall type 2 diabetes population and 61% in those aged ≥ 65 years. In the UK, using a similar definition, the prevalence was 42%. The increasing number of individuals with diabetes commencing kidney replacement therapy in many countries is due mainly to type 2 diabetes and is partly accounted for by increased acceptance of older, sicker individuals for treatment and improved cardiovascular survival.
GLP-1 receptor agonists (GLP-1RAs) do not interact with the hepatic metabolism of other medications such as acetaminophen, digoxin, oral contraceptives, lisinopril, metformin, HMG-CoA reductase inhibitors, or warfarin. However, all GLP-1RAs delay gastric emptying upon acute dosing, which may prolong the absorption of concurrently administered oral medications. This effect is more clinically relevant with short-acting GLP-1RAs because the impact on gastric emptying diminishes quickly over time with continuous-acting formulations due to rapid tachyphylaxis. To minimize this interaction, other medications can be taken either one hour before or four hours after a short-acting GLP-1RA dose.
MODY (Maturity-Onset Diabetes of the Young) is associated with heterozygous variants in transcription factor genes, most commonly affecting hepatic nuclear factors 1A and 4A (HNF1A and HNF4A), and can also result from variants in other transcription factor-encoding genes such as HNF1B and insulin promoter factor-1 (IPF-1).
Many myocardial structural and biochemical alterations found in the failing heart are also present in the diabetic heart, including changes in myocardial energy production, altered expression of contractile proteins, desynchronized excitation-contraction coupling, β-adrenergic receptor stimulation, myocyte depletion, and increased cytokine activity. These aberrations are independent of the etiology of myocardial dysfunction and represent both general pathophysiological features and diabetes-specific factors in heart disease.
The SLC5A2 gene, which encodes the SGLT-2 protein, contains genetic variants such as the AA genotype rs9934336 that are associated with increased glucose excretion in the urine through enhanced SGLT-2 activity. Additionally, other single-nucleotide polymorphisms (SNPs), including rs3116150 and rs11646054, result in a loss of function of the SGLT-2 cotransporter, leading to higher excretion of both glucose and sodium. These genetic variations may influence the effectiveness of SGLT-2 inhibitors by affecting blood pressure reduction and glucose control, with ongoing studies investigating this potential impact.
Racial disparities in type 2 diabetes risk persist among African Americans even when socioeconomic status improves, indicating that better income or education does not eliminate these disparities. Poverty contributes to increased type 2 diabetes risk in this population, but systemic inequities reduce the expected health benefits associated with higher socioeconomic status. For example, increases in household income lead to smaller health improvements for African Americans compared to non-Hispanic white Americans, and the negative relationship between income and obesity is weaker in Black Americans. Additionally, within the African American population, higher socioeconomic status is linked to increased rates of depression, which may be influenced by experiences of racial discrimination, particularly in the workplace. Even in affluent African American neighborhoods, residential conditions often lag behind those of white neighborhoods with similar socioeconomic profiles.
Increased glucose flux through the hexosamine pathway may contribute to hyperglycemia-induced increases in gene transcription of key genes such as PAI-1, which is relevant to diabetes-related vascular complications. The transcription factor Sp1 is involved in this process, as its O-GlcNacylated form, resulting from covalent glycation by N-acetylglucosamine, appears to be more transcriptionally active than its nonglycosylated counterpart. O-GlcNacylation and phosphorylation of Sp1 may compete for modifying the same sites, with increased O-GlcNacylation leading to reduced phosphorylation, potentially influencing gene expression under hyperglycemic conditions.
Amniotic erythropoietin levels are elevated in diabetic pregnancies compared to non-diabetic pregnancies and correlate inversely with cord blood pH and pO₂ at birth, as well as neonatal hypoglycemia, while showing a positive correlation with maternal HbA₁c levels in late pregnancy. Elevated amniotic erythropoietin may serve as a marker for chronic fetal hypoxia in late diabetic pregnancies, though its clinical utility requires further assessment through trials. Additionally, the increased oxygen affinity of glycated hemoglobin in diabetic pregnancies may contribute to impaired fetal oxygen delivery, potentially exacerbating fetal hypoxia.
Various strategies have been explored to generate functional insulin-producing cells for diabetes treatment. Protocols have been developed to create cells that secrete human C-peptide in response to glucose and effectively manage hyperglycaemia in diabetic mice. Mesenchymal stem cells (MSCs) have been used to generate insulin-producing cells, enhance islet engraftment, and improve metabolic control in experimental diabetes. Clinical trials in type 2 diabetes suggest that bone marrow–derived mononuclear cells can positively influence metabolic measures without causing adverse effects when delivered via intra-arterial injection into the pancreas. Pancreatic progenitor cells have demonstrated the ability to produce glucose-responsive, insulin-secreting cells that can prevent or reverse diabetes in mice. Researchers have also successfully reprogrammed terminally differentiated cells into β cells; for example, mouse acinar cells were directly converted into β cells in vivo through viral gene expression, leading to improved glycaemic control in diabetic mice. Adult mouse α cells can also be reprogrammed to adopt β cell characteristics. The process of endocrine differentiation involves the expression of neurogenin-3 (NGN3), which enables precursor cells to become α cells or bipotential β/δ precursors. Studies using lineage-tracing methods have revealed that pancreatic duct-lining precursor cells can re-express NGN3 and transform into glucagon-expressing and β-like cells through mechanisms involving the epithelial-to-mesenchymal transition. Insulin-producing cells can be restored throughout life via spontaneous reprogramming of δ- or α-cell populations, indicating dynamic intraislet cell interconversion. Additionally, adult cells can be reprogrammed into induced pluripotent stem cells (iPSCs), and differentiation protocols have successfully generated insulin-producing cells from human iPSCs derived from reprogrammed fibroblasts.
Free of severe hypoglycaemic episodes at 10 years with reduced insulin requirements has been observed, and while closed-loop systems and islet transplantation may effectively reduce hypoglycaemia, their cost and complexity limit widespread use. Patient motivation and education are crucial for optimal outcomes with new technologies, and psycho-educational interventions such as blood glucose awareness training have shown reductions in severe hypoglycaemia in recent trials.
Studies have shown that disruption of dopaminergic pathways in the hypothalamus contributes to insulin resistance, which can be reversed by localized dopamine infusion. In individuals with type 2 diabetes, low-dose rapid-acting bromocriptine administered in the morning enhances hypothalamic dopamine activity, helping to restore normal circadian rhythms in glucose homeostasis by lowering sympathetic tone and improving neural suppression of liver glucose production. This treatment also decreases adipose tissue lipolysis and enhances peripheral glucose uptake without increasing plasma insulin levels, reflecting improved peripheral insulin sensitivity.
Increased risk of childhood-onset type 1 diabetes has been linked to maternal enterovirus infections during pregnancy in some studies, though findings are inconsistent. Prospective studies using serum enterovirus antibodies and RNA as markers of postnatal infection have not consistently shown associations between enterovirus and islet autoimmunity. Earlier research indicated that virus particles in the blood were more strongly correlated with type 1 diabetes than those in stool, but more recent data from the DIPP study in Finland found a link between faecal enterovirus shedding and later risk of islet autoimmunity. The TEDDY study reported that prolonged faecal shedding of enterovirus B was associated with higher risk of islet autoimmunity but not with type 1 diabetes itself. Metagenomic studies using next-generation sequencing of the virome in relation to islet autoimmunity or type 1 diabetes have yielded only weak associations, primarily with enteroviruses, and have been limited by small sample sizes and varying methodologies.
Exenatide, an incretin mimetic, was studied in patients with type 2 diabetes mellitus (T2DM) with a baseline HbA1c of 8.3% ± 1.0 (67 mmol/mol), mean fasting glucose of 9 ± 2 mmol/L, and a mean diabetes duration of 6.7 ± 5.0 years. Patients were either drug-naive or on one or more oral antidiabetic agents. The study compared once-weekly administration of 2 mg exenatide with twice-daily administration of 10 μg exenatide, showing that once-weekly dosing resulted in a greater reduction in HbA1c at 30 weeks (−1.9 ± 0.1% vs. −1.5 ± 0.1%, 95% CI −0.54% to −0.12%, P = 0.0023). Additionally, more patients on once-weekly exenatide achieved HbA1c levels of 7.0% (53 mmol/mol) or less compared to those on twice-daily dosing (77% vs. 61%, P = 0.0039). The once-weekly formulation demonstrated improved fasting glycemic control, suggesting a potential advantage in antihyperglycemic efficacy, possibly due to differences in pharmacokinetics or sustained levels of the drug in the bloodstream.
central obesity (waist circumference ≥94 cm in Europid men and ≥90 cm in Europid women) plus any two of the following four factors: raised triglycerides (≥1.7 mmol/l), reduced HDL cholesterol (<1.0 mmol/l in men and <1.3 mmol/l in women), raised blood pressure (≥130/85 mmHg), and raised fasting plasma glucose (≥5.6 mmol/l).
Urban areas in India consistently show higher prevalence rates of diabetes compared to rural areas, with studies indicating a progressive increase in diabetes prevalence with increasing urbanization. For instance, prevalence rates were reported as 2.4% in rural areas, 5.9% in semiurban areas, and 11.6% in urban areas. More recent data show even higher rates, with 18.6% prevalence in Chennai city compared to 16.4% in towns and 9.2% in peri-urban villages. A study across 77 centers in India found a standardized prevalence rate of 4.3% overall, 5.9% in urban areas, and 2.7% in rural areas. However, the rural-urban gap in diabetes prevalence appears to be narrowing. A nationwide study across 15 Indian states reported an overall diabetes prevalence of 7.3%, with 47.3% of cases undiagnosed, and an additional 10.3% of the population having prediabetes, showing significant variation between states.
GLP-1 receptor agonists (GLP-1RAs) commonly cause gastrointestinal side effects such as nausea, vomiting, and diarrhea, which are dose-dependent and tend to lessen over time. These medications, when added to standard care, have demonstrated cardiovascular benefits in large-scale trials, reducing the risk of major adverse cardiovascular events including non-fatal stroke, non-fatal myocardial infarction, and cardiovascular-related death. An amylin-based non-insulin parenteral therapy is available as an adjunct treatment for both type 1 and type 2 diabetes; amylin, co-secreted with insulin from pancreatic β cells, slows gastric emptying, reduces appetite, and decreases post-prandial glucagon secretion. Amylin analogues offer clinical improvements in HbA1c levels and body weight. Additionally, emerging non-insulin parenteral therapies involving single-molecule dual- or triple-receptor agonists targeting the GLP-1 receptor, GIP receptor, amylin receptor, and/or glucagon receptor are under evaluation for treating type 2 diabetes.
Men with diabetes and erectile dysfunction should have their serum testosterone levels measured, especially if they do not respond to PDE5 inhibitors, as hypogonadism due to pituitary or testicular disease may be present and typically responds well to testosterone treatment; in cases of late-onset male hypogonadism, testosterone replacement may improve erectile dysfunction either as a sole treatment or by enhancing the effectiveness of PDE5 inhibitors.
Several risk factors are known to be associated with increased risk of T2DM including increasing age, obesity (especially central obesity), dietary excess, increased intake of animal fats and carbonated drinks, sedentary lifestyle, a positive family history, history of gestational diabetes, polycystic ovary syndrome, severe mental illness, presence of hypertension, hyperlipidemia or cardiometabolic risk factors. The clustering of hypertension, elevated blood glucose, elevated triglyceride, low HDL cholesterol, and abdominal obesity is termed the metabolic syndrome. Many of these risk factors are linked to a westernized lifestyle and increase with urbanization and mechanization. Recognition of these factors in T2DM pathogenesis has led to recommendations for selective screening in individuals with such risk factors.
Gestational diabetes mellitus (GDM), as defined by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), is independently associated with an increased risk of childhood obesity and higher measures of child adiposity, such as sum of skin folds or body fat percentage, regardless of maternal body mass index (BMI). Offspring of women with GDM have a higher prevalence of overweight or obesity (39.5%) and obesity alone (19.1%) compared to offspring of normoglycemic mothers (28.6% and 9.9%, respectively), with these associations being stronger than those linked to BMI alone, which may reflect contributions of both fat and lean body mass. The HAPO study also demonstrated that maternal GDM has independent and additive effects on newborn adiposity outcomes.
High dietary sodium intake is associated with reduced effectiveness of angiotensin receptor blockers (ARBs) in lowering blood pressure and reducing albuminuria in individuals with type 2 diabetes, as observed in post hoc analyses of the RENAAL and IDNT trials.
Viral infections, particularly enterovirus infections, have been linked to an increased risk of islet autoimmunity, which is a precursor to type 1 diabetes. Studies have shown that children who develop islet autoantibodies, such as insulin autoantibodies (IAA), experience more enterovirus infections compared to control children, often occurring more than one year before the first detection of islet autoantibodies. Specifically, coxsackie A virus accounted for approximately 50% of these infections. In addition, prolonged enterovirus B infections, especially those involving coxsackie B1, have been associated with the appearance of IAA as the first islet autoantibody, suggesting a potential role for this virus in the initiation of islet autoimmunity. Early-life human mastadenovirus C infection and the coxsackievirus B-adenovirus receptor (CXADR) have also been independently linked to the first appearance of islet autoantibodies, particularly IAA. However, no association has been found between coxsackie B antibodies and glutamic acid decarboxylase autoantibodies (GADA). Neutralizing antibodies against coxsackie B1 may serve as surrogate markers for infection and appear before or at the time of islet autoantibody development. It has been hypothesized that certain genetic factors, such as HLA-DQ8, may lead to an impaired immune response to coxsackie B viruses, resulting in prolonged viral shedding and potentially contributing to the development of type 1 diabetes.
DPP-4 inhibitors have a generally good safety profile based on clinical experience and trials lasting 6–12 months, with tolerability and adverse events similar to placebo or comparator treatments. These medications carry a low risk of serious hypoglycaemia due to their glucose-dependent action on the pancreas, unless used in combination with agents that themselves pose a hypoglycaemic risk, such as sulfonylureas or insulin. In such cases, dose reduction of the hypoglycaemic agent may be appropriate, especially for those with mild hyperglycaemia. DPP-4 inhibition has been linked to exocrine pancreatic hyperplasia and some studies suggest an increased risk of acute pancreatitis in type 2 diabetes, though findings are not consistent and statistical significance is often lacking; nonetheless, these drugs should be discontinued if pancreatitis is suspected and avoided in those with a history of the condition. Long-term cardiovascular studies indicate possible associations between certain DPP-4 inhibitors and increased risks of angina and heart failure, particularly with saxagliptin and possibly alogliptin, though the evidence remains inconclusive.
Thiazide diuretics in high doses worsen glycemic control in type 2 diabetes and exacerbate hyperlipidemia, prompting recommendations to reduce the dose or use loop diuretics or alternative antihypertensive drugs. Patients with retinopathy, particularly those with proliferative changes, should avoid anticoagulants and abciximab due to the risk of vitreous hemorrhage, and ophthalmologic advice should be sought before using mydriatics. Somatropin can worsen proliferative retinopathy and should be avoided. In the context of autonomic neuropathy, phosphodiesterase inhibitors like sildenafil aggravate postural hypotension, especially in the elderly or those taking nitrates, and should be avoided, as should ganglion-blocking agents and vasodilators, which also worsen postural hypotension. Ganglion-blocking agents, β-adrenergic blockers, clonidine, and α-methyldopa aggravate erectile failure and alternative antihypertensive drugs such as ACE inhibitors, calcium-channel blockers, or α-adrenergic blockers are recommended instead.
Neonates born to mothers with type 1 diabetes require close monitoring of blood glucose levels using methods validated for neonatal use, with early and frequent feeding initiated within 30 minutes of birth and continued every 2–3 hours to maintain pre-feeding capillary plasma glucose levels of at least 2.0 mmol/l. If glucose levels fall below this threshold on two consecutive readings despite feeding support, or if there are abnormal clinical signs or ineffective oral feeding, interventions such as tube feeding or intravenous dextrose may be necessary. Up to half of these infants may require neonatal intensive care admission for complications outlined in a referenced table. Discharge to community care should only occur after the infant is at least 24 hours old, maintaining normal blood glucose levels, and feeding adequately.
Genetic mutations affecting pancreatic β-cell function, including variants of transcription factors such as Pax6, Nkx2-2, Nkx6-1, and NEUROG3, have been reported in patients with type 1 or type 2 diabetes. The pancreatic β-cell ATP-sensitive K+ channels (KATP channels), composed of Kir6.2 and SUR1 subunits, play a key regulatory role in insulin secretion. Genetic variants in KCNJ11 (encoding Kir6.2) and ABCC8 (encoding SUR1) are associated with reduced insulin secretion and diabetes across different ethnic populations, including Asians. Recent genome-wide association studies have also linked polymorphisms in KCNJ11 and KCNQ1, components of the KATP channels, to a 20–30% increased risk of diabetes in both Caucasian and Asian populations.
Sitagliptin, in doses of 100 mg for patients with normal renal function, reduced HbA1c by 0.6% (7 mmol/mol) and 0.18% (9 mmol/mol) respectively in two monotherapy studies of 18 and 24 weeks' duration, and further reduced HbA1c by 0.7% (8 mmol/mol) when added to either metformin or pioglitazone in 24-week duration studies. DPP-4 inhibitors are weight neutral, likely due to an appetite effect from raising endogenous GLP-1. A pilot trial of 12 weeks showed that adding the bile acid sequestrant colesevelam to treatment for type 2 diabetes mellitus (T2DM) reduced HbA1c by 0.5% (5 mmol/mol) along with lipid benefits. Further studies examined combination therapy, including a trial by Bays et al. that evaluated colesevelam at doses of 3.75 g/day compared with placebo in subjects with T2DM on metformin.
Mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce albuminuria in diabetic nephropathy but are limited by hyperkalaemia, making them contraindicated in diabetes with kidney disease. Non-steroidal MRAs like esaxerenone and finerenone cause fewer potassium-related issues and moderately lower albuminuria in type 2 diabetes. In the FIDELIO-DKD study, finerenone reduced the risk of kidney failure, sustained eGFR decline, or kidney death in patients with type 2 diabetes and chronic kidney disease (CKD), with a hazard ratio of 0.82. It also reduced cardiovascular events, including death, myocardial infarction, stroke, or hospitalization for heart failure (HR 0.86). However, finerenone was associated with higher rates of hyperkalaemia-related discontinuation compared to placebo. The FIGARO-DKD study supported these findings in type 2 diabetes with less advanced CKD, focusing on cardiovascular outcomes.
In diabetes, hepatic glucose production is influenced by counter-regulatory hormones such as glucagon, catecholamines, and glucocorticoids, which increase glucose output through glycogenolysis and gluconeogenesis. Insulin, typically administered exogenously in diabetes management, suppresses hepatic glucose production by inhibiting these processes. Gluconeogenesis, a key pathway in glucose homeostasis, is regulated by gene expression of enzymes like phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase), with PEPCK catalyzing a rate-limiting step and G-6-Pase responsible for the final step that produces free glucose. Transcription of PEPCK is tightly controlled by cAMP, highlighting its role in the regulation of glucose production in diabetic conditions.
Combined diet and physical activity promotion programmes aim to prevent type 2 diabetes, with weight loss being the most modifiable risk factor influencing diabetes risk. Although such interventions have successfully achieved weight loss and reduced BMI, these outcomes have not consistently led to a lower incidence of type 2 diabetes. Lifestyle modifications have been found to be as effective as metformin in reducing diabetes incidence by 50% compared to controls, and a Spanish study showed that fewer women in an intervention group developed glucose disorders after three years compared to the control group. However, further research is needed to determine the key elements that will ensure long-term effectiveness of these prevention programmes.
In individuals with type 1 diabetes mellitus (T1DM), plasma insulin concentrations do not decrease with exercise as they do in non-diabetic individuals, and depending on the timing of insulin administration, this may prevent the normal increase in free fatty acid (FFA) availability that occurs during physical activity. As a result, people with T1DM rely on the catecholamine response to exercise to mobilize FFA, but this response can be impaired in those with long-standing diabetes. In cases of fasting hyperglycemia where insulin levels are low, resting FFA flux is already elevated, and exercise further increases FFA flux. When combined with high glucagon concentrations, this leads to elevated rates of ketone body production.
In type 2 diabetes, experimental studies suggest a possible superiority of ACE inhibitors over ARBs in reducing atherosclerosis, although there is no conclusive evidence demonstrating the superiority of one class of antihypertensive drugs over another in people with diabetes. The beneficial effects of these drugs on cardiovascular events are mainly attributed to their antihypertensive actions. The ONTARGET study found no significant difference between ACE inhibitors and ARBs regarding cardiovascular outcomes, and combined RAAS blockade did not provide additional cardiovascular protection but was linked to more adverse events; however, only 30% of participants had diabetes, and no specific subgroup analysis has been conducted to assess the impact of different RAAS-blocking strategies on microvascular and macrovascular outcomes in diabetes.
Elevated JNK activity in obesity contributes to insulin resistance and diabetes, and loss of JNK1 can prevent these conditions in mouse models. The IKB protein influences insulin signaling by phosphorylating IRS-1 and activating the NF-κB transcription factor, which promotes inflammation through cytokines like TNF-α and IL-6. Mice with reduced IKB function are partially protected against insulin resistance from lipid infusion, high-fat diets, or genetic obesity. Additionally, activation of the JNK and IKB/NF-κB pathways occurs via pattern recognition receptors, including TLR-4, which can be activated by saturated fatty acids in obesity. Mice with TLR-4 deficiency are protected from diet-induced insulin resistance and show reduced NF-κB and JNK activity, although TLR-4 deficiency does not reduce TNF-α and IL-6 expression.
Diabetes has been managed through various approaches across history, with early lifestyle modifications such as avoiding wine, sex, and salty cereals recommended by Li Hsuan in the seventh century. Thomas Willis suggested food restriction in the seventeenth century, which later evolved into specific dietary interventions like the animal diet by John Rollo in 1797 and the oatmeal cure by Carl von Noorden in 1903. In the 20th century, Frederick Allen introduced a starvation diet for early-onset diabetes, while Karl Petren advocated for a high-fat, low-carbohydrate diet. A significant breakthrough came in 2015 when Roy Taylor demonstrated that a very low-calorie diet could lead to remission of diabetes. Insulin treatment began with Georg Zuelzer and Nicolas Paulesco isolating pancreatic extracts with hypoglycaemic activity in the early 20th century, culminating in Frederick Banting, Charles Best, J.J.R. Macleod, and James Collip isolating and clinically using insulin in Canada between 1922–1923. Hans Christian Hagedorn developed protamine insulin as the first long-acting insulin in 1936, and in 1979, David Goeddel produced synthetic human-sequence insulin using recombinant DNA technology. Innovations in insulin delivery included continuous subcutaneous infusion described by John Pickup in 1978 and the pen-injection device invented by John Ireland in 1981. Oral anti-diabetes agents also evolved over time, from ancient use of lupin, fenugreek, and zedoary seeds by Avicenna in the tenth century to the introduction of modern drug classes like sulfonylureas, biguanides, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors starting from the mid-20th century onwards. Monitoring advancements began with the first randomized trial in diabetes by the University Group Diabetes Program in 1969, followed by self-blood glucose monitoring introduced by Peter Sönsen and Robert Tattersall in 1978, and the identification of HbA1c as glycated haemoglobin by R. Flückiger and K.H. Winterhalter in 1975. The World Health Organization contributed to diabetes care through the St. Vincent Declaration in 1991, which identified treatment targets, and James Scott developed the first direct electronic glucose testing in 1991.
Infants of women with diabetes may exhibit selective organomegaly, particularly in the liver, which is not fully captured by standard measures of accelerated fetal growth such as birth weight over 4000 g or 4500 g, or above the 90th centile for gestational age and sex. While accelerated fetal growth can be detected by measuring fetal abdominal circumference at 28 weeks’ gestation, this finding is not specific to diabetes and can also result from maternal obesity and excess gestational weight gain. Fetal liver length measurements may offer a more specific indicator of hyperglycaemia in utero, though they are technically challenging to obtain.
Liraglutide, a GLP-1 receptor agonist with 97% homology to native GLP-1, was approved for clinical use in Europe in 2009 and in the USA in 2010. In the LEAD phase III clinical trials, liraglutide at a dose of 1.8 mg daily significantly lowered HbA1c, fasting plasma glucose, and body weight compared to placebo. It also reduced post-prandial plasma glucose excursions, primarily through lowering pre-prandial glucose levels, consistent with its small to moderate effects on gastric emptying. Additionally, liraglutide reduced systolic blood pressure by up to 6 mmHg but caused a small increase in heart rate of 2–4 beats per minute.
SGLT-2 inhibitors are a class of medications used in the treatment of diabetes, and their response can be influenced by genetic variations. Variants in the UGT1A9 gene, specifically UGT1A9\*3 and UGT2B4\*2, which encode enzymes involved in the metabolism of canagliflozin, lead to increased drug exposure and improved availability. Additionally, genetic variants of the SLC5A2 gene, responsible for encoding the SGLT-2 cotransporter, have been identified, but none of these single nucleotide polymorphisms (SNPs) showed a significant association with the therapeutic response to empagliflozin regarding changes in HbA1c, body weight, or systolic blood pressure.
Rosiglitazone, a medication used in the management of diabetes, has been associated with an increased relative risk of cardiac events by 43% according to a meta-analysis, raising concerns about its cardiac safety profile.
Rosiglitazone and pioglitazone are rapidly and almost completely absorbed, with peak concentrations occurring within 1 to 2 hours, though absorption is slightly delayed when taken with food. Both drugs undergo extensive liver metabolism, with rosiglitazone being metabolized mainly by CYP2C8 into inactive or weakly active metabolites that have a long plasma half-life of 100–160 hours and are primarily excreted in the urine, while pioglitazone is metabolized by CYP2C8 and CYP3A4 into active metabolites eliminated in the bile. Rosiglitazone may interact with gemfibrozil, but pioglitazone does not significantly reduce plasma concentrations of other CYP3A4-metabolized drugs like oral contraceptives. Both thiazolidinediones are highly plasma protein-bound but do not reach concentrations that interfere with other protein-bound medications.
Persistent hyperglycaemia, defined as blood glucose greater than 7.0 mmol/l in the 72 hours following an acute stroke, is linked to increased infarct size and poorer stroke outcomes. Despite this association, there is currently no conclusive evidence from outcome studies on the effectiveness of plasma glucose control in improving stroke outcomes. The largest study involving 993 individuals did not achieve normalized plasma glucose levels within 24 hours, and no research has yet evaluated glucose management in the critical early hours after stroke presentation, which may be the optimal time to address this form of hyperglycaemia.
GLP-1 receptor agonists (GLP-1 RAs) are used in the treatment of diabetes and vary in pharmacokinetics and approval timelines. Short-acting formulations such as exenatide twice daily and lixisenatide have faster onset but shorter duration, with time to peak around 2 hours and half-life of approximately 2.4 to 3 hours, primarily eliminated through the kidneys. Long-acting formulations like liraglutide, exenatide once weekly, dulaglutide, semaglutide, and oral semaglutide have extended half-lives ranging from 13 hours to 7 days, allowing for less frequent dosing. These long-acting agents are either based on GLP-1 with high homology (90–97%) or exendin-4 with lower homology (53%), influencing their metabolic stability and duration of action. Antibody development occurs more frequently with exendin-4-based agents, affecting up to 70% of individuals, while GLP-1-based long-acting formulations show lower immunogenicity, with antibody development as low as 0.01–3.5%.
Women with preexisting diabetes have higher rates of shoulder dystocia, with reported rates of 7.9% in the UK, more than double that of the general population, and this risk increases significantly with higher birth weight, from less than 1% for infants under 2.5 kg to 43% for those over 4.5 kg. Brachial plexus injury, such as Erb’s palsy, occurs at a rate of 4.5 per 1000 births in this population, which is ten times higher than in the general population, while fracture rates, typically involving the clavicle or humerus, are 7 per 1000 births. A separate study noted a 2% incidence of Erb’s palsy in infants of mothers with type 1 diabetes, and although most brachial plexus injuries resolve without long-term effects, the most severe cases occur in the largest babies. Infants born small for gestational age (SGA) to mothers with diabetes face an even greater risk of adverse outcomes, particularly neurodevelopmental complications, which are often worsened by preterm delivery. Due to these risks, delivery should be planned at a facility equipped with specialist neonatal care, as outcomes would likely be worse if more normal term deliveries occurred without appropriate intervention.
Dulaglutide, a GLP-1 receptor agonist, was studied in the REWIND trial for its effects on cardiovascular outcomes in patients with diabetes, showing a reduced incidence of MACE over 5.4 years with a hazard ratio of 0.88 compared to placebo. The trial included participants with and without prior cardiovascular disease, some of whom had risk factors such as tobacco use, dyslipidaemia, hypertension, or obesity, or other conditions like myocardial ischaemia, arterial stenosis, left ventricular hypertrophy, reduced eGFR, or albuminuria. Dulaglutide significantly lowered the risk of non-fatal stroke but not non-fatal myocardial infarction or cardiovascular death. Additionally, dulaglutide reduced the risk of a composite kidney outcome, including macroalbuminuria, a sustained decline in eGFR, or renal replacement therapy, primarily by decreasing the occurrence of new-onset macroalbuminuria.
Increased expression of GLUT-4, which enhances glucose uptake in adipocytes, and GLUT-2 in pancreatic β-cells, which facilitates glucose sensing, may improve insulin secretion and glucose homeostasis. Upregulation of adiponectin, which is associated with increased leptin, can enhance insulin sensitivity, while downregulation of inflammatory markers such as TNF-α, IL-6, CRP, and NFκB suggests a reduction in systemic inflammation that can contribute to improved insulin action. Additionally, decreased levels of resistin, RBP4, PAI-1, and MMP-9 may further support better glucose metabolism and reduced insulin resistance.
Liraglutide, when added to existing diabetes medications such as rosiglitazone and metformin, leads to significant reductions in HbA1c levels in patients with type 2 diabetes inadequately controlled on oral agents. In clinical trials, liraglutide at doses of 1.2 mg and 1.8 mg daily resulted in mean HbA1c reductions of 1.5% each, compared to a 0.5% reduction with placebo over 26 weeks. It also improved fasting plasma glucose and postprandial glucose levels more effectively than placebo, with greater decreases observed in both measurements. Liraglutide induced dose-dependent weight loss and reduced systolic blood pressure more than placebo. When compared directly with exenatide in a 26-week study, liraglutide demonstrated a greater reduction in HbA1c by 0.3%, with more patients achieving an HbA1c below 7%. Liraglutide also showed superior fasting plasma glucose control compared to exenatide, while both drugs resulted in similar weight loss, though liraglutide was associated with less persistent nausea and fewer episodes of minor hypoglycemia.
In diabetic cells with high glucose levels, increased glucose oxidation in the TCA cycle leads to a higher production of electron donors NADH and FADH2, which enter the electron transport chain and elevate the mitochondrial membrane voltage gradient. When this voltage surpasses a critical threshold, electron transfer in Complex III is blocked, causing electrons to accumulate at coenzyme Q, which then transfers them one at a time to molecular oxygen, generating superoxide. The mitochondrial isoform of superoxide dismutase converts superoxide into hydrogen peroxide, which is further broken down into water and oxygen by other enzymes. Intracellular hyperglycemia raises the mitochondrial membrane voltage beyond the threshold needed for increased superoxide formation, leading to elevated production of reactive oxygen species (ROS).
Bile acid signaling through the G-protein-coupled bile acid receptor (TGR5) has been shown to induce GLP-1 secretion in enteroendocrine and primary intestinal cell cultures, with TGR5 activation confirmed as the mediating factor. Animal studies demonstrate that TGR5 signaling contributes to glucose homeostasis, as selective TGR5 agonists in high-fat fed mice reduce plasma glucose and insulin levels while improving glucose clearance. Transgenic mice overexpressing TGR5 exhibit enhanced glucose clearance and increased post-prandial GLP-1 and insulin secretion, whereas TGR5 knockout animals show impaired glucose tolerance and GLP-1 secretion. Clinical studies with bile acid sequestrants in humans indicate that GLP-1 responses align with changes in insulin sensitivity, supporting a link between bile acid signaling and diabetes risk. Additionally, TGR5 activation by bile acids may indirectly influence insulin signaling through inhibitory effects on inflammatory cytokine production.
For pregnant women with gestational diabetes, food choices should support adequate weight gain, maintain normoglycemia, and prevent ketone production. Overweight or obese women may require modest energy and carbohydrate restriction, while weight loss is not advised. Salivation ketosis should be avoided, and those on insulin therapy need individualized carbohydrate-controlled meal plans with consistent meal timing and portions to prevent hypoglycemia. Insulin and meal plan adjustments should be based on blood glucose self-monitoring, considering changes in insulin sensitivity across pregnancy trimesters. Additionally, increased nutritional needs for protein (1.2–2 g/kg body weight), calcium (1300 mg/day), iron (30 mg/day), iodine (230 μg/day), and folate (600 μg/day) should be addressed starting in the second trimester.
Basal insulin is used to meet basic metabolic needs and is typically initiated in people with type 2 diabetes progressing to insulin therapy as a once-daily bedtime dose, though some types like NPH and insulin detemir can be given twice daily. The starting dose is generally 10 units or 0.1–0.2 units/kg, with adjustments based on fasting glucose levels. Among basal insulin analogues, differences in blood glucose control are small and of limited clinical relevance. Newer options such as insulin degludec and glargine U300 offer longer duration of action and reduced risk of nighttime hypoglycaemia, while insulin detemir may be associated with less weight gain. Concentrated formulations like degludec U-200 and glargine U-300 are beneficial for individuals with insulin resistance due to the smaller injection volume required. Although basal insulin analogues are more expensive than NPH insulin, biosimilars are now available at a lower cost, and cardiovascular safety data for glargine and degludec are reassuring.
Social context significantly influences diabetes self-management in adolescents, particularly those with type 1 diabetes. Adolescents who are highly peer-oriented may view diabetes as a hindrance to participating in social activities. Research has shown that teenagers with type 1 diabetes are more likely to monitor their blood glucose levels when they wish to blend in with peers, while they are less likely to do so when trying to impress others. Frequent blood glucose monitoring is important as it helps identify abnormal glucose levels, enabling timely intervention to prevent episodes of hypoglycaemia or hyperglycaemia, which can cause embarrassment due to their sudden and noticeable symptoms.
Autoimmune type 1 diabetes mellitus (T1DM) arises from the loss of immunologic tolerance to beta cells, with environmental factors potentially initiating or promoting autoimmunity. The disease involves specific autoimmune mechanisms targeting beta cells, characterized by infiltration of pancreatic islets by CD4+ and CD8+ T lymphocytes and macrophages, leading to insulitis. Before clinical symptoms appear, autoantibodies against specific islet autoantigens such as insulin, glutamic acid decarboxylase (GAD65), islet antigen-2 (IA-2), and zinc transporter (ZnT8) may be present for months to years. While the presence of these autoantibodies, like GAD65Ab and IA-2Ab, has been associated with insulitis, recent findings suggest that not all individuals with islet autoantibodies develop insulitis, indicating that their role as markers of beta-cell destruction remains unclear and requires further investigation.
In type 2 diabetes, plasma concentrations of GIP are normal or slightly reduced, while those of GLP-1 show a reduced late phase. The insulin-releasing effect of GIP is reduced in type 2 diabetes, whereas that of GLP-1 is mostly retained. Both GIP and GLP-1 increase glucose-induced insulin secretion, proinsulin biosynthesis, and β-cell mass in rodents, but differ in other actions relevant to diabetes. GLP-1 decreases gastric emptying, appetite, and weight gain, while GIP has no significant effect or may even increase weight gain. GLP-1 also decreases glucagon secretion, has possible benefits on myocardial metabolism, and plays a more favorable role in diabetes management compared to GIP.
Infections have been linked to type 1 diabetes mellitus (T1DM) through various studies, including in vitro research, animal models, clinical and pathologic investigations, and epidemiologic studies. Congenital rubella syndrome (CRS) is associated with a significantly increased incidence of T1DM, serving as a notable example of a non-genetic factor influencing diabetes risk, particularly during intrauterine development. While CRS is no longer a major contributor to T1DM in most countries today, it highlights the potential role of viral infections in the disease's development, though the consistency and magnitude of its effect may have been exaggerated in some assessments.
DPP-4 inhibitors are a class of medications used in the treatment of diabetes, particularly type 2 diabetes, by enhancing the activity of incretin hormones that stimulate insulin secretion and reduce glucagon release.
Limited joint mobility is a syndrome characterized by joint contractures and decreased passive mobility in people with diabetes, particularly affecting the proximal interphalangeal and metacarpophalangeal joints of the hands, with the fifth proximal interphalangeal joint being the first affected. The skin on the back of the hands often appears tight and waxy. Other joints such as the wrists, elbows, ankles, and cervical spine may also be involved, and severe cases can lead to reduced lung volumes. Pain is typically mild or absent in the early stages, and there is usually no synovitis, distinguishing it from systemic sclerosis.
Improvement of carbohydrate metabolism in Cushing syndrome can be achieved by reducing cortisol levels, though diabetes or glucose intolerance may not fully resolve in all cases, possibly due to irreversible changes in insulin secretion or action from prolonged cortisol exposure or other predisposing conditions. For acute severe hyperglycemia in Cushing syndrome, intensive insulin therapy with multiple daily injections is recommended, often combined with steroidogenesis inhibitors. In less severe cases, oral anti-diabetes medications such as metformin and PPAR-γ agonists are preferred. Metformin has shown additional benefits in reducing inflammation, improving fibrinolysis, and lowering infection rates and hospitalizations. Thiazolidinediones enhance lipid storage and reduce visceral fat but are associated with weight gain and uncertain cardiovascular effects, making them less favorable than metformin. SGLT-2 inhibitors help lower glucose and weight and offer cardiovascular and renal protection, though they may increase the risk of urogenital infections, especially with glucocorticoid excess. GLP-1 receptor agonists and DPP-4 inhibitors aid in glucose-dependent insulin secretion and glucagon reduction, with GLP-1 agonists also suppressing appetite and positively affecting fat distribution.
Adiponectin has beneficial effects such as enhancing insulin sensitivity, improving endothelial function, and reducing inflammation, but its levels are decreased in individuals with overweight, obesity, or type 2 diabetes. While supplementing adiponectin directly may not be practical, small-molecule agonists of adiponectin receptors show potential in improving insulin resistance and glycaemic control based on pre-clinical studies. Other adipocyte hormones, including resistin and retinol-binding protein 4, reduce insulin sensitivity, whereas omentin and visfatin enhance it. Many adipocyte-derived peptides affect inflammatory processes, with proinflammatory adipokines like TNF-α and IL-6 being linked to insulin resistance, though their suitability as glucose-lowering targets remains uncertain.
SGLT-2 inhibitors effectively lower glucose levels in type 2 diabetes, both as monotherapy and when used with other glucose-lowering agents including insulin, with a rapid onset of action in reducing postprandial and basal hyperglycaemia. HbA1c levels typically decrease by approximately 0.6–1.2% (7–13 mmol/mol), with greater reductions observed in individuals with severe hyperglycaemia and good renal function. These inhibitors maintain efficacy over several years and carry a low risk of hypoglycaemia unless combined with medications that independently cause hypoglycaemia, such as sulfonylureas or insulin. Weight loss of around 2–4 kg is common, primarily from visceral fat reduction, and tends to stabilize after 6–12 months. In insulin-treated type 2 diabetes, adding an SGLT-2 inhibitor improves glycaemic control while allowing a slight reduction in insulin dose without the need for dose escalation over time, and also mitigates insulin-associated weight gain.
Rosiglitazone, when used as initial monotherapy for newly diagnosed type 2 diabetes mellitus (T2DM), demonstrated a longer duration of monotherapy success (60 months) compared to metformin (45 months) or glyburide (33 months) in the ADOPT trial. At the 4-year mark, 40% of patients on rosiglitazone achieved a glycated hemoglobin level below 7% (<53 mmol/mol), compared to 36% on metformin and 26% on glyburide, with statistically significant differences. Despite this relative advantage, most patients with T2DM eventually require combination therapy within 3 to 6 years of starting medication, as no therapy has been shown to fundamentally alter the progressive decline of β-cell function.
Islet transplantation faces challenges due to the limited availability of donor pancreases, with most patients requiring multiple islet infusions to achieve insulin independence. Advances have been made in achieving insulin independence using islets from a single donor through improved islet preparation, recipient selection, and immunosuppressive strategies. Alternative sources of islets, such as xenografts like porcine islets or stem cells, are under preclinical investigation but not yet in clinical use.
MODY2 and MODY3, caused by mutations in GCK and HNF1A respectively, are the two most prevalent subtypes of maturity-onset diabetes of the young (MODY), accounting for approximately 50-60% of all MODY cases. Other subtypes include MODY1 caused by HNF4A mutations, MODY5 caused by TCF2/HNF-1β mutations, and rarer forms such as those resulting from mutations in PDX1 and NEUROD1. The prevalence of these subtypes varies across populations, potentially due to genetic differences or ascertainment bias in family recruitment.
Autoantibodies to GAD are considered sensitive markers for type 1 diabetes mellitus (T1DM) in Caucasians and can also be present in patients with type 2 diabetes mellitus (T2DM), particularly those with autoimmune diabetes in adults, known as latent autoimmune diabetes in adults (LADA). Studies, including the UK Prospective Diabetes Study (UKPDS), have shown that around 10% of individuals with T2DM possess anti-GAD antibodies, with most progressing to insulin dependency. Research across various ethnic groups indicates that LADA may account for approximately 10% of diabetic populations, while in Asians, the prevalence of anti-GAD antibodies among those with diabetes and acute or early onset of disease ranges from 10% to 50%, depending on selection criteria and assay methods.
ACE inhibitors are particularly beneficial for individuals with diabetes who have albuminuria or more advanced diabetic nephropathy, and other antihypertensive agents such as diuretics, beta-1 selective blockers, and calcium-channel antagonists are also effective for blood pressure control in these patients.
ACE inhibitors do not have adverse metabolic effects and may improve insulin sensitivity, with hypoglycemia rarely reported. They are especially beneficial in diabetic nephropathy by reducing albuminuria and potentially slowing the progression of renal damage. This antiproteinuric effect may result from the relaxation of efferent arterioles in the glomerulus, which are highly sensitive to angiotensin II-induced vasoconstriction, thereby lowering intraglomerular hypertension that is thought to promote albumin filtration, although the significance of this mechanism is debated.
In individuals with type 2 diabetes mellitus (T2DM), treatment with a fixed dose of perindopril and indapamide led to a mean reduction in systolic and diastolic blood pressure of 5.6 and 2.2 mmHg respectively, resulting in an 18% reduction in cardiovascular deaths and a 14% reduction in coronary events compared to the control group. There may be no lower limit for blood pressure reduction at which cardiovascular benefits are not observed, with a similar trend reported for renal disease. The ongoing ACCORD trial is investigating whether lowering systolic blood pressure to 120 mmHg further reduces cardiovascular event rates compared to the standard target of 140/90 mmHg.
Meglitinides, such as nateglinide and repaglinide, are secretagogues that act on different pancreatic β-cell receptors than sulfonylureas but have a similar mechanism of action, with a rapid onset and short duration, making them effective for controlling post-prandial glucose excursions. These agents require frequent dosing and may be suitable for individuals with irregular meal schedules. They carry a similar risk of weight gain as sulfonylureas but may have a lower risk of hypoglycaemia. Repaglinide is primarily metabolized by the liver and can be used safely in patients with mild to moderate renal impairment, though meglitinides should be titrated slowly based on blood glucose levels to reduce the risk of hypoglycaemia.
Common variants in monogenic diabetes genes, such as single nucleotide polymorphisms (SNPs), may play a minor role in susceptibility to type 2 diabetes mellitus (T2DM), with some variants showing modest effects on disease risk. For example, the -30G/A polymorphism in the β-cell specific promoter of glucokinase (GCK) modulates diabetes risk, where the -30A allele is associated with an increased risk. This variant also influences fasting glycemia and insulin secretion as measured by the HOMA-B index. A meta-analysis found a modest overall effect of the GCK (-30A) variant on T2DM risk in European populations, with an odds ratio of 1.08 (P = 0.004). Additionally, an intronic variant of TCF2/HNF-1β showed strong effects in a case-control study involving multiple clinical samples.
Current consensus guidelines recommend early adoption of insulin therapy for diabetes, though it remains underutilized due to patient and provider hesitancy related to concerns such as weight gain and severe hypoglycemia. Addressing these barriers can improve the success of insulin initiation. Combining insulin with sulfonylureas has been extensively studied and forms the basis for many basal insulin strategies. A common approach involving twice-daily administration—bedtime insulin and daytime sulfonylurea—has shown effectiveness, particularly before metformin became widely used in the USA. Bedtime insulin helps suppress hepatic glucose production, complementing the prandial insulin support provided by sulfonylureas.
Fasting hyperglycemia outside pregnancy, defined as blood glucose levels between 5.5–8 mmol/L, and a small rise in blood glucose during a 2-hour oral glucose tolerance test (OGTT), defined as less than 4.6 mmol/L, are indicators related to diabetes. Additionally, a requirement for insulin treatment during previous pregnancies that is later controlled by diet, having a first-degree relative with type 2 diabetes mellitus (T2DM), and experiencing gestational diabetes mellitus (GDM) or fasting hyperglycemia during pregnancy, defined as blood glucose levels above 5.5 mmol/L, are also associated risk factors.
HRT (hormone replacement therapy) has been studied for its effects on lipid profiles and metabolic parameters in women with diabetes. In a small randomized crossover study involving women with overweight and type 2 diabetes, conjugated oestrogen therapy was found to reduce central obesity, HbA1c levels, and total cholesterol, while also improving physical functioning. Another small study showed that conjugated oestrogens decreased total and LDL cholesterol and increased HDL cholesterol in women both with and without diabetes; however, the addition of medroxyprogesterone acetate negated the increase in HDL without affecting fasting glucose or insulin levels. In a larger study of 61 postmenopausal women with diabetes, combined HRT reduced total and LDL cholesterol but did not alter serum HDL or triglyceride levels.
Increased intracellular calcium levels due to primary hyperparathyroidism cause insulin resistance and reduced cellular glucose uptake, contributing to a threefold higher prevalence of diabetes in individuals with more severe cases of this condition compared to the general population. The effectiveness of parathyroidectomy in normalizing glucose tolerance in these individuals is not well established when compared to other forms of diabetes secondary to endocrine disorders. Management of diabetes in people with hyperparathyroidism follows standard diabetes treatment guidelines.
Integrated specialist diabetes care is resource-intensive, often described as "Rolls Royce" in nature, and its implementation in "super centers" creates a challenge in balancing advanced services with everyday diabetes care for a large population. Resource limitations make this balance difficult, particularly for units reliant on patient throughput for funding, prompting the need for a rational discussion on defining who requires specialist care and what it should include.
GLP-1 is produced by pancreatic islet α cells and its production is increased in islets from donors with type 2 diabetes, while DPP-4 activity, which inactivates GLP-1, is reduced in these individuals. This suggests a potential compensatory mechanism to increase intra-islet GLP-1 availability, possibly aimed at protecting β cells.
Sulfonylureas are a class of drugs used in the management of diabetes, and they act by binding to sulfonylurea receptors (SURs). There are different isoforms of these receptors, such as SUR2A and SUR2B, which are found in cardiac and vascular smooth muscle, respectively. These isoforms lack the sulfonylurea binding site but retain the benzamido binding site, meaning they can only interact with sulfonylureas containing a benzamido group, such as glibenclamide, glipizide, and glimepiride. In contrast, sulfonylureas without a benzamido group, like tolbutamide, chlorpropamide, and gliclazide, have minimal interaction with cardiac and vascular SUR receptors. The presence of a benzamido group in certain sulfonylureas may influence cardiovascular effects, as these compounds can block the action of nicorandil, an anti-anginal drug with cardioprotective properties that acts through the opening of ATP-sensitive potassium ($\mathrm{K}^{+}$ ATP) channels.
Hypoglycaemia in older people with diabetes is common but can be difficult to recognize and diagnose due to the predominance of neurological symptoms such as dizziness or visual disturbance, which may lead to misdiagnosis. The clinical presentation of hypoglycaemia can resemble dementia, with symptoms including agitation, increased confusion, or behavioural changes, and its symptoms tend to be less specific with increasing age. Many older individuals report no specific diabetes-related symptoms when blood glucose levels drop, making hypoglycaemic episodes harder to identify. Studies such as the ACCORD trial have shown that nonspecific symptoms like fatigue or weakness are common manifestations of hypoglycaemia in older adults. In older people, autonomic symptoms of hypoglycaemia occur at lower blood glucose levels while cognitive dysfunction occurs at higher levels compared to younger adults, leading to nearly simultaneous onset of autonomic and neurological symptoms with little warning, a condition known as impaired awareness of hypoglycaemia. Subclinical hypoglycaemia or episodes with fewer symptoms can further reduce awareness, creating a cycle where one episode increases the likelihood of subsequent ones, resulting in many hypoglycaemic events being unrecognized and under-reported by both patients and healthcare professionals, thereby underestimating its true frequency.
Predisposing factors to urinary tract infections (UTI) in the context of diabetes include glycosuria, longer duration of diabetes, poor glycemic control, and diabetes-related complications such as macroalbuminuria and neutrophil dysfunction. These factors contribute to an increased risk of UTI due to mechanisms like increased *E. coli* adhesion, decreased urinary cytokine excretion, and impaired immune function. Additionally, diabetes-associated conditions like renal papillary necrosis and chronic renal failure further contribute to susceptibility to urinary tract infections.
Hypoglycaemia unawareness occurs when there is reduced awareness of the onset of hypoglycaemia, typically due to a blunted response of counter-regulatory hormones in the setting of recurrent hypoglycaemic events, and it is usually seen in children who have multiple periods of blood glucose ${ < } 7 0 \mathrm { m g / d l }$ $\left( 3 . 9 \mathrm { m m o l } / \mathrm { l } \right)$. A single hypoglycaemic episode can lead to hypoglycaemia unawareness secondary to a decrease in counter-regulatory responses, but avoiding subsequent hypoglycaemia for 2–3 weeks may reverse this loss of awareness, although these changes can persist for months or years in some individuals.
Insulin resistance, a key factor in the development of type 2 diabetes, is closely associated with obesity, ectopic fat accumulation, and impaired lipid metabolism in insulin-responsive tissues such as skeletal muscle, liver, and adipose tissue. The earliest development of insulin resistance most likely occurs in adipose tissue in humans. The accumulation of plasma membrane sn-1,2-DAGs due to an imbalance between lipid influx and oxidation or TAG synthesis leads to activation of PKC enzymes and subsequent insulin resistance. This mechanism explains the high prevalence of obesity-associated insulin resistance, where lipid delivery exceeds storage and oxidation, as well as insulin resistance linked to impaired adipocyte storage capacity in lipodystrophy and reduced substrate oxidation in inherited or acquired conditions such as in lean, insulin-resistant relatives of individuals with type 2 diabetes or during ageing. Rapid reversibility of hepatic insulin resistance with moderate weight loss in individuals with NAFLD, and the effects of leptin replacement in generalized lipodystrophy and type 2 diabetes further support this mechanism.
Orlistat has been studied for its role in the prevention and treatment of type 2 diabetes mellitus (T2DM), particularly in patients on metformin or insulin. In the XENDOS trial involving 3305 obese individuals at risk for T2DM, those with impaired glucose tolerance who received orlistat alongside therapeutic lifestyle changes experienced a 37% relative risk reduction in developing T2DM over four years, along with beneficial effects on lipid profiles.
In diabetes, increased superoxide inhibits GAPDH activity, leading to the accumulation of glycolytic intermediates above the enzyme, which are then directed into four pathways of hyperglycemic damage. Two of these intermediates, fructose-6-phosphate and glyceraldehyde-3-phosphate, are also products of the transketolase reaction, a rate-limiting step in the pentose phosphate pathway. High concentrations of these intermediates in diabetes suggest that activating transketolase could lower their levels by converting them into pentose phosphates, thereby diverting their flux away from three damaging hyperglycemia-activated pathways. Transketolase requires thiamine as a co-factor, and while thiamine alone activates the enzyme by 25% in arterial endothelial cells, the thiamine derivative benfotiamine achieves a 250% activation.
HIV infection and its treatment with antiretroviral therapy increase the risk of type 2 diabetes, insulin resistance, and other metabolic complications. Studies show that HIV-infected men have higher odds of insulin resistance compared to uninfected men, and those on antiretroviral therapy have a fourfold higher incidence of diabetes. In a large cohort study, the incidence rate of diabetes among people with HIV was 4.4 cases per 1000 person-years, with increased risk observed in men, older individuals, those with obesity, and people of African American or Asian ethnicity. Certain antiretroviral therapy combinations, particularly those involving nucleoside reverse-transcriptase inhibitors (NRTI), NRTI/protease inhibitor (PI) combinations, and NRTI/PI/non-nucleoside reverse-transcriptase inhibitors (NNRTI) combinations, were strongly associated with increased diabetes risk, while NRTI/NNRTI combinations were not.
Insulin duration of action in bolus calculator software is adjusted based on clinical factors such as hypoglycemia risk and the need for tight glycemic control, particularly in preconception and pregnancy. Patients with frequent hypoglycemia, hypoglycemia unawareness, or a history of severe hypoglycemic reactions may require a longer duration of action setting, typically 5 hours or more, while those who are pregnant or trying to conceive often have the duration set at 2–3 hours. Incorrect settings can lead to either hypoglycemia due to insulin "stacking" if the programmed duration is too short, or poor glycemic control if the duration is set too long. Patient glucose records can help assess the appropriateness of these settings.
In type 2 diabetes, microsomal triglyceride transfer protein (MTP), which is responsible for assembling chylomicrons in the intestine and VLDL particles in the liver, is increased in the intestine. Additionally, cholesterol absorption is negatively affected, with higher levels of NPC1L1 protein, involved in cholesterol absorption, and reduced levels of ATP-binding cassette transporters ABCG5 and ABCG8, which help in the efflux of dietary cholesterol and non-cholesterol sterols from the intestine and liver. Lipoprotein lipase (LPL), an insulin-dependent enzyme crucial for converting lipoprotein triglycerides into free fatty acids, shows reduced activity in both type 1 and type 2 diabetes, a condition further worsened by adipose-derived cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6).
Some sulfonylureas have been reformulated to alter their duration of action, with examples including a micronized formulation of glibenclamide (glyburide) that increases gastrointestinal absorption for faster onset, and extended-release formulations of glipizide and gliclazide designed for once-daily dosing, where the 30mg modified-release preparation of gliclazide offers comparable efficacy to 80mg of the unmodified version while reducing the risk of severe hypoglycaemia.
Defects in insulin signaling and impaired insulin secretion in type 2 diabetes mellitus (T2DM) can be partially reversible with therapeutic normalization of glycemia over approximately 2–3 weeks. Elevated glucose concentrations contribute to these defects through a mechanism known as "glucose toxicity." One key pathway involved in glucose-induced insulin resistance is the hexosamine biosynthetic pathway, where glucose metabolism leads to the production of UDP-N-acetylglucosamine (UDP-GlcNAc), which serves as a substrate for O-linked N-acetylglucosamine transferase (OGT). OGT adds O-GlcNAc modifications to cytoplasmic and nuclear proteins, affecting their activity, degradation, and interactions. UDP-GlcNAc levels respond to the availability of glucose, glutamine, uridine, and non-esterified fatty acids, allowing the hexosamine biosynthetic pathway to function as a nutrient sensor and regulator in the context of diabetes.
Some indications for admitting diabetic patients in the hospital and managing them intensively include severe hyperglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic state, severe hypoglycemia, acute complications such as infections or cardiovascular events, and the need for intensive insulin therapy or close monitoring.
Certain amino acid residues on the DQ A-chain (α44, α157, α196) and DQ B-chain (β9, β30, β57, β70, β135) are associated with islet autoimmunity and play a role in the genetic susceptibility or resistance to type 1 diabetes, with specific motifs such as DCAA-YSARD (DQ2.5), DQAA-YYARD (DQ8), and DQDA-YYARD (DQ8.1) accounting for the structural basis of islet autoimmunity linked to the disease.
Genetic variants of HK1, which encodes hexokinase type 1 predominantly found in erythrocytes and also expressed in glucose-dependent tissues like brain and muscle, may influence HbA1c levels and could affect glycation through altered erythrocyte glucose metabolism or systemic glucose metabolism, potentially influencing diabetes risk. Additionally, the study found associations between HbA1c levels and loci such as GCK, G6PC2, and SLC30A8 in individuals without diabetes, with SLC30A8 being a diabetes-related gene. The role of HK1 in muscle, an insulin-sensitive tissue important for glucose metabolism, suggests that HK1 variations may be linked to diabetes development. It remains unclear whether genetic polymorphisms affecting hemoglobin glycation also impact glycation in other tissues linked to diabetes complications.
The developmental stage of the disease presents as acute inflammation with swelling, warmth, and erythema of the foot, sometimes accompanied by pain despite peripheral sensory neuropathy, and is associated with easily palpable peripheral pulses. Gradual worsening leads to deformity, bone resorption, fracture, and dislocation, resulting in foot instability and a rocker-bottom appearance. Imaging findings include normal plain radiographs in the early acute phase (Stage 0), with MRI showing bone marrow edema, subchondral cysts, and microfractures, while bone scintiscan demonstrates increased uptake. As the disease progresses to Stage 1, radiographs reveal osteolysis, bone fragmentation, and disordered architecture. In Stage 2 (coalescence phase), hyperemia resolves, swelling decreases, and bone debris is resorbed with possible sclerosis. Stage 3 (reconstructive stage) involves bone remodeling, ankylosis, bone proliferation, and a stable foot. The acute phase (Stages 0 and 1) lasts 2–6 months, and the reparative phase (Stages 2 and 3) may last up to 24 months, with both phases carrying a risk of ulceration and secondary osteomyelitis due to abnormal load bearing from deformity.
Hyperglycaemia-induced mitochondrial superoxide production contributes to ongoing tissue damage even after hyperglycaemia is corrected, a phenomenon known as hyperglycaemic memory. This process involves post-translational modifications of histones, leading to chromatin remodelling and altered gene expression, which are classified as epigenetic changes due to their independence from DNA sequence. Transient hyperglycaemia can induce long-lasting activating epigenetic changes in the promoter region of the Fibsubunit p65 gene in human aortic endothelial cells and in aortic cells of non-diabetic mice, resulting in sustained increases in p65 gene expression and the expression of p65-dependent pro-inflammatory genes. These epigenetic and gene expression changes can persist for at least six days under subsequent normal glycaemic conditions. Hyperglycaemia-induced epigenetic changes and elevated p65 expression can be prevented by normalizing mitochondrial superoxide production or reducing superoxide-induced methylglyoxal levels.
Some infections that are more common in people with diabetes include malignant otitis externa, mucormycosis, emphysematous cholecystitis, emphysematous cystitis, emphysematous pyelonephritis, and Fournier gangrene, likely due to the compromised immune response and other metabolic factors associated with diabetes.
A very low calorie diet (VLCD) can lead to rapid improvements in insulin resistance and glycemic control, even over short periods, and may be particularly beneficial for patients with poor metabolic control. However, VLCD can only be applied for a limited time and requires intensive medical supervision. While VLCD shows moderately better long-term results compared to conventional diets, significant weight regain is common. Combining intermittent VLCD with conventional hypocaloric diets may offer better long-term outcomes. Additionally, modifying nutrient intake to reduce adipose tissue inflammation is a potential strategy, although there is limited evidence on whether specific dietary components can independently improve adipose tissue inflammation beyond calorie restriction. Further research is needed to explore the role of dietary components in managing obesity and improving diabetes outcomes.
Patients with diabetes are susceptible to Candida infections, which can manifest as flexural infections with satellite lesions or chronic paronychia caused by *Candida albicans*, characterized by swollen and erythematous nailfolds.
Patients with diabetes who are at risk of foot ulcers often lack the necessary knowledge and skills for proper foot self-care, including understanding the risks of insensate feet, the importance of regular self-inspection, maintaining foot hygiene, and seeking professional chiropody or podiatry treatment when needed. Misconceptions about neuropathy, such as viewing it as primarily a circulatory issue or directly linking it to amputation, can hinder the effectiveness of education programs aimed at preventing foot ulcers. Effective education must address these distorted beliefs and emphasize that foot ulcers typically precede amputations, highlighting the importance of timely intervention and self-care practices at various stages leading to neuropathic ulceration.
Hyperglycemia contributes to the overproduction of reactive oxygen species (ROS) through dynamic changes in mitochondrial morphology, and mitochondrial fission inhibition can prevent periodic ROS fluctuations during high glucose exposure. ROS production during hyperglycemia can be mitigated by collapsing the mitochondrial membrane voltage gradient via uncoupling protein 1 (UCP-1) or degrading superoxide using manganese superoxide dismutase (MnSOD), which also prevents the inhibition of eNOS activity. Inhibiting hyperglycemia-induced superoxide overproduction via overexpression of SOD prevents experimental diabetic nephropathy and retinopathy in animal models. In humans, gene expression profiles from skin fibroblasts of patients with type 1 diabetes mellitus (T1DM) show that those with a fast progression of diabetic nephropathy exhibit increased expression of oxidative phosphorylation genes, electron transport system Complex II, and TCA cycle genes compared to those with slower progression, supporting the role of mitochondrial ROS in diabetic complications.
Psychological adaptation to diabetes diagnosis in adulthood is not fully understood due to limited longitudinal studies. The Diabetes Control and Complications Trial (DCCT), a major study on type 1 diabetes, showed no change in self-reported psychological symptoms over 6–9 years and found no link between treatment type (conventional or intensive insulin therapy) and psychological distress. Additionally, rates of clinically significant depression were higher in both treatment groups (25%) compared to the general population (14%) as measured by self-report questionnaires.
Several risk factors are known to be associated with increased risk of type 2 diabetes, including increasing age, obesity (especially central obesity), dietary excess, dietary factors such as increased intake of animal fats and sugar-sweetened beverages, sedentary lifestyle, positive family history, history of gestational diabetes, polycystic ovary syndrome, presence of hypertension, hyperlipidaemia, or other cardiometabolic risk factors. Many of these risk factors are associated with a Westernized lifestyle and increase with increasing urbanization and mechanization. The recognition of the role of these factors in the pathogenesis of type 2 diabetes has led to recommendations for selective screening for type 2 diabetes in people with these risk factors.
GLP-1 secretion is stimulated by meal ingestion, with plasma concentrations rising within 5–15 minutes of eating and peaking after 45–60 minutes. Nutrients such as fat, carbohydrates, and protein interact with L cells in the intestine, leading to GLP-1 release into the bloodstream, a process linked to glucose absorption and metabolism within the L cells. L cells also express G protein-coupled receptors activated by fatty acids, bile acids, and other factors, further promoting GLP-1 secretion, which is modulated by paracrine and neurohormonal mechanisms involving somatostatin, GIP, and the vagus and sympathetic nerves.
NAFLD, particularly NASH with liver fibrosis, worsens systemic and hepatic insulin resistance and promotes the release of pro-inflammatory cytokines, hepatokines, and other diabetogenic mediators, contributing to the development of type 2 diabetes. Additionally, adipose tissue dysfunction and high-fat, high-carbohydrate diets increase hepatic lipid availability through excessive lipolysis and delivery of chylomicron remnants and free fatty acids. When combined with inadequate mitochondrial adaptation, this leads to the hepatic accumulation of diacylglycerols and metabolites like ceramides, further promoting NAFLD progression and indirectly influencing diabetes risk.
In type 2 diabetes mellitus (T2DM), treatment with thiazolidinediones (TZDs), specifically rosiglitazone and pioglitazone, has been associated with an increased fracture risk, particularly in women. Data from randomized controlled trials showed a twofold increase in the risk of distal limb fractures in women using TZDs, though no such increase was observed in men. Observational studies in older male T2DM populations indicated that men also experience higher fracture risks with TZD use, including an elevated incidence of classic osteoporotic fractures such as those of the hip, forearm, and humerus.
Insulin resistance has been linked to hypertension, although the relationship is inconsistent and remains controversial. In insulin-resistant individuals, basal intracellular Ca²⁺ levels are elevated, and insulin's ability to counteract angiotensin II-induced increases in intracellular Ca²⁺ is impaired in skin fibroblasts. However, in patients with type 2 diabetes mellitus (T2DM), insulin's renal action to reabsorb sodium remains unchanged, suggesting that alterations in insulin’s antinatriuretic effect do not account for the higher prevalence of hypertension in insulin-resistant individuals or those with T2DM. Insulin resistance also correlates with increased sodium-lithium counter-transport in erythrocytes, which may reflect heightened Na⁺-H⁺ pump activity in other tissues, potentially raising intracellular Na⁺ and Ca²⁺ concentrations and increasing vascular smooth muscle contractility. These mechanisms may contribute to hypertension in both insulin-resistant non-diabetic individuals and patients with T2DM. Additionally, impaired insulin-induced vasodilatation could theoretically lead to increased peripheral vascular resistance and elevated diastolic blood pressure.
DPP-4 inhibitors such as sitagliptin, vildagliptin, saxagliptin, and alogliptin improve glycemic control in a manner similar to GLP-1 analogs, though differences exist due to increased endogenous GIP levels and lower concentrations of endogenous incretins compared to exogenously administered GLP-1 analogs. As a result, DPP-4 inhibitors are less likely to cause initial nausea or significant satiety effects, leading to minimal changes in body weight. These agents demonstrate high specificity for DPP-4 inhibition, with therapeutic concentrations achieving nearly complete inhibition of DPP-4 activity for around 12 hours, offering glucose-lowering efficacy comparable to existing DPP-4 inhibitors.
New antidiabetic drugs must be safe, well-tolerated, and conveniently administered with minimal risk of serious hypoglycemia, offering durable efficacy and potentially additional benefits such as a novel mode of action or favorable pharmacokinetics suited for specific populations like the elderly. Ideally, these drugs should be compatible with combination therapy and provide advantages against conditions commonly associated with diabetes, including abdominal obesity, dyslipidemia, hypertension, and other vascular diseases or risk factors. A new drug may also target underlying metabolic disturbances such as countering insulin resistance, improving β-cell function, reducing hyperglucagonemia, or decreasing glucotoxicity or lipotoxicity.
For individuals with type 1 or type 2 diabetes treated with multiple insulin injections, the dose of short-acting insulin before exercise can be reduced instead of adjusting diet, with the reduction tailored to individual blood glucose responses before, during, and after exercise. The required reduction can be as much as 75% of the usual dose, though 20–50% is more common, depending on the exercise's intensity and duration. The insulin formulation to reduce is the one with peak action during exercise, and in cases of brief, intense activity like sprinting or weightlifting, insulin reduction may not be necessary. If blood glucose rises during exercise, insulin dosage might need a slight increase or a change in injection timing to achieve higher plasma insulin levels during activity. Insulin pumps offer advantages for active individuals by allowing more precise adjustments to insulin levels for meals, snacks, and exercise, with generally reduced glucose absorption variability lowering hypoglycemia risk. Insulin reductions for pump users may or may not require carbohydrate supplementation.
CSII therapy with insulin pumps was first described in 1978 for individuals with insulin-dependent diabetes, but initially declined in popularity due to concerns over size, safety, and efficacy. Following the Diabetes Control and Complications Trial (DCCT) in the 1990s, which showed slightly better glycaemic control with CSII compared to multiple daily injections (MDI), there was a resurgence in its use, aided by technological advances in glucose monitoring and insulin delivery systems. Since then, CSII has been shown to reduce glycated haemoglobin (HbA1c) and the frequency of hypoglycaemia, and is now incorporated into management pathways for selected individuals with type 1 diabetes. However, access to CSII therapy varies significantly by region, with 11.7% of people with type 1 diabetes in England currently using it compared to 40% in the USA.
Monogenic diabetes, often misdiagnosed as type 1 or type 2 diabetes, was identified in 2.8% of a multiethnic cohort of young people under 20 years old with a clinical diagnosis of type 2 diabetes through whole-exome sequencing revealing pathogenic or likely pathogenic variants in MODY-associated genes such as HNF4α, GCK, HNF1α, PDX1, INS, and CEL. Those with MODY had younger age at diagnosis, lower fasting C-peptide levels, were less likely to have hypertension, and had higher HDL cholesterol levels compared to those without these variants. Identifying MODY through genetic sequencing led to changes in clinical management for 89% of these individuals, highlighting the importance of accurate diagnosis, although current clinical criteria are insufficient to distinguish MODY from other diabetes types, indicating a need for improved tools to guide genetic testing.
Rosiglitazone was associated with increased risks of heart failure, myocardial infarction, and cardiovascular death based on meta-analyses by 2007, leading to its withdrawal in Europe in 2010 and restricted use in the USA under a Risk Evaluation and Mitigation Strategy (REMS). However, the RECORD study later did not confirm these risks, and the REMS restriction was lifted in 2013. In contrast, pioglitazone, as shown in the PROactive study in 2007, did not demonstrate an increased risk of myocardial infarction or cardiovascular death and has since been linked to a reduced risk of stroke. Despite these benefits, the use of pioglitazone has been limited in some countries due to concerns about weight gain, edema, and an increased risk of bone fractures.
In the regulation of glucagon secretion, signals from the sympathetic and parasympathetic nervous systems increase glucagon release, which can impact blood glucose levels. Within the islet, paracrine signals from β cells, such as insulin, γ-aminobutyric acid, or Zn²⁺, directly inhibit α cells, while δ cells inhibit glucagon secretion through somatostatin, which is enhanced by β-cell activation via the urocortin 3 system. Endocrine signals such as incretins influence α cell function, with GIP acting directly and GLP-1 exerting indirect effects. These pathways are relevant to diabetes due to their roles in glucose homeostasis and hormone regulation.
Pentamidine has a propensity to cause both hypoglycaemia and hyperglycaemia, with its dysglycaemic effects attributed to impaired insulin secretion and direct cytotoxicity leading to β-cell apoptosis. In a study of 128 immunocompromised individuals with P. jirovecii pneumonia treated with pentamidine, 23 cases of overt diabetes were observed, along with 7 cases of hypoglycaemia and 18 cases of hypoglycaemia followed by diabetes, with 75% receiving the drug parenterally. Hyperglycaemia occurred on average 52 days after administration, requiring insulin in 63% of those affected. Risk factors for developing diabetes included high doses, impaired renal function, and poor clinical status. A retrospective review of 106 HIV-infected individuals found 9 cases of hyperglycaemia, with average blood glucose levels of 369 mg/dl (20.4 mmol/l) and a mean time to onset of 14 days. Hyperglycaemia associated with pentamidine is a notable adverse drug reaction that requires appropriate monitoring.
GLP-1 and GIP are key incretin hormones involved in the defective incretin action observed in diabetes. Patients with type 2 diabetes mellitus (T2DM) exhibit slightly impaired GIP secretion and a more pronounced impairment in GLP-1 secretion, particularly during the second and third hours after a meal, although the initial response remains intact. The reduced GLP-1 secretion correlates with higher body mass index (BMI) and the presence of diabetes itself. Obesity and insulin resistance are independently associated with decreased GLP-1 meal responses, though not all obese or insulin-resistant individuals show this defect. Factors such as the duration of diabetes and treatment influence GLP-1 secretion, with metformin shown to enhance it. Impaired GLP-1 secretion contributes to the diminished incretin effect in T2DM.
Hyperglycaemia contributes to heart failure risk both directly and indirectly by promoting the formation of advanced glycation end-products, which impair cardiac structure and function through extracellular protein cross-linking, leading to diastolic dysfunction. These end-products also affect the vascular system, promoting coronary atherosclerosis and increasing heart failure risk. Hyperglycaemia further worsens cardiac outcomes by enhancing neurohormonal activation, particularly through upregulation of the renin-angiotensin system, leading to adverse cardiac remodelling. Diabetes commonly coexists with other cardiovascular risk factors such as hypertension, dyslipidaemia, chronic kidney disease, and obesity, which together amplify heart failure risk through overlapping and distinct pathways.
Smart insulin pen attachments and caps are being developed to help manage insulin dosing by passively tracking doses and timing, integrating with health records and glucose monitoring systems, and alerting users to prevent missed or extra doses. These devices can be particularly helpful for people with type 1 diabetes, as forgetting or questioning insulin doses can disrupt treatment adherence and increase anxiety. A pilot study involving 16 individuals with poorly managed type 1 diabetes evaluated the InsulClock device, which displays insulin type, time, and dose, and connects to an app for reminders and data input. The study found that using InsulClock improved time in range, reduced hyperglycemia, and enhanced insulin administration and treatment satisfaction.
Patients with diabetic nephropathy are more likely to have other microvascular complications, and the absence of such complications may question the diagnosis of diabetic nephropathy. In type 1 diabetes, significant retinopathy is almost always present in those with microalbuminuria or more severe kidney disease, while in type 2 diabetes, significant retinopathy is typically present in cases of classic nephropathy with progressive increases in urine albumin excretion, but may be absent in non-classic cases with nonprogressive low-level microalbuminuria.
Hepatic insulin resistance in type 2 diabetes is linked to impaired tyrosine phosphorylation of IRS-2 and increased activities of PKCε and JNK1, which phosphorylate serine residues of IRS-2. Studies on human liver biopsies have shown elevated levels of certain PKC isoforms (ε, α, and ζ) in individuals with type 2 diabetes and obesity. Research also indicates that hepatic DAG content and PKCε activity negatively correlate with hepatic insulin sensitivity in people with NAFLD and obesity, highlighting the importance of the DAG/PKCε pathway in insulin resistance. Further findings suggest that PKCε-induced phosphory of the insulin receptor on threonine1160 is necessary for lipid-induced hepatic insulin resistance, with plasma membrane-bound sn-1,2-diaglycerols being responsible for PKCε activation, and PKCε being both necessary and sufficient for this form of insulin resistance. Hepatic ceramide content, in contrast, does not consistently correlate with insulin resistance, indicating that ceramides, like triglycerides, do not mediate hepatic insulin resistance.
Metformin, pioglitazone, GLP-1 receptor agonists, and SGLT-2 inhibitors are medications used in diabetes management and have varying effects on liver parameters and adverse effects. Metformin increases serum liver enzymes and liver fat content without affecting liver inflammation, fibrosis, or NASH resolution, and is associated with lactic acidosis, diarrhoea, nausea, vomiting, and flatulence. Pioglitazone also increases serum liver enzymes and liver fat content, while additionally increasing liver inflammation, fibrosis, and promoting NASH resolution, with adverse effects including moderate weight gain, fluid retention, distal bone fractures, and possibly bladder cancer. GLP-1 receptor agonists increase serum liver enzymes and liver fat content, have an uncertain effect on liver fibrosis, and do not impact liver inflammation or NASH resolution, with common adverse effects being loss of appetite, nausea, constipation, and diarrhoea. SGLT-2 inhibitors increase serum liver enzymes and liver fat content but have unknown effects on liver inflammation, fibrosis, and NASH resolution, with common adverse effects including genitourinary infections, diabetic ketoacidosis, and hypotension.
Hyperinsulinaemia contributes to tumour development and progression by enhancing survival of mutated cells, increasing cell proliferation, and promoting epithelial-to-mesenchymal transition. Cancer cells express the mitogenic insulin receptor isoform IR-A and the type 1 insulin-like growth factor receptor (IGF-IR), allowing hyperinsulinaemia to act directly on tumour cells through IR-A or indirectly by increasing the bioavailability of IGF-I, which activates IGF-IR. Insulin resistance promotes cancer growth by altering the tumour microenvironment, including tumour-associated adipose tissue and immune cells, and systemically leads to decreased sex hormone-binding globulins, excess bioavailable oestrogen, dyslipidaemia, increased nonesterified fatty acids and bioactive lipids, and elevated pro-inflammatory cytokines and adipokines. Hyperinsulinaemia may synergize with hyperglycaemia and other metabolic factors linked to insulin resistance to drive tumorigenesis.
An estimated 700,000 children worldwide have diabetes, with 100,000 new cases diagnosed annually, and the incidence has been rising by up to 5% each year over decades. Type 1a (autoimmune) diabetes mellitus (T1aDM) accounts for nearly all cases in children younger than 10 years, over 90% in older children of European ancestry, and 20–70% in children from other ethnic groups over 10 years of age. The presence of two or more islet autoantibodies predicts diabetes development in most children under 10 years, though prevention of T1aDM remains elusive despite extensive research. Childhood diabetes is diagnosed based on symptoms such as polyuria, polydipsia, weight loss, and fatigue, along with a random blood glucose level greater than 200 mg/dL (11.1 mmol/L), and oral glucose tolerance testing is rarely required. Diabetic ketoacidosis (DKA) occurs at diagnosis in fewer than 30% of cases in developed countries, presenting with features such as Kussmaul breathing, abdominal pain, vomiting, dehydration, and impaired neurological status in affected children. Management of DKA in children differs significantly from adults, with a focus on preventing cerebral edema. Following diagnosis, childhood diabetes is managed in outpatient settings by a multidisciplinary team including a pediatric diabetes specialist, diabetes nurse educator, dietitian, and mental health professionals trained in pediatric diabetes care. Comprehensive and ongoing education for parents and patients on diabetes self-management is essential for reducing the risk of both acute and long-term complications.
Insulin suppresses hepatic glucose output by regulating gene transcription, a process first observed in 1963 with the discovery that insulin negatively controls PEPCK expression. Insulin influences over 800 genes, exerting both stimulatory and inhibitory effects. These effects are mediated through insulin response elements (IREs), which include sequences like the serum response element, AP-1 motif, E-box motif, and TTF-2 motif that promote gene transcription. Conversely, a PEPCK-like motif, with the consensus sequence T(G/A)TTT(T/G)(G/T), mediates insulin's inhibitory effects on genes such as PEPCK, IGFBP-1, tyrosine aminotransferase, and G-6-Pase. Additionally, GC-rich IREs that bind the transcription factor Sp1 also play a key role in insulin's regulation of gene expression.
Young patients with diabetes are more prone to develop microvascular complications due to the long duration of disease, highlighting the importance of family screening. Mutations in transcription factors such as HNF-1α and HNF-1β are associated with MODY (Maturity-Onset Diabetes of the Young), where MODY 3 (HNF-1α mutations) presents with a low renal threshold for glucose, while MODY 5 (HNF-1β mutations) may present with mild diabetes and increased susceptibility to severe renal disease and urogenital malformations. A novel missense genetic variant (E260D) in the HNF-1β gene has been identified in young Chinese patients with T2DM and nephropathy, showing phenotypic heterogeneity including varying degrees of diabetes, impaired glucose tolerance, and microalbuminuria. A silent polymorphism Q378Q was also found in another subject, though further studies are needed to confirm these findings.
Diabetes associated with glucagonoma is typically mild and is one of the four major components of the glucagonoma syndrome, which also includes increased glucagon levels, weight loss, and necrolytic migratory erythema. This syndrome, caused by tumors of the α cells of the pancreas, should be considered in people with diabetes who present with atypical rashes. The skin rash, occurring in 70% of cases, may appear as an annular erythematous and figurate erythema with peripheral vesicles, pustules, and erosions, often involving intertriginous areas and the face, and can precede the diagnosis of glucagonoma by 1 to 6 years. Other associated findings include glossitis, stomatitis, dystrophic nails, and alopecia, with skin biopsy revealing suprabasal acantholysis and psoriasiform hyperplasia. While the exact role of hyperglucagonemia in causing the rash is unclear, deficiencies in essential fatty acids, zinc, and amino acids may contribute to the condition. Treatment options include resection of the pancreatic tumor, chemotherapy, supplementation with amino and fatty acids, and the use of somatostatin or octreotide to suppress glucagon levels and improve skin lesions.
LDL cholesterol is the strongest risk factor for coronary heart disease (CHD) in people with diabetes, with HDL cholesterol being the second strongest. Studies have shown that simvastatin therapy in individuals with type 2 diabetes (T2DM) can lead to a 55% reduction in major CHD events, which is a greater relative benefit compared to those without diabetes. This suggests that the absolute benefit of cholesterol-lowering therapy may be greater in diabetic patients due to their higher baseline risk for atherosclerotic events and CHD. Earlier studies often excluded or limited participation to those with good glycemic control (HbA1c < 8.0% or 64 mmol/mol), but more recent trials have increasingly included larger populations of people with T2DM.
Women with type 1 diabetes may not experience changes in glycaemic levels from menopausal hormone therapy (MHT), though evidence is limited due to a lack of sufficient high-quality studies. In contrast, women with type 2 diabetes may experience improved glycaemic control with MHT, as indicated by lower HbA1c and fasting blood glucose levels in observational studies. For example, one large observational study found significantly lower age-adjusted mean HbA1c levels in women using MHT compared to those not using it, and data from NHANES III also showed lower fasting glucose and HbA1c in postmenopausal women currently taking MHT. Despite these findings, causation cannot be established from observational studies, and ongoing monitoring of glycaemic indices is recommended for women with diabetes using MHT, with appropriate adjustments to their anti-diabetes medications as needed.
Inhaled insulin preparations offer an alternative method of insulin delivery for patients with a phobia of needles, though the first marketed inhaled insulin was withdrawn due to poor sales and safety concerns; future long-acting formulations may renew interest in this approach.
Insulin pumps offer greater dosing precision, which is particularly beneficial for young children, especially infants and neonates, as well as adults on very low insulin doses. This precision allows for accurate administration of insulin boluses in fractions of a unit, enabling patients to correct hyperglycemia more effectively without inducing hypoglycemia. For individuals whose fear of hypoglycemia hinders achieving tight glycemic control, the reliability of precise dosing can be crucial in addressing this concern. Additionally, insulin pumps can help reduce missed food boluses, support interprandial correction bolusing, and simplify eating in social settings through features like extended or square wave boluses and multiple bolusing options.
Glycated haemoglobin (HbA₁c) is a key biomarker used to assess long-term blood glucose control in diabetes. Cardiovascular disease (CVD) and major adverse cardiovascular events (MACE) are significant complications associated with diabetes. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are a class of medications used in the management of diabetes that have shown benefits in reducing cardiovascular risk. Confidence intervals (CI) and hazard ratios (HR) are statistical measures often used in clinical studies to evaluate the effectiveness and risks of diabetes treatments.
Prolonged hyperglycaemia in diabetes leads to various secondary changes, including increased formation of reactive oxygen species (ROS) through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, alterations in lipid profile, cellular lipid accumulation, and foam cell formation. Hyperglycaemia also promotes the formation of advanced glycation end products (AGEs), which modify proteins and lead to altered cellular structure and function, including the inhibition of scavenger receptor class B type 1-mediated cholesterol efflux to high-density lipoprotein (HDL) by modified albumin. Additionally, glucose directly activates monocytes-macrophages in vitro, increasing cytokine expression such as interleukin-1β (IL-1β) and IL-6, and triggering pathways involving protein kinase C (PKC) and nuclear factor κB (NFκB), further contributing to oxidative stress and atherogenesis. Auto-oxidation of glucose also generates ROS and mediates oxidized low-density lipoprotein (oxLDL), which is taken up by scavenger receptors on activated macrophages, promoting lipid accumulation and atherosclerosis.
Improved insulin sensitivity has been linked to changes in gut microbiota or hormone secretion, as well as reduced endoplasmic reticulum stress. Conversely, chronically elevated lipid levels can induce mitochondrial and endoplasmic reticulum stress, leading to the production of reactive oxygen species that activate proinflammatory NF-κB. Under these conditions, intracellular lipid metabolites such as DAGs, ceramides, and acylCoA contribute to insulin resistance. Research by Lyu et al. demonstrated that increases in plasma membrane sn-1,2-DAGs and subsequent PKC activation, which leads to insulin receptor threonine phosphorylation, were responsible for lipid-induced white adipose tissue insulin resistance in rodents after short-term high-fat feeding. This highlights the importance of the plasma membrane sn-1,2-DAG/PKC/IRK pathway in lipid-induced insulin resistance across insulin-responsive tissues including liver, skeletal muscle, and white adipose tissue.
Bariatric surgery has been shown to have significant effects on type 2 diabetes through both weight loss-dependent and -independent pathways, leading to improvements in glycaemia that occur rapidly and independently of weight loss, mediated in part by neurohormonal changes. Multiple randomized controlled trials have demonstrated consistent positive effects on glucose levels following bariatric surgery compared to medical treatment for type 2 diabetes, even before weight loss occurs. As a result, the second Diabetes Surgery Summit (DSS-II) included bariatric surgery as a key element in the treatment of type 2 diabetes in individuals with obesity, with these guidelines being endorsed by international organizations such as the American Diabetes Association and the International Diabetes Federation as part of their management strategies.
Maturity-onset diabetes of the young (MODY) is caused by specific gene mutations that affect glucose metabolism and pancreatic islet and β-cell development, influencing treatment choices. Mutations in HNF4α and HNF1α are typically managed with sulfonylureas, while mutations in PDX1, NEUROD1, KLF11, and PAX4 may be treated with diet, oral anti-diabetes drugs, or insulin. HNF1β mutations are primarily treated with insulin, and GCK mutations, which cause a glucose-sensing defect, require only dietary management without medication. Insulin secretion defects due to BLK or APPL1 mutations can be addressed with diet, oral medications, or insulin, and INS gene defects are treated with oral drugs or insulin. ATP-sensitive potassium channel dysfunction caused by ABCC8 mutations responds to sulfonylureas, while KCNJ11 mutations are managed with oral drugs or insulin. CEL mutations, which lead to pancreas endocrine and exocrine dysfunction, are treated with oral anti-diabetes drugs or insulin.
Diabetes is associated with an increased risk of ischaemic heart disease, and both impaired glucose tolerance and diabetes are commonly found in individuals presenting with acute coronary syndromes such as acute myocardial infarction and unstable angina. Type 2 diabetes may first present during hospitalization for these cardiac events, often complicated by stress hyperglycaemia, which results from elevated catecholamines and cortisol during acute illness and can occur in people with or without pre-existing diabetes. Stress hyperglycaemia and established diabetes both lead to increased mortality following myocardial infarction, with studies showing similar death rates between the two groups. In a New York study, three-year mortality was 52% in those with stress hyperglycaemia and 42% in those with diabetes, compared to 24% in those with normal glucose levels. A meta-analysis confirmed a higher risk of death with stress hyperglycaemia (3.9-fold) than with established diabetes (1.7-fold). The DIGAMI study highlighted that reasonable glycaemic control (blood glucose <10 mmol/l) in individuals without prior insulin use and with low coronary risk improved mortality by 52%, particularly benefiting those with stress hyperglycaemia, while acute glucose control showed no significant benefit for those already on insulin therapy.
Self-monitoring of blood glucose helps patients achieve glycemic targets by adjusting insulin doses and improves their understanding of diabetes and blood sugar levels. Pre-meal blood sugar readings should ideally fall between 4 and 7 mmol/L, while post-meal levels should be between 4 and 10 mmol/L, with a pre-bed value below 7 mmol/L to achieve strict glycemic control as demonstrated in the T1DM DCCT study. Patients are advised to test at different times on different days, including pre-meal and 2-hour postprandial testing, to obtain a 24-hour glucose profile rather than performing many tests daily. Insulin dose adjustments typically involve a change of 2 units or 10% of the current dose, whichever is greater, though individual specialists may use their own algorithms.
Healthcare expenditure for individuals with diabetes is significantly higher, ranging from 2 to 5.6 times that of the general population, with costs influenced by complications and hospital care in high-income countries, and medication costs in low-income countries. Medication accounts for 32–60% of diabetes expenditures in nations like Mexico, India, Pakistan, and Sudan. In low- and middle-income countries, out-of-pocket spending for diabetes ranges from 40–60%, and in some cases, insulin alone can cost up to 65% of a household's income, leading to financial hardship and reduced access to care. These expenses disproportionately affect the poorest individuals, increasing the risk of severe complications and perpetuating cycles of poverty. At the national level, the economic burden is heightened in low- and middle-income countries where diabetes predominantly affects those in the productive age range of 15–59 years, potentially slowing economic development and disease control efforts, thereby worsening global health disparities between high- and low-income countries.
Declining mortality among people with diabetes leads to more years lived with the condition, potentially resulting in new complications such as cancer, mental health disorders, cognitive impairment, and disability, while also increasing the risk of established macrovascular and microvascular complications, infections, and issues like those posed by Covid-19. In 2019, global direct health expenditure on diabetes was estimated at US $760 billion, with the majority spent in high-income countries despite a greater diabetes burden in low- and middle-income countries, highlighting growing disparities. Diabetes can impair domestic and occupational functioning, reduce workplace productivity, strain interpersonal relationships, and create perceived discrimination, all of which can hinder self-management and social integration. Addressing the rising diabetes burden requires better standardized data collection globally, especially in low- and middle-income countries where data on mortality, complications, disability, and costs are scarce. Tackling diabetes in vulnerable populations also necessitates addressing political, social, cultural, behavioural, and economic barriers that prevent the effective implementation of preventive strategies.
First-degree relatives of a person with type 1 diabetes mellitus (T1DM) are at increased risk of developing the condition compared to the general population. Approximately 4–6% of siblings of T1DM probands develop T1DM by the age of 20 years in European-origin populations, whereas the prevalence in the general population is around 0.2–1.0%. The risk is also elevated in offspring of affected parents, particularly fathers. Despite this increased familial risk, around 80–90% of newly diagnosed T1DM patients do not have a family history of the disease.
Hyperglycemia in diabetes leads to impairments in innate immune function, affecting macrophages, monocytes, and neutrophils by reducing their ability to adhere to endothelium, perform chemotaxis, phagocytosis, and bacteriocidal activity. Additional abnormalities include altered apoptosis, wound healing, and cytokine responses to infection, with antioxidant systems also being compromised. These immune dysfunctions are worsened by hyperglycemia and acidemia but can be significantly reversed by normalizing blood glucose and pH levels. The severity of these effects does not always correlate predictably with HbA1c levels, possibly due to long-term changes such as the accumulation of advanced glycation end products (AGEs), and better diabetes control generally improves immune cell function.
Neonatal diabetes resulting from KCNJ11 and ABCC8 variants is associated with neurological features such as developmental delay and learning difficulties, which persist into adulthood regardless of sulfonylurea therapy. This persistence is attributed to the limited function of the $\mathrm{K_{ATP}}$ channel in the brain rather than long-standing diabetes. The most severe form of this condition, characterized by neonatal diabetes along with developmental delay and epilepsy, is known as developmental delay, epilepsy, and neonatal diabetes (DEND), while a less severe variant without epilepsy is referred to as intermediate DEND (iDEND). The severity of the condition correlates with the specific genetic variant and its impact on $\mathrm{K_{ATP}}$ channel ATP sensitivity.
Oral semaglutide, approved by the FDA in 2019 and the EMA in 2020, is a treatment for type 2 diabetes that combines semaglutide with SNAC, an absorption enhancer that protects semaglutide from degradation in the stomach and facilitates its absorption. Evaluated in the PIONEER phase III clinical trial program, oral semaglutide demonstrated efficacy in reducing HbA1c levels, showing superiority over empagliflozin and sitagliptin when used as a second-line treatment for individuals not meeting glycemic targets on metformin, and was non-inferior to subcutaneous liraglutide. Body weight reductions were comparable to empagliflozin but greater than those observed with sitagliptin and liraglutide, suggesting potential benefits in weight management. It is generally well tolerated, with a safety profile consistent with other GLP-1RAs, low risk of hypoglycemia, and common gastrointestinal adverse events such as nausea and diarrhea. Higher doses of oral semaglutide, up to 50 mg, are currently under investigation for treating type 2 diabetes and obesity.
Complications of type 2 diabetes mellitus (T2DM), such as neuropathy, vascular disease, and impaired vision, likely increase the risk of falling and thereby of fracture. Observational studies show that individuals with T2DM have a 22% higher risk of non-spine fractures compared to those without diabetes, with insulin-treated individuals showing even higher risk, coinciding with a greater prevalence of complications. In older adults with T2DM, those who develop fractures have higher prevalences of neuropathy, cerebrovascular disease, and falls than those who do not. Risk factors for falls, including medications associated with falls, are more common in T2DM populations, and low-impact falls occur more frequently in insulin-treated patients than in healthy controls. Notably, adjusting for diabetes complications or falls risk does not reduce the observed increased fracture risk in T2DM.
Rosiglitazone, a thiazolidinedione used in diabetes treatment, has been linked with an increased risk of myocardial infarction and cardiovascular death, though stroke was not separately assessed in some studies; in the RECORD trial, rosiglitazone showed a trend toward decreased stroke risk but was offset by a higher risk of heart failure, with potential confounding due to lower statin use in the control group; pioglitazone, another drug in the same class, was not associated with worse cardiovascular outcomes and actually reduced a secondary outcome combining all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke by 16%.
GLP-1 improves myocardial and endothelial function and reduces blood pressure, making GLP-1 analogs potentially beneficial for individuals with type 2 diabetes mellitus (T2DM) and heart failure due to their effects on promoting renal sodium and water excretion. GLP-1 analogs also require further long-term studies to assess safety. Additionally, research is needed to evaluate GLP-1's potential to prolong remission, reduce insulin requirements, and lower the risk of hypoglycemia in patients with newly diagnosed type 1 diabetes mellitus (T1DM) and those with long-standing T1DM who have no residual beta-cell function.
South Asians and peninsular Arabs exhibit markedly elevated metabolic risk, while Japanese have the highest prevalence of genetic polymorphisms, indicating patterns of genetic and/or ethnic propensity relevant to diabetes. Rural-urban differences in prevalence further suggest the involvement of gene-environment interactions and the influence of the "thrifty" genotype in diabetes risk.
Technosphere insulin is an inhaled insulin formulation developed by MannKind Corporation, designed with insulin particles optimized for inhalation (2.5 μm in diameter) that dissolve rapidly after inhalation due to pH-sensitive carrier particles. Pharmacokinetic studies show that it achieves very rapid systemic insulin uptake (Tmax approximately 12–14 minutes), has a fast onset of action (maximum activity approximately 20–30 minutes), and a short duration of action (approximately 2–3 hours), potentially offering better post-prandial glucose control compared to subcutaneously injected insulin.
Mutations in transcription factors such as HNFs, PPARG, IPF-1, NEUROD1/β2, IB1/MAPK8IP1, and TIEG2/KLF11 contribute to the genetic risk for type 2 diabetes mellitus (T2DM) by affecting glucose and lipid metabolism, impairing β-cell development and differentiation, and increasing β-cell apoptosis. Deleterious mutations in these genes can lead to monogenic-like forms of diabetes with late onset, representing an intermediary phenotype between MODY and common T2DM. The TIEG2/KLF11 gene, which encodes a pancreas-expressed transcription factor induced by TGF-β, plays a role in regulating cell growth in the exocrine pancreas. A common polymorphism (Q62R) in KLF11 has been associated with polygenic T2DM in adulthood and reduced insulin levels in carriers of the minor allele, although replication studies have shown inconsistent results. Missense mutations in KLF11 identified in families with early-onset T2DM have been found to segregate with diabetes, suggesting a role for the TGF-β signaling pathway in pancreatic diseases affecting both endocrine islets and exocrine cells.
HLA DR3-DQ2 and DR4-DQ8 genotypes are strongly associated with type 1 diabetes, with the combination found in over 95% of individuals under 30 years old with the condition compared to 25–30% of the general population. These haplotypes are considered necessary but not sufficient for the development of type 1 diabetes, influencing the risk of acquiring a first islet autoantibody. In children who develop a second islet autoantibody, there is an estimated 70% risk of progressing to clinical onset of diabetes within 10 years.
Increased in old age due to multiple comorbidities, undernutrition, polypharmacy, long duration of diabetes, and renal or hepatic impairment.
Skin care is important for individuals using diabetes-related devices such as sensors, and products based on saturated hydrocarbons, alcohol, silicone, or oil can be used to remove adhesive residues. In cases of irritation, skin protection products that create a barrier between the skin and adhesive, such as hydrocolloid-based plasters commonly used in ostomy care, can be beneficial due to their high skin compatibility and ability to maintain a protective barrier during sensor use. To enhance adhesion, a protective film may be applied, and most sensors can be taped over without pressure, with a small piece of swab or tissue preventing the foil from adhering to the transmitter or sensor. Waterproof covers are recommended during bathing or swimming, and while removal of the waterproof foil is not necessary, its adhesive may cause skin redness. When standard options are insufficient, alternatives without IBOA, such as the implantable Eversense system, are recommended.
In patients with diabetes, post hoc analysis of the CAPRIE study found that clopidogrel reduced the combined risk of stroke, myocardial infarction, or death by 15.6% compared to 17.7% with aspirin. Additionally, a post hoc subgroup analysis of a cilostazol study showed a 41.7% relative risk reduction in recurrent stroke among those with diabetes, particularly in patients with lacunar stroke. However, these findings require further trial verification.
Patients with diabetes can exhibit varying gastric emptying patterns, including normal, delayed, or accelerated emptying, as demonstrated by imaging studies using  $^{99m}\mathrm{Tc}$-labeled egg meals. Normal gastric emptying ranges are defined as  $11 - 39\%$ emptied at 1 hour,  $40 - 76\%$ at 2 hours, and  $84 - 98\%$ at 4 hours.
In low- and middle-income countries (LMICs), access to diabetes medicines, particularly insulin, is limited by availability and affordability, which are influenced by factors such as the level of the health system, location, and whether care is provided in the public or private sector. Significant disparities exist between LMICs and high-income countries (HICs) in the ability of individuals to afford essential diabetes treatments like metformin and insulin, with 27% of households in LMICs unable to afford metformin compared to 0.7% in HICs, and 63% of people with diabetes in LMICs unable to afford insulin versus 2.8% in HICs. Globally, one in two people with type 2 diabetes requiring insulin cannot access it, with the situation being more severe in sub-Saharan Africa, where one in seven people faces this issue. These challenges are compounded by variations in government purchasing prices, mark-ups within the supply chain, and the lack of adherence to treatment guidelines, all of which affect healthcare worker training, access to care, and patient outcomes.
Self-monitoring of blood glucose helps manage diabetes by detecting and documenting high and low blood sugar levels, determining daily insulin needs, and assisting in hypoglycemia management. Measuring blood glucose is recommended at specific times such as during the night, after an overnight fast, before meals, and two hours after eating, typically 4–6 times daily. It should also be done during illness, exercise, and before driving. More frequent monitoring is linked to better $\mathrm{HbA}_{1c}$ levels in type 1 diabetes patients, and despite the use of continuous glucose monitoring, SMBG remains a key aspect of diabetes care.
Hypoglycemia in diabetes management is typically caused by an excess of insulin, whether endogenous or exogenous, combined with impaired defenses against falling plasma glucose levels. Treatments associated with hypoglycemia risk include insulin and insulin secretagogues such as sulfonylureas (e.g., glibenclamide, glipizide, glimepiride, gliclazide) and glinides (e.g., repaglinide, nateglinide). In early type 2 diabetes mellitus (T2DM), certain medications like metformin, thiazolidinediones (e.g., pioglitazone, rosiglitazone), α-glucosidase inhibitors (e.g., acarbose, miglitol), GLP-1 receptor agonists (e.g., exenatide, liraglutide), and DPP-4 inhibitors (e.g., sitagliptin, vildagliptin) may lower plasma glucose without inducing hypoglycemia under normal conditions because they do not increase insulin levels at low or normal plasma glucose concentrations. These medications rely on endogenous insulin secretion, which appropriately declines as glucose levels normalize. GLP-1 receptor agonists and DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, meaning they do not stimulate insulin release at normal or low glucose levels; however, hypoglycemia can occur if these drugs are combined with insulin secretagogues. All five categories of these glucose-lowering drugs can increase the risk of hypoglycemia when used alongside insulin or insulin secretagogues.
The sulfonylurea moiety of glibenclamide, containing the benzamido group, stimulates insulin secretion similar to other sulfonylureas. These compounds have pharmacokinetic properties that result in a rapid but short-lived insulin secretory effect, making them suitable for administration with meals to promote prandial insulin release. By causing a prompt increase in insulin that coincides with meal digestion, these agents help restore the first phase of glucose-induced insulin response, which is typically lost in type 2 diabetes mellitus (T2DM). Targeting post-prandial hyperglycemia may also reduce vascular risk associated with prandial glucose fluctuations and lower the risk of interprandial hypoglycemia. Two agents, repaglinide (a meglitinide derivative) and nateglinide (a phenylalanine derivative), introduced in 1998 and 2001 respectively, function as "prandial insulin releasers." While their primary action occurs during the prandial and early post-prandial periods, they also have some effect on reducing fasting hyperglycemia, especially repaglinide.
PTDM is commonly observed in up to 28% of adults receiving tacrolimus, a potent immunosuppressive agent, though more recent trials suggest that the risk of developing PTDM can be reduced by using low-dose tacrolimus (0.15 – 0.2 mg/kg/day). Altered insulin and glucagon responses to arginine in patients treated with these drugs indicate a defect in the β-cell–α-cell axis within the islet. The diabetogenic effects of both ciclosporin and tacrolimus are largely reversible with appropriate reductions in drug dosage.
Lifestyle modification involving reduced intake of total calories, refined carbohydrates, and fats, along with avoidance of sugar and inclusion of fiber-rich foods, was associated with a 28.5% relative risk reduction in diabetes incidence. Metformin alone resulted in a 26.4% relative risk reduction, while the combination of lifestyle modification and metformin led to a 28.2% relative risk reduction compared to the control group. The study followed participants for a median of 30 months, with three-year cumulative diabetes incidences of 55.0%, 39.3%, 40.5%, and 39.5% in Groups 1 to 4, respectively.
Offspring of women with type 2 diabetes during pregnancy have an increased risk of early-onset type 2 diabetes compared to those without maternal diabetes, a finding observed across multiple populations including the Pima and an ethnically diverse group in Chicago. In the Chicago study, offspring exposed to maternal pregestational gestational diabetes mellitus (GDM) had a 20% prevalence of impaired glucose tolerance by age 16, which is ten times higher than in the general population. Similarly, in Denmark, offspring of women with GDM had a 21% prevalence of type 2 diabetes or pre-diabetes compared to 12% in offspring of women without GDM. Offspring of women with type 1 diabetes also showed higher rates, with 11% prevalence of type 2 diabetes or pre-diabetes compared to 4% in offspring of women without diabetes. Studies in the Pima population suggest that the intrauterine environment plays a significant role, as siblings born before a mother’s diabetes diagnosis had lower diabetes prevalence and lower mean BMI compared to those born after. Some studies indicate a higher frequency of maternal versus paternal transmission of diabetes, though this is not consistently observed across all populations.
Several clinical trials have investigated interventions for diabetes prevention and treatment, particularly focusing on type 1 diabetes. Interventions such as hydrolysed casein formula, gluten-free diet during the first year, and intranasal insulin in primary prevention stages did not show positive outcomes. In secondary prevention stages, oral insulin showed a transient benefit in a subgroup with high IAA levels, while parenteral insulin, subcutaneous insulin, and nicotinamide did not demonstrate effectiveness. Trials involving Alum-GAD, either alone or combined with vitamin D3, are ongoing. In tertiary interventions, some immunotherapies such as teplizumab, abatacept, alefacept, and golimumab showed benefits in preserving stimulated C-peptide levels, indicating some success in modifying the disease course, whereas other agents like canakinumab, anakinra, mycophenolate mofetil/daclizumab, rituximab, otelixizumab, and anti-thymocyte globulin did not show significant long-term effects.
Glycaemia should be assessed using HbA₁c measurement in all adults with type 1 diabetes every 3–6 months, with more frequent assessments if blood glucose levels are rapidly changing or treatment goals are not being met. HbA₁c methods should be calibrated to the IFCC standard, and participation in an EQA scheme is strongly recommended, with NGSP certification required in the USA and some other countries. HbA₁c targets vary by guideline and are influenced by factors such as age, comorbidities, and risk of hypoglycaemia, with common goals being 48 or 53 mmol/mol (6.5% or 7.0%), though these may be adjusted for older adults or those with multiple comorbidities.
Studies have shown that in individuals with type 1 diabetes mellitus (T1DM), dysfunction along the somatosensory afferent pathways is influenced by the stage of peripheral neuropathy, not by the duration of diabetes or glycemic control, and is marked by changes in the cortical sensory complex and peripheral conduction deficits. Magnetic resonance imaging (MRI) has identified a higher occurrence of subcortical and brainstem lesions in T1DM patients with diabetic peripheral neuropathy (DPN), and these patients also exhibit a reduced cross-sectional chord area at C4/5 and T3/4. Positron emission tomography (PET) using [18F]-2-deoxy-2-fluoro-D-glucose (FDG) has shown decreased cerebral glucose metabolism in T1DM patients with DPN compared to those newly diagnosed and healthy controls. Additionally, spectroscopic analysis revealed a lower N-acetyl aspartate (NAA) to creatine ratio in the thalamus, indicating potential thalamic neuronal dysfunction in these patients.
Precise diagnosis, classification, and treatment are particularly important in young individuals presenting with type 2 diabetes, as young-onset diabetes in Chinese people is associated with a 1.5–6-fold increased risk of hospitalization due to acute or chronic complications, cardiovascular-renal issues, and premature death, partly because of long disease duration and poor risk factor management. The insidious nature of symptoms can lead to delayed presentation with complications, while early diagnosis through family screening upon identifying an index case may prevent adverse outcomes. With the rising prevalence of young-onset diabetes, especially in low- and middle-income countries, healthcare professionals must recognize the possibility of multiple coexisting diabetes etiologies in atypical cases. Precision diagnosis in such cases can significantly influence treatment choices, with some patients benefiting from early insulin therapy, such as in LADA, and others from oral glucose-lowering drugs, as in MODY.
Metformin response varies due to genetic factors, including the rs11212617 polymorphism in the ATM gene, where the C allele is linked to better treatment outcomes. ATM influences metformin's effect on AMPK, plays a role in insulin signaling, and contributes to pancreatic β-cell dysfunction. It activates AMPK through phosphorylation of the AMPK α-subunit and regulates mitochondrial biogenesis via AMPK, both of which are essential for a full response to metformin. The SLC2A2 gene encodes GLUT2, a protein involved in glucose transport, and genetic variations in GLUT2 are associated with higher risk of hyperglycemia and more severe type 2 diabetes symptoms. Individuals with the C allele (rs8192675) of GLUT2 experience a greater reduction in HbA1c levels when treated with metformin, likely due to reduced hepatic GLUT2 activity, which limits glucose entry into liver cells and decreases glucose clearance.
Studies have shown that individuals with type 1 diabetes exhibit somatosensory afferent pathway dysfunction, which is linked to the severity of diabetic neuropathy and involves neuroplasticity and alterations in the cortical sensory complex. Research using positron emission tomography (PET) with $[^{18}\mathrm{F}]$ 2-deoxy-2-fluoro-D-glucose (FDG) has demonstrated reduced cerebral glucose metabolism in those with type 1 diabetes and diabetic sensorimotor polyneuropathy compared to newly diagnosed patients and healthy controls. The thalamus plays a role in modulating sensory information from the periphery to the somatosensory cortex, with sensory pathways terminating in the ventroposterior lateral thalamic subnucleus before being projected to the cortex. Proton magnetic resonance spectroscopy has revealed abnormalities in brain metabolites, specifically a lower N-acetyl aspartate-to-creatine ratio, indicating thalamic neuronal dysfunction in diabetic sensorimotor polyneuropathy.
Women with type 1 diabetes undergoing elective caesarean section should be placed first on the operating list and admitted either the previous day or early on the morning of surgery, fasting from 22:00 the evening before. Long-acting insulin is taken as normal prior to a light supper, while rapid-acting insulin should be withheld on the day of surgery. Hourly monitoring of blood glucose begins 1–2 hours prior to surgery, and a glucose-insulin infusion may be commenced to maintain blood glucose between 4 and 7 mmol/L, with insulin dose and/or rate adjusted based on maternal or capillary glucose levels. During induced or spontaneous labour, women should continue their insulin regimen until labour is confirmed, often consuming an early-morning breakfast with their normal morning insulin dose. Once fasting, a glucose-insulin infusion is initiated as per protocol unless delivery is imminent. In spontaneous labour, the woman is fasted upon admission, with blood glucose measured on admission and hourly thereafter, maintaining levels between 4 and 7 mmol/L through adjustments in insulin dose or rate according to local protocols.
Patients with diabetes have poorer health compared to those without, making them more likely to undergo surgery, with an estimated 50% requiring surgery in their lifetime. Diabetes is linked to higher risks of perioperative infection and postoperative cardiovascular complications, including morbidity and mortality. The combination of surgical procedures, anesthesia, fasting, and postoperative factors like artificial feeding and emesis contributes to unstable glycemic control during the perioperative period.
Several psychological interventions have been developed to improve adherence in patients with diabetes, particularly for adults with severe non-compliance leading to "brittle diabetes," where a therapeutic approach beginning with crisis management followed by psychotherapy, similar to that used for borderline personality, has been recommended. Intensive inpatient psychoanalytic psychotherapy involving 3–5 weekly sessions over 5–28 weeks has also been shown to improve metabolic control over a one-year period, though it is considered less practical due to limited availability in hospital settings for children.
In young patients with type 1 diabetes mellitus (T1DM), hypertension is strongly associated with renal damage, even with minor degrees of proteinuria. Blood pressure begins to rise when urinary albumin excretion (UAE) exceeds 30 mg/24 hours (microalbuminuria) and typically exceeds the WHO threshold when UAE surpasses 300 mg/24 hours (macroalbuminuria). This association may have a genetic component, as individuals with diabetes and microalbuminuria often have parents with hypertension and may inherit increased activity of the cell-membrane Na⁺-H⁺ pump, as indicated by elevated Na⁺-Li⁺ countertransport in red blood cells.
Glycosylated hemoglobin should be maintained at 6.5% or lower every three months, and self-monitoring of blood sugar is recommended daily before meals and at bedtime, with fasting levels between 80-110 mg/dL and other readings between 80-140 mg/dL. Urine testing for sugar and ketones is advised using the first morning sample, along with urine testing for proteins at each visit. Annual serum lipid profiling, including cholesterol, HDL, LDL, VLDL fractions, and triglycerides, should be normal, and thyroid function tests should also be conducted annually. An annual eye evaluation, including fundus examination by an ophthalmologist, is recommended, with more frequent exams if vascular changes are detected, and dental examinations by a hygienist or dentist should occur every six months.
Several strategies target the modulation of T cells for the treatment of type 1 diabetes. One approach involves converting pathogenic T cells, including those specific to pancreatic $\beta$ cells, into regulatory T cells (Tregs) using ex vivo gene transfer of Foxp3 via lentiviral or retroviral vectors. Additionally, Tregs have been engineered with antigen-specific immunoreceptors to create islet-specific Tregs, demonstrating antigen-specific suppression in vitro and showing potential comparable to polyclonal Treg therapy. While polyclonal Treg therapy is being tested in clinical trials, antigen-specific Tregs offer greater potency. Another method involves using adenoviral vectors encoding a CTLA4-Fas ligand fusion protein, which induces apoptosis, blocks co-stimulation of autoreactive T cells, and significantly reduces the incidence of type 1 diabetes. Ex vivo antigen-specific targeting of autoreactive CD8 or CD4 T cells has been shown to selectively eliminate diabetogenic T cells in vitro and reduce diabetes incidence and delay onset in NOD mice. Similarly, engineered CAR-T cells targeting diabetogenic antigen-presenting cells (APCs) have been effective in delaying the onset of type 1 diabetes in NOD mice.
Hyperglycemia during embryonic development, particularly during neural tube closure, leads to reduced levels of arachidonic acid and prostaglandins such as PGE₂, which are associated with malformations like neural tube defects. High glucose concentrations inhibit rostral neural tube fusion in rat embryos, an effect that can be counteracted by adding myoinositol or PGE₂, but not when prostaglandin synthesis is blocked by indometacin. Administering arachidonic acid to diabetic rats decreases the incidence of neural tube defects, and reduced PGE₂ levels in the yolk sac have been observed in early human pregnancies complicated by diabetes.
MODY (Maturity-Onset Diabetes of the Young) is associated with heterozygous mutations in transcription factor genes, most commonly affecting hepatic nuclear factors 1A and 4A (HNF1A and HNF4A), and can also result from mutations in other transcription factor genes such as HNF1B, insulin promoter factor 1 (IPF-1), and NEUROD1.
Angiotensin II receptor blockers (ARBs) such as losartan, irbesartan, valsartan, candesartan, and telmisartan are effective antihypertensive drugs in people with diabetes and have been shown to slow the progression of nephropathy in patients with diabetes and varying degrees of albuminuria. Losartan has also been shown to be better than atenolol in reducing both cardiovascular endpoints and total mortality in high-risk patients with type 2 diabetes mellitus (T2DM) with hypertension and left ventricular hypertrophy. The combination of an ACE inhibitor with an ARB was more effective than either agent alone in lowering blood pressure and urine albumin excretion in patients with T2DM, although recent studies showed no extra benefits on cardiovascular endpoints compared to monotherapy.
Metformin is an effective anti-diabetes medication that improves insulin sensitivity, particularly in people with HIV lipodystrophy, but it should be used cautiously in individuals receiving certain NRTIs like zidovudine, didanosine, and stavudine, as well as in those with impaired renal function due to the risk of lactic acidosis. Dolutegravir, an integrase strand transfer inhibitor, can increase metformin levels by reducing its renal clearance, necessitating close monitoring and possible dosage adjustment. Thiazolidinediones such as pioglitazone may also enhance insulin sensitivity in people with HIV lipoatrophy, and insulin therapy should be administered following standard guidelines. Substituting an NNRTI for a PI can improve insulin resistance, but this must be weighed against potential risks to viral control, making consultation with HIV physicians crucial, with the possibility of intensifying diabetes treatment instead of altering antiretroviral therapy.
Common genetic variants in the GCK promoter and genes encoding GCKR and G6PC2 are associated with individual variation in fasting plasma glucose (FPG), with minimal effects on type 2 diabetes mellitus (T2DM) risk. However, non-coding variants in MTNR1B, which encodes the melatonin receptor MT2, are consistently linked to higher FPG levels, reduced β-cell function measured by HOMA-B index, increased T2DM risk, impaired early insulin response to glucose, and faster deterioration of insulin secretion over time. MTNR1B is expressed in the brain, retina, and human islets, with increased MT2 expression observed in β-cells of individuals carrying the risk allele and those with T2DM. Melatonin inhibits insulin secretion from β-cells, suggesting that melatonin's interaction with MT2 contributes to T2DM pathogenesis, potentially making the melatonin ligand-receptor system a therapeutic target in T2DM.
Mouse genetics studies have shown that insulin signaling varies in different tissues, with the Pi3k→Ak pathway playing a key role. In the liver, this pathway inhibits FOXO1, leading to increased de novo lipogenesis and decreased hepatic glucose production. In adipose tissue, it activates phosphodiesterase 3β to reduce cAMP and suppress lipolysis while inhibiting AS160 to enhance glucose influx. In muscle, the pathway reduces protein degradation and promotes protein and glycogen synthesis along with glucose oxidation. These tissue-specific effects of insulin signaling are crucial for understanding diabetes pathophysiology.
Telemedicine is used to link community health services with specialist diabetes care, particularly in managing diabetic foot disease through routine and urgent consultations between urban centers and rural sites. Routine consultations involve prior review of standardized digital foot images emailed in advance, followed by a phone linkup where images are discussed and a management plan is developed for local implementation. Urgent consultations are available on demand with immediate advice provided until further review. This system reduces patient travel, supports ongoing clinical care, and offers training to community health professionals. Similar approaches, such as mobile diabetes buses in India, enable retinal photographs taken in rural areas to be transmitted via satellite for specialist review, facilitating access to care in regions with limited diabetic foot services. Financial support for such initiatives often comes from charities, international organizations, government satellite agencies, and private medical centers.
HbA₁c levels below 7% (53 mmol/mol) and LDL cholesterol below 2.6 mmol/L are treatment targets in diabetes management. Achieving these targets is influenced by various patient-related factors such as age, disease duration, presence of complications, and body weight. Health care system factors, including health insurance coverage, availability of specialist care, and training by diabetes educators, also play a role. Self-care practices, like self-adjustment of insulin dosage, further impact the likelihood of reaching these targets. In low and middle-income settings, reaching these targets is more challenging due to limited resources, which are further strained by the burden of infectious diseases and other issues such as accidents and injuries.
Lipoatrophy, a complication associated with insulin injections, manifests as a loss of subcutaneous fat at injection sites, particularly with longer-acting insulin preparations, and is more common in young females with diabetes. It can lead to circumscribed depressed areas of skin appearing 6 to 24 months after starting insulin therapy. The condition is less frequent with purer insulin formulations and is thought to result from an immunologic reaction, supported by findings of immunoglobulin M and complement in biopsies of affected areas. Additional contributing factors may include mechanical trauma from injection technique, surface alcohol contamination, or local tumor necrosis factor production by macrophages in response to injected insulin, with repeated injections in the same location increasing the risk.
FGF21 gene therapy mediated by AAV vectors has been shown to counteract obesity, non-alcoholic steatohepatitis (NASH), and insulin resistance in models of obesity and type 2 diabetes, leading to improvements in glucose homeostasis, increased glucose uptake in adipocytes, normalization of adiponectin and leptin levels, and reduced insulin and glucagon levels. Additionally, this therapy prevented islet hyperplasia and obesity-associated liver neoplasms without causing side effects, even with continuously elevated serum FGF21. Overproduction of FGF21 in healthy animals also prevented age-related weight gain and insulin resistance, confirming its safety and potential therapeutic role in diabetes.
GLP-1 receptor agonists (GLP-1RAs) are associated with the development of antibodies, with varying incidence depending on the specific medication, ranging from 1–9% for those with higher homology to native human GLP-1 such as liraglutide, semaglutide, albiglutide, and dulaglutide, to higher rates with exenatide, where high levels of neutralizing antibodies in 1–6% of individuals are linked to reduced clinical efficacy. Hypersensitivity and injection-site reactions, including local nodule formation, redness, or itching, occur in 0–22% of individuals treated with GLP-1RAs for up to a year, with higher frequency in those who develop antibodies. Other factors such as drug formulation components, including prolonged-release delivery systems or fatty acid side chains, may also contribute to injection-site reactions, as evidenced by higher rates with exenatide once weekly compared to twice daily and with albiglutide compared to liraglutide.
Elevated gingival levels of interleukin 1β (IL-1β), tumour necrosis factor α (TNF-α), IL-6, RANKL/osteoprotegerin (OPG), and reactive oxygen species (ROS) have been found in people with sub-optimally managed diabetes, potentially contributing to tissue destruction. Individuals with both diabetes and periodontitis also show high levels of circulating TNF-α, C-reactive protein (CRP), and ROS, which can be reduced through successful periodontal treatment.
LADA (latent autoimmune diabetes in adults) is associated with GAD autoantibodies and shows a strong response to insulin treatment, with a greater reduction in HbA1c compared to individuals without GAD autoantibodies. Those with LADA have fewer cardiometabolic risk factors and a lower likelihood of cardiovascular events than individuals with type 2 diabetes but are three times more likely to develop end-stage kidney disease compared to those with type 1 diabetes. GAD autoantibody levels correlate with pancreatic β-cell function, where higher titres are linked to a faster decline in β-cell function as measured by HOMA2-B and a greater likelihood of β-cell failure.
Intensive diabetes therapy or a target-driven intensified intervention aimed at multiple risk factors does not appear to favorably influence the development or progression of diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus (T2DM), as indicated by a relative risk of 1.09 (95% CI 0.54–2.22) for DPN progression with no statistically significant difference (P = 0.66). However, for autonomic neuropathy, intensive therapy showed a lower risk of progression compared to conventional therapy, with a relative risk of 0.37 (95% CI 0.18–0.79; P = 0.002) at the initial assessment and 0.53 (95% CI 0.34–0.81; P = 0.004) after 13.3 years of follow-up. Peripheral neuropathy progression showed little difference between the two therapy groups, with a relative risk of 0.97 (95% CI 0.62–1.51; P = 0.89).
Insulin was first isolated in 1922 and used to treat the first patient, marking a breakthrough in diabetes management. Advances continued with the development of protamine insulin in 1936, NPH isophane insulin in 1946, and zinc lente insulin in 1951, which offered varying durations of action. Biphasic insulin was introduced in 1959, combining different insulin types for more flexible control. In 1977, continuous subcutaneous insulin infusion was developed, improving delivery methods. The introduction of recombinant DNA (rDNA) human insulin in 1980 enhanced safety and effectiveness, followed by the development of insulin pens in 1981 for easier administration. Further refinements included monomeric short-acting insulins and soluble prolonged-action insulin in 1987. Rapid-acting insulin analogs became available in 1996, offering faster onset, and long-acting insulin analogs were introduced in 2001 for more stable blood glucose control.
In diabetes, glucagon contributes to hyperglycemia by promoting glucose production in the liver through glycogenolysis and gluconeogenesis, especially in the absence of sufficient insulin action. It antagonizes insulin's effects, leading to increased blood glucose levels during fasting, stress, or exercise. Additionally, glucagon enhances lipid oxidation in the liver and has central effects that may influence energy balance by reducing food intake and increasing resting energy expenditure, which can be relevant in the metabolic dysregulation seen in diabetes.
Repaglinide and nateglinide are agents used in the management of diabetes, with Repaglinide administered in doses ranging from 0.5 to 4.0 mg per meal, a maximum daily dose of 16 mg, and a duration of action of 4–6 hours, while nateglinide is given at 60–180 mg per meal, up to a maximum of 540 mg daily, and acts for 3–5 hours. Repaglinide is primarily eliminated through bile (~90%) as inactive metabolites, whereas nateglinide is excreted in urine (~80%) with one of its metabolites being slightly active.
Increased body fat mass is closely linked to a higher risk of diabetes, with the risk rising even within the upper normal range of BMI. Women with a BMI of 23.0–24.9 kg/m² have a four- to fivefold increased risk of developing diabetes over 14 years compared to those with a BMI below 22 kg/m², and the risk rises dramatically to 27.6-fold for those with a BMI of 29.0–30.9 kg/m². Similar patterns are observed in men, with nearly two-thirds of women and men newly diagnosed with type 2 diabetes mellitus (T2DM) being obese. Weight changes also influence diabetes risk, as gaining 11.0–19.9 kg after age 18 increases the risk 5.5-fold in women, while equivalent weight loss reduces the risk by about 80%. In men, similar associations between weight change and diabetes risk are observed. Additionally, gaining one BMI unit between ages 25 and 40 increases the relative risk of T2DM by 25%, with greater impact compared to the same gain between ages 40 and 55. The duration of obesity further contributes to the likelihood of developing T2DM.
Self-monitoring of blood glucose is a crucial component of diabetes care, particularly for individuals with type 1 diabetes, as it helps maintain blood glucose levels that reduce the risk of complications. It is also necessary for those with type 2 diabetes who use insulin and for some individuals with type 2 diabetes who have specific indications. Proper glucose monitoring allows people with diabetes to evaluate their personal response to treatment and gain insight into whether they are meeting their target blood glucose goals.
Increases in intramyocellular triacylglycerols (TAGs) are a strong predictor of insulin resistance in muscle and liver, with lipid-induced insulin resistance characterized by impaired insulin signaling through reduced tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), decreased IRS-1-dependent phosphatidylinositol 3-kinase (PI3K) activation, and serine phosphorylation of Akt. This impairment may result from the accumulation of intramyocellular long-chain fatty acyl-CoA (LCFA-CoA), diacylglycerols (DAGs), or ceramides, with studies showing that elevated fatty acids increase LCFA-CoA, CoA, and DAGs, but not ceramide content, while also stimulating TAG synthesis via DAG O-acyltransferase-1 (DGAT-1) and activating protein kinase C-θ (PKCθ), leading to serine phosphorylation of IRS-1. In humans, lipid infusion causes a transient rise in intramyocellular DAGs followed by PKCθ activation and increased phosphorylation of IRS-1’s serine1101 residues, which inhibits insulin signaling and glucose disposal in muscle. Similar DAG increases and PKCθ activation occur in individuals with type 2 diabetes and obesity even without lipid infusion, with DAG subspecies containing C18-acyl residues showing the strongest correlation with insulin resistance, while ceramides do not appear to be significantly involved in insulin resistance associated with obesity or type 2 diabetes.
Hyperglycaemia and hypoglycaemia were commonly reported during hospital stays, with 20% experiencing hyperglycaemia and 7% hypoglycaemia, while 26% had at least one severe hypoglycaemic episode. Frequent occurrences of these conditions were linked to lower overall satisfaction, negative well-being scores, and dissatisfaction with medication timing relative to meals. Higher satisfaction levels were associated with increased time spent with a diabetes inpatient specialist nurse and the practice of insulin self-administration.
Inhibition of SGLT-1 and SGLT-2 with sitagliptin showed preliminary evidence in the SOLOIST-WHF trial of reducing cardiovascular death and heart failure hospitalizations among individuals with diabetes and heart failure with preserved ejection fraction. The EMPEROR-Preserved trial, which included 5998 participants with HFpEF, demonstrated that empagliflozin, an SGLT-2 inhibitor, reduced the risk of cardiovascular death or heart failure hospitalization by 21% compared to placebo, with similar risk reduction observed in participants with and without diabetes.
The provided text outlines plasma glucose level categories for fasting and two-hour post-glucose challenge measurements, which are relevant to diabetes diagnosis and classification. Fasting plasma glucose levels are categorized as follows: category 1 <90 mg/dl (5.0 mmol/l), category 2 91–108 mg/dl (5.1–6.0 mmol/l), category 3 109–125 mg/dl (6.1–6.9 mmol/l), category 4 126–143 mg/dl (7.0–7.9 mmol/l), category 5 144–161 mg/dl (8.0–8.9 mmol/l), category 6 162–180 mg/dl (9.0–10.0 mmol/l), category 7 ≥181 mg/dl (10.1 mmol/l). Two-hour plasma glucose levels are categorized as: category 1 <90 mg/dl (5.0 mmol/l), category 2 91–108 mg/dl (5.1–6.0 mmol/l), category 3 109–125 mg/dl (6.1–6.9 mmol/l), category 4 126–139 mg/dl (7.0–7.7 mmol/l), category 5 140–157 mg/dl (7.8–8.7 mmol/l), category 6 158–177 mg/dl (8.8–9.8 mmol/l), category 7 ≥178 mg/dl (9.9 mmol/l). These glucose thresholds are used to assess glucose tolerance and identify individuals at risk for diabetes.
Meticulous metabolic control may have beneficial effects on the progression and prognosis of chronic heart failure (CHF) in patients with diabetes. European guidelines recommend maintaining HbA1c below 6.5% (48 mmol/mol), fasting plasma glucose below 6 mmol/L (<108 mg/dL), and postprandial plasma glucose below 7.5 mmol/L (<135 mg/dL). The evidence supporting these recommendations is limited, though it is stronger for type 1 diabetes than type 2 diabetes. Some recent trials on aggressive glucose lowering have shown negative outcomes, highlighting the uncertainty surrounding such treatment strategies, especially in patients with CHF, as these trials did not specifically include such patients. Epidemiologic studies suggest an increased risk of complications with higher plasma glucose and HbA1c levels, even below current normal thresholds. Further research is needed to determine whether aggressive glucose normalization can improve outcomes in patients with CHF.
Dysregulation of cytokine production is essential for the pathogenesis of diabetes, and increased levels of pro-inflammatory cytokines such as TNF-α, IL-1-β, IL-6, and IL-18, which are elevated in both diabetes and periodontitis, may contribute to insulin resistance, diabetes-related complications, and destruction of pancreatic β cells. Adipose tissue serves as an important source of cytokine production, and obesity is a risk factor for both type 2 diabetes and periodontitis.
In patients with type 2 diabetes mellitus (T2DM), insulin resistance contributes to increased basal endogenous glucose production, which is significantly related to fasting plasma glucose concentration despite hyperglycemia and normoinsulinemia or hyperinsulinemia. This hepatic insulin resistance is linked to excess fat accumulation in the liver. After an overnight fast, glucose uptake remains normal or even increased due to the mass-action effect of hyperglycemia, which is insulin-independent. These findings suggest that therapeutic strategies to lower fasting glucose in T2DM should focus on inhibiting excessive glucose production from the liver rather than enhancing glucose uptake.
Self-monitoring of blood glucose, including fasting and one-hour post-meal measurements, serves as an early indicator of worsening hyperglycaemia and the potential need for additional treatment, particularly when linked to increased fetal growth. In 80–90% of cases, lifestyle modifications alone are sufficient to manage hyperglycaemia, and women who respond to dietary changes alone generally have a lower risk profile, allowing for less intensive management approaches.
Blood glucose meters used at home must meet specific accuracy standards set by the US Food and Drug Administration (FDA), where 95% of readings must be within 15% of the true laboratory-measured value and 99% within 20%. These standards emphasize greater accuracy for hypoglycaemic measurements compared to the 2013 ISO standard used internationally.
Pregabalin and duloxetine are the only two medications approved by both the FDA and European Medicines Agency for treating painful diabetic neuropathy. The COMBO-DN study compared high-dose monotherapy with standard-dose combination therapy of these drugs in patients who had not achieved sufficient pain relief with standard-dose monotherapy. No significant difference in pain reduction, as measured by the Brief Pain Inventory score, was found between the two treatment approaches overall. However, exploratory analysis indicated that high-dose monotherapy was more effective in patients with severe pain, while combination therapy was more beneficial for those with moderate or mild pain. Additionally, patients who initially received duloxetine at 60 mg/day responded better to the combination of duloxetine and pregabalin for evoked or severe tightness, but experienced greater benefit from high-dose duloxetine (120 mg/day) for paraesthesia or dysaesthesia.
Cognitive-behavioral therapy (CBT) has been shown to be effective in reducing depressive symptoms in individuals with type 2 diabetes mellitus (T2DM), with 85% of patients achieving remission compared to 27% in a control group receiving non-therapeutic diabetes education. At 6-month follow-up, 70% of CBT-treated patients remained in remission versus 33% in the control group. Those with fewer complications and better adherence to blood glucose monitoring tend to benefit most from CBT. In studies involving type 1 diabetes mellitus (T1DM), variations of CBT have led to reductions in diabetes-related distress and depressive symptoms, although no significant differences were found between group CBT and blood glucose awareness training. Neither intervention resulted in meaningful improvements in glycemic control at 6 or 12 months, but both modestly reduced depressive symptoms.
Faecal microbial transplantation from healthy lean donors has been shown to improve peripheral insulin sensitivity and reduce endogenous glucose production in men with metabolic syndrome, although these effects may not be sustained beyond six weeks, and individuals with low baseline microbial diversity may experience more favorable metabolic responses.
In individuals with diabetes, PCSK9 inhibition through monoclonal antibodies such as evolocumab and alirocumab leads to additional LDL cholesterol lowering by approximately 50–60%, and reduces cardiovascular risk by 15% in high-risk individuals with established cardiovascular disease, with a more pronounced absolute risk reduction observed in those with diabetes due to their higher baseline risk; furthermore, novel therapies like inclisiran, a small interfering RNA molecule, and bempedoic acid, a pro-drug metabolized to an ATP-citrate lyase inhibitor, offer additional LDL cholesterol reduction of about 50% and 15–30%, respectively, with the latter currently under evaluation for cardiovascular efficacy in statin-intolerant individuals including those with diabetes.
Persistent and excessive activation of certain protein kinase C (PKC) isoforms, particularly PKC-β and PKC-δ, contributes to tissue injury in diabetes due to hyperglycemia and associated metabolic abnormalities. This activation arises from increased de novo synthesis of diacylglycerol (DAG) from glucose via triose phosphates, which is amplified by elevated intracellular glucose levels enhancing glucose flux through the glycolytic pathway. Enhanced PKC activity is also linked to the interaction between advanced glycation end products (AGEs) and their cell-surface receptors. In diabetic conditions, increased levels of various PKC isoforms have been observed, including PKC-α, PKC-β, PKC-δ, and PKC-ε, particularly in the retina and glomeruli of diabetic animals.
Diabetes during pregnancy in women with renal transplants occurs at a reported incidence of 5% to 12%, with hypertension prior to pregnancy ranging from 40% to 72%, potentially due to pre-existing conditions or side effects of immunosuppressive drugs. Management includes delaying pregnancy for at least one year after transplantation to ensure graft stability, defined by serum creatinine levels below 133 μmol/l, minimal proteinuria (≤500 mg/24h), and stable immunosuppressive therapy. These pregnancies are associated with increased maternal and perinatal complications such as miscarriage (15–20%), pre-eclampsia (30–35%), preterm delivery (50–55%), urinary tract infections (2–5%), fetal growth restriction (5–10%), rejection during pregnancy (35–40%), and graft rejection within two years postpartum (30–50%). Effective management strategies mirror those for diabetic nephropathy and emphasize preconception care, frequent prenatal monitoring, optimal glycaemic and blood pressure control, intensive fetal surveillance, and timely delivery to improve outcomes.
Bariatric surgery, particularly Roux-en-Y gastric bypass and sleeve gastrectomy, contributes to the improvement of type 2 diabetes through various mechanisms including changes in meal-stimulated gut hormone profiles, reductions in inflammation, and alterations in the intestinal microbial profile. Roux-en-Y gastric bypass leads to a significant increase in circulating levels of PYY, GLP-1, and other anorectic peptides, which are associated with improved glycemic control. Sleeve gastrectomy reduces ghrelin levels by removing most of the ghrelin-producing cells in the stomach. Individual responses to these procedures vary and are correlated with baseline meal-stimulated gut hormone levels, with poor responders showing lower levels of GLP-1 and PYY. Understanding this variability may aid in developing more effective, personalized treatments for obesity and type 2 diabetes.
The Treat to Target Trial compared insulin glargine with NPH insulin at bedtime for diabetes management, with both groups starting at 10 units and increasing doses weekly based on fasting glucose levels to reach a glycemic goal of less than 5.5 mmol/L (100 mg/dL). The study aimed for an HbA1c below 7% (53 mmol/mol), which was achieved in about 60% of patients using either NPH or glargine insulin. Patients did not need to reach the targeted fasting plasma glucose due to concerns about frequent hypoglycemia, particularly overnight, which was more common with NPH insulin because of its earlier peak effect compared to glargine.
Young people with type 2 diabetes are at risk of acute complications such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemia, as well as chronic complications and comorbidities including hypertension, dyslipidaemia, nephropathy, retinopathy, non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), depression, and binge eating. Studies show that hypertension, dyslipidaemia, and microalbuminuria may be present early and progress over time, with over half of young adults developing at least one complication within 10 years. Risk factors for complications include minority race or ethnicity, hyperglycaemia, hypertension, and dyslipidaemia, highlighting the need for early aggressive management of hyperglycaemia to prevent complications and preserve health. Additionally, mental health issues such as depression, reduced quality of life, and disordered eating behaviours are also concerns in this population.
Blood glucose targets for diabetes management include pre-prandial capillary plasma glucose levels of 4.4 to 7.2 mmol/l (80–130 mg/dl) and peak post-prandial levels below 10.0 mmol/l (<180 mg/dl), as recommended by the ADA guidance.
Retinopathy in people with diabetes can lead to varying degrees of vision loss, which is associated with adverse social impacts such as social isolation, increased dependence on others, and disruption to family functioning, as well as emotional impacts including loss of confidence, fear, vulnerability, anger, stress, and depression. However, the level of psychological distress resulting from visual loss may not be specific to diabetes, as one study found no significant difference in psychological adjustment between older adults with and without diabetes at the onset of visual loss or 12 months later.
Recent research has identified genetic variants associated with an increased risk of developing type 2 diabetes, particularly variants of the TCF7L2 gene, which encodes a transcription factor involved in the Wnt-β catenin signaling pathway. The T allele of the SNP rs7903146 is linked to a higher risk of type 2 diabetes across most populations, except the Pima, and is associated with impaired insulin secretion both in vivo and ex vivo. TCF7L2 variants may directly and indirectly affect β cells, as increased TCF7L2 expression in human pancreatic islets carrying the T risk allele correlates with reduced glucose-stimulated insulin release. Additionally, individuals with the risk allele show diminished insulin secretion in response to GLP-1 infusion, suggesting that TCF7L2 variants are associated with decreased insulin secretion in response to both glucose and incretin hormones. Further studies have found reduced TCF7L2 gene expression in type 2 diabetes pancreatic islets, along with impaired insulin secretion and β-cell survival.
First-degree relatives of individuals with type 1 diabetes are at increased risk of developing the condition, although around 80–90% of newly diagnosed individuals do not have affected siblings or parents. In European-origin populations, approximately 4–6% of siblings of type 1 diabetes probands develop the disease by age 20, compared to 0.2–1.0% in the general population. Offspring of affected fathers have a 1.5–3 times higher risk than offspring of affected mothers, with 5–8% of children of diabetic fathers and 2–5% of children of diabetic mothers developing type 1 diabetes by age 20. The reason for this difference based on parental sex remains unexplained.
Some medications used in diabetes management include DPP-4 inhibitors, which enhance the activity of incretin hormones such as GLP-1 and GIP, thereby improving glucose control. GLP-1 receptor agonists, including those with a long-acting release (LAR) formulation, help regulate blood sugar levels by increasing insulin secretion and reducing glucagon release in a glucose-dependent manner. SGLT-2 inhibitors are another class of antidiabetic drugs that lower blood glucose by promoting urinary glucose excretion. Neutral protamine Hagedorn (NPH) insulin is an intermediate-acting insulin used to manage blood sugar levels in patients with diabetes. These therapies may have specific considerations in patients with chronic kidney disease (CKD), as estimated glomerular filtration rate (eGFR) can influence drug selection and dosing.
Hypoglycemia activates widespread but interconnected brain regions, including the medial prefrontal cortex, the lateral orbitofrontal cortex, the thalamus, the globus pallidus, and the periaqueductal gray, as indicated by studies using [15O] water and positron emission tomography (PET). Research also shows that recent antecedent hypoglycemia reduces the sympathoadrenal and symptomatic responses, which serves as a model of hypoglycemia-associated autonomic failure (HAAF), and leads to greater synaptic activity in the dorsal midline thalamus during subsequent hypoglycemia. A proposed cerebral network suggests thalamic inhibition of hypothalamic activity in HAAF, a concept supported by various patterns of [18F] deoxyglucose uptake observed in type 1 diabetes mellitus (T1DM) patients with and without hypoglycemia unawareness.
Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications, with its prevalence increasing by more than 30% in one or two decades across several countries, partly due to changes in diagnostic criteria. In 2019, hyperglycaemia in pregnancy affected 15.8% of live births, with 83.6% of these cases attributed to GDM. The prevalence of GDM rises with maternal age, affecting 37.0% of women aged 45–49 years compared to 10.1% in those aged 20–24 years. There are notable regional differences in age-adjusted GDM prevalence, with 27.0% of live births affected in South-East Asia versus 7.5% in the Middle East and North Africa. Over 85% of women with GDM reside in low- and middle-income countries where access to antenatal care is often limited.
Most patients with type 2 diabetes mellitus (T2DM) and elevated urinary albumin excretion (UAE) often require additional antihypertensive therapy to manage blood pressure, especially since the guideline target of less than 125/75 mmHg in proteinuric patients is difficult to achieve. Additional agents such as diuretics and calcium-channel blockers are commonly appropriate, and individualized treatment is necessary. Adding aliskiren, a direct renin inhibitor, to 100 mg/day of losartan in hypertensive T2DM patients with nephropathy has been shown to reduce UAE by 20% compared to placebo without increasing adverse events. Spironolactone, either alone or with background ACE inhibitor or ARB, can also reduce UAE and blood pressure but may negatively affect glycemic control.
DPP-4 inhibitors are generally well tolerated and have a favourable safety profile, making them a potentially attractive treatment option for frail individuals where intensive glycaemic management may pose risks. Concerns about an increased risk of pancreatic adverse events, including acute pancreatitis and pancreatic cancer, initially arose from post-marketing surveillance and animal studies suggesting higher rates of pancreatic intraepithelial neoplasia with incretin therapies, but these safety signals have been largely alleviated. Some adverse effects have been reported with DPP-4 inhibitors, including elevated liver enzymes, skin lesions, inflammatory bowel disease, and joint pain, though associations with respiratory and urinary tract infections have been largely refuted, with uncertainty remaining about a possible link between sitagliptin and increased rates of nasopharyngitis.
Increased modification of key signaling molecules by O-GlcNAc has been shown to reduce insulin signal transduction, contributing to the development of diabetic complications. Additionally, pathway selective insulin resistance in vascular cells leads to overactivation of the MAPK pathway due to hyperinsulinemia, further exacerbating diabetic microvascular damage.
Hyperfiltration is commonly observed at the onset of type 1 diabetes and in some cases of type 2 diabetes diagnosis, with eGFR typically normalizing as glucose levels stabilize, although it may persist in some individuals. Persistent hyperfiltration is hypothesized to increase the risk of diabetic nephropathy, though this remains debated. SGLT-2 inhibitors, initially developed to lower glucose in type 2 diabetes, have shown kidney-protective effects by slowing kidney disease progression and reducing hyperfiltration, particularly in type 1 diabetes, possibly through lowering intraglomerular hypertension. However, their effects on hyperfiltration in type 2 diabetes are less conclusive.
Different individual susceptibilities to microvascular complications in diabetes have been linked to genetic polymorphisms, and several pathogenic factors associated with hyperglycaemia contribute to these complications, including metabolic factors, haemodynamic factors, growth factors/cytokines, intracellular factors, and the complement system. Incretin drugs, such as glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, along with sodium-glucose cotransporter 2 inhibitors, have demonstrated cardio- and renoprotective effects that go beyond their glucose-lowering and weight-reducing properties.
Kidney failure due to diabetes is the most common single cause for entry into kidney replacement programs worldwide, with most cases involving individuals with type 2 diabetes and major comorbidities. The presence of moderately elevated albuminuria or greater warrants the use of a renin-angiotensin system inhibitor, which should be titrated to the maximum tolerated dose. Blood pressure should be maintained at 120–130/75 mmHg using additional antihypertensive agents if needed, reducing the annual decline in GFR from 10–12 to 3–5 ml/min/1.73 m². Dietary protein intake should be limited to 0.8 g/kg body weight per day to slow kidney function deterioration. Aggressive management of cardiovascular risk factors and aspirin use can reduce cardiovascular events and progression to nephropathy by 60%. Sodium-glucose cotransporter 2 inhibitors slow kidney disease progression and reduce cardiovascular events, hospitalization for heart failure, and mortality in people with type 2 diabetes and nephropathy, independent of glucose effects. For individuals with end-stage kidney disease and significant comorbidities, dialysis should be offered, while some may benefit from kidney or kidney-pancreas transplantation after appropriate cardiovascular assessment and treatment.
Fetal monitoring in women with diabetes follows routine antenatal care protocols and includes a 20-week anomaly scan and fetal cardiac scan. According to UK guidelines, women with diabetes should undergo ultrasound monitoring of fetal growth and amniotic fluid volume every four weeks from 28 to 36 weeks, along with individualized monitoring of fetal well-being if there is a risk of intrauterine growth restriction (IUGR), or if the woman has macrovascular disease or nephropathy. Tests of fetal well-being before 38 weeks, such as biophysical profiles and Doppler studies, are not recommended unless IUGR is suspected.
Semaglutide, a medication administered once-weekly via subcutaneous injection, was evaluated in the SUSTAIN-6 trial involving individuals with type 2 diabetes and a high cardiovascular risk profile, showing that both the 0.5 mg and 1 mg doses were more effective than placebo in reducing three-component MACE (major adverse cardiovascular events) with a hazard ratio of 0.74 (95% CI 0.58 to 0.95) and in reducing the risk of new or worsening nephropathy, including macroalbuminuria, doubling of serum creatinine, or need for renal-replacement therapy, with a hazard ratio of 0.64 (95% CI 0.46 to 0.88), although it was associated with an increased frequency of diabetic retinopathy complications compared to placebo (HR 1.76; 95% CI 1.11 to 2.78).
Agents that activate adenosine 5′-monophosphate-activated protein kinase (AMPK) have shown improvements in glycaemic control in preclinical studies and are being explored as potential therapies for type 2 diabetes. AMPK, a key enzyme in cellular energy regulation, is activated when energy levels drop and AMP concentrations rise, leading to increased glucose and fatty acid uptake and oxidation to restore ATP production. It also suppresses gluconeogenesis and lipogenesis. Metformin, certain PPARγ agonists, and adiponectin receptor agonists are believed to target AMPK among other mechanisms. Additionally, compounds such as AMP analogues, α-lipoic acid, polyphenols, and salicylates can activate AMPK, though further clinical research is needed to evaluate their effectiveness and potential side effects on other AMP-sensitive enzymes.
Combinations of gastrointestinal and pancreatic hormones have been studied for their effects on diabetes management. Coadministration of GLP-1 with glucagon has been shown to reduce hyperglycaemia and increase energy expenditure more effectively than individual agents alone, while coadministration of GLP-1 with GIP reduces hyperglycaemia and body weight to a greater extent. Triple combinations of GLP-1, glucagon, and GIP, as well as GLP-1, oxyntomodulin, and peptide YY, have also demonstrated enhanced effects on lowering blood glucose levels, food intake, and body weight. Pre-clinical studies indicate that GLP-1 combined with gastrin or CCK-8 increases islet β-cell mass and supports appetite control, and xenin combined with GLP-1 or GIP provides additional glucose-lowering benefits. The amylin analogue pramlintide, used in some regions to reduce appetite and weight gain in insulin-treated individuals, enhances appetite regulation and weight loss when combined with GLP-1. Similarly, combining cagrilintide, another amylin analogue, with a GLP-1 receptor agonist leads to significant weight loss and improved glycaemic control. Due to challenges in mixing these peptides at required concentrations for a single injection, research has focused on developing hybrid peptides designed to target multiple receptors for optimized therapeutic effects in diabetes treatment.
Background retinopathy in young adults is associated with white matter abnormalities on MRI and impaired cognitive performance, including attention, fluid intelligence, and information processing speed. Patients with significant retinopathy show abnormal brain activation during working memory tasks. Peripheral neuropathy and other microvascular complications are also linked to alterations in brain function and structure.
Social determinants of health directly influence the options individuals have for engaging in type 2 diabetes prevention behaviors, affecting their choices and outcomes. Healthcare systems and providers can implement strategies to improve individual options and choices related to type 2 diabetes care by addressing system-level factors.
Improved glycaemic control can be achieved through lifestyle management and weight loss. Adjustments to Neversapid insulin may be necessary, and if fasting glucose levels remain above 7mmol/l, a gradual increase in evening Lantus dosage could be considered. An HbA1c level of 7.2% is deemed acceptable in patients with a long history of diabetes and comorbidities such as ischaemic heart disease. Evidence from the ACCORD Study indicates that aiming for an HbA1c below 6.5% may lead to worse outcomes in certain patient populations.
α-Glucosidase inhibitors are used in the management of type 2 diabetes mellitus (T2DM), particularly for patients with post-prandial hyperglycemia and only slightly elevated fasting glycemia, and can be used either as monotherapy or more commonly as an add-on therapy to target post-prandial glucose levels. These inhibitors can also help extend the post-prandial period to reduce interprandial glycemic troughs or hypoglycemia in individuals using sulfonylureas and/or insulin. Acarbose, an α-glucosidase inhibitor, has been shown to prevent the progression of impaired glucose tolerance (IGT) to T2DM, though this application is not a licensed use.
SGLT-2 inhibitors, specifically dapagliflozin and empagliflozin, have demonstrated significant cardiovascular benefits in patients with heart failure and reduced ejection fraction, including those with type 2 diabetes. In the DAPA-HF trial, dapagliflozin reduced the risk of the composite outcome of worsening heart failure or cardiovascular death by 26% over 18.2 months, with similar benefits observed in the subgroup of participants who had type 2 diabetes. The EMPEROR-Reduced trial showed that empagliflozin reduced the same composite outcome by 25% over 16 months, with consistent effects in participants with diabetes. A meta-analysis of both trials confirmed that these SGLT-2 inhibitors consistently lower the risk of hospitalization for heart failure and cardiovascular death by approximately 25%, irrespective of diabetes status.
Several trials are investigating agents aimed at preserving β-cell function in diabetes. DiaPep77 (HSP60), a subcutaneous peptide derived from heat shock protein 60, has shown β-cell preservation over 12–18 months in adults with diabetes, although no similar effect was observed in children, and a Phase III trial (DIA-AID) is ongoing. Alum-GAD (Diamyd®), a formulation of GAD65 administered subcutaneously, has demonstrated preservation of β-cell and C-peptide levels in patients with recent-onset type 1 diabetes (T1DM) and in those with latent autoimmune diabetes in adults (LADA), with Phase III trials ongoing. NBI-6021, an altered peptide ligand insulin B:9–23 vaccine, was tested in adolescents and adults with new-onset T1DM but the trial has been completed. BHT-3021, a pro-insulin-based DNA vaccine administered intramuscularly over 12 weeks, is being assessed for safety in patients aged ≥18 years with T1DM, with ongoing phases including 12 months of blinded treatment, 12 months of cross-over, and 12 months of follow-up.
Control of hypertension reduces the risk of developing microalbuminuria in patients with diabetes. Studies have shown that tight blood pressure control, with a target of 144/82 mmHg compared to 154/87 mmHg, leads to a 29% reduction in the risk of microalbuminuria over six years. There is no evidence of a "J" shape curve where lower blood pressure increases risk. Both captopril and atenolol were found to be equally effective in reducing this risk, although the study was not designed to compare differences between treatments. In normoalbuminuric patients with diabetes, adding ramipril to existing antihypertensive therapy reduced the risk of developing proteinuria compared to placebo. In the BENEJECT study, hypertensive and normoalbuminuric patients with type 2 diabetes receiving trandolapril alone or with verapamil had a 50% lower risk of developing microalbuminuria compared to those taking verapamil or placebo. The ADVANCE trial also demonstrated a 17% reduction in the incidence of microalbuminuria in patients receiving perindopril and indapamide. These findings suggest a specific benefit of renin-angiotensin system (RAS) blockade in reducing microvascular complications in patients with diabetes.
Interleukin-10 (IL-10) contributes to the development of regulatory T cells (Tregs), and its gene transfer to murine muscle increases Tregs in a dose-dependent manner, preventing diabetes development. Interleukin-35 (IL-35), secreted by Tregs, enhances their suppressor function and promotes the differentiation of CD4+ T cells into induced regulatory Th35 suppressor cells. AAV-mediated, β-cell-specific expression of IL-35 in NOD mice suppresses β-cell autoimmunity and prevents diabetes onset, characterized by reduced infiltration of islet CD4+ and CD8+ T cells and dendritic cells, along with the formation of a distinct islet Foxp3+ Treg pool that suppresses effector CD4+ T cell differentiation. CCL22, a ligand for the chemokine receptor CCR4 highly expressed on Tregs, when overexpressed in β cells, recruits endogenous Tregs to the islets, limiting the expansion and effector activity of autoreactive T cells and providing long-term protection against autoimmune diabetes.
Insulin is initially required for all cases of diabetes in the neonatal period, but treatment after relapse can vary, including options such as diet, oral antidiabetes agents, or insulin. In cases of transient neonatal diabetes mellitus (TNDM) caused by KCNJ11 and ABCC8 variants, sulfonylureas may effectively manage the condition. For 6q24-related TNDM, the optimal treatment after relapse is not well established, though recent evidence suggests that non-insulin-based therapies, including sulfonylureas, can be effective.
Thiazide diuretics impair glucose tolerance, primarily by reducing pancreatic insulin release rather than causing insulin resistance, with the severity of glucose intolerance linked to hypokalemia. Potassium depletion inhibits the conversion of proinsulin to insulin, leading to postprandial hyperglycemia and elevated proinsulin levels between meals, which may downregulate insulin receptors in peripheral tissues. This effect occurs in individuals without diabetes and those with type 2 diabetes mellitus (T2DM), but not in patients with type 1 diabetes mellitus (T1DM) on exogenous insulin therapy. The impairment of insulin secretion due to hypokalemia is reversible upon restoration of normal potassium levels.
Colesevelam provides a modest but consistent reduction in HbA₁c, averaging about 0.5% (6 mmol/mol), in individuals with type 2 diabetes mellitus (T2DM) across various treatment regimens, including those on metformin alone, combined therapies such as sulfonylureas or glitazones, and even in patients on insulin therapy who are not adequately controlled. Clinical studies have shown that when added to sulfonylurea therapy, colesevelam at 3.75 g/day for 26 weeks resulted in a placebo-corrected HbA₁c reduction of 0.54% (6 mmol/mol), and in another study, a 16-week course led to a 0.41% decrease in HbA₁c compared to placebo. The drug is generally well tolerated, though it may cause constipation and, in individuals with pre-existing high triglyceride levels (>250 mg/dL), can lead to hypertriglyceridemia. In the absence of elevated triglycerides, colesevelam is safe and can significantly reduce LDL cholesterol, especially in patients also taking statins, thereby potentially contributing to cardiovascular risk reduction.
An immunohistochemical study found that in young individuals with recent-onset type 1 diabetes, the β cells of multiple islets stained positive for enterovirus capsid protein VP1 in 44 out of 72 cases, supporting previous findings linking enteroviruses, particularly the coxsackie B4 serotype, to type 1 diabetes. However, a more recent study using serotype-specific neutralizing antibody tests in the DIPP study suggested a novel association between coxsackie B1 and an increased risk of islet autoimmunity, while finding an inverse relationship between coxsackie B4 and islet autoimmunity, contradicting earlier evidence. Technical challenges in detecting low quantities of virus particles persist, but recent research has confirmed signs of enterovirus in fresh pancreatic tissue of newly diagnosed type 1 diabetes patients using multiple techniques across different laboratories.
Men with diabetes who have failed conventional treatments for erectile dysfunction and desire to resume full sexual activity may benefit from referral for insertion of a penile prosthesis.
High-intensity resistance training, when combined with a moderate energy restriction diet, can lead to a decrease in HbA₁c levels by 1.2% (13 mmol/mol) over a 26-week program, and by 1.0% (11 mmol/mol) over a 16-week program. Meta-analyses have confirmed that resistance training effectively reduces HbA₁c in individuals with type 2 diabetes mellitus (T2DM), with exercise interventions resulting in HbA₁c levels that were 0.66% (7 mmol/mol) lower post-intervention compared to control groups. Both aerobic and resistance exercises show similar effects on glycemic control, and the benefits of exercise on glucose control appear to be independent of weight loss. Combining resistance exercise with aerobic training also contributes to improved glycemic outcomes in T2DM.
Atypical antipsychotics, particularly clozapine and olanzapine, have been associated with the development of de novo diabetes mellitus and worsening of pre-existing diabetes, although a definitive causative relationship has not been established. Many patients who develop diabetes while on these medications already have traditional risk factors, and diabetes rates in those with severe mental illness were high even before the use of antipsychotics. Potential mechanisms linking antipsychotics to diabetes include hepatic dysregulation due to antagonism of hepatic serotonergic pathways, weight gain leading to fasting hyperglycemia and hyperinsulinemia, and possible direct effects on insulin secretion. In some cases, discontinuation of the drug may lead to normalization of blood glucose levels. Despite various studies showing an association between atypical antipsychotics and glucose intolerance, the absolute excess risk of diabetes attributed to these drugs is low, ranging from 0.05% for risperidone to 2.03% for clozapine. Most individuals on antipsychotics do not develop diabetes, and when they do, the cause is often unrelated to the medication. Nonetheless, baseline screening and ongoing monitoring of glucose levels are recommended when prescribing atypical antipsychotics.
GLP-1 receptor agonists, such as exenatide and liraglutide, are used in the treatment of diabetes and have been studied for their effectiveness in managing antipsychotic-induced weight gain. These drugs contribute to weight loss, with clinical trials reporting significant reductions in body weight among patients treated with GLP-1 receptor agonists.
Pre-proliferative diabetic retinopathy (DR) is characterized by specific clinical features that indicate progression of diabetes-related retinal damage, including microaneurysms, intraretinal hemorrhages, cotton wool spots, and venous beading, which serve as important indicators for monitoring and managing diabetic eye disease.
High intake of refined sugars and simple carbohydrates is associated with an increased risk of developing diabetes, as these foods can lead to rapid spikes in blood glucose levels and contribute to insulin resistance over time.
Synthetic ligands activating the FXR, such as obeticholic acid (OCA), improve insulin resistance and have shown benefits in glucose and lipid metabolism, particularly in animal models of non-alcoholic steatohepatitis (NASH). In a phase 2 randomized controlled trial (RCT) involving 283 individuals, approximately half of whom had type 2 diabetes, OCA treatment improved histological features of NASH, including fibrosis. An 18-month interim analysis of a larger phase 3 RCT with 931 participants, 57% having type 2 diabetes, confirmed that OCA (25 mg/day) significantly improved liver fibrosis compared to placebo. However, OCA was associated with side effects such as pruritus and elevated plasma LDL cholesterol levels, which are of clinical concern given the increased cardiovascular disease risk in individuals with NAFLD. The rise in LDL cholesterol was noted to be around 20% from baseline but appeared transient and manageable with statin treatment.
In individuals with type 2 diabetes, PCSK9 inhibitors have been studied in recent trials involving those with acute coronary syndrome and additional cardiovascular disease risk factors. These studies, including the FOURIER trial, demonstrated that the reduction in cardiovascular events with PCSK9 inhibitor use was similar in people with and without diabetes, with a 16% reduction in events after one year and 25% after two years, corresponding to a 1 mmol/l reduction in LDL cholesterol.
During adolescence, teenagers with diabetes undergo physical, developmental, behavioral, and emotional changes that significantly affect insulin needs, largely due to pubertal growth-associated insulin resistance. This period demands increased vigilance in diabetes management through frequent blood glucose monitoring, careful attention to carbohydrate intake, physical activity, and precise insulin delivery. In type 1 diabetes, a temporary phase called the honeymoon stage occurs shortly after diagnosis, during which the pancreas still produces a small amount of insulin. As this phase diminishes, exogenous insulin requirements rise, particularly during puberty when insulin needs can increase rapidly by up to 50% or more.
Many drugs can cause hypoglycemia by interacting with and enhancing the action of glucose-lowering drugs, acting as insulin secretagogues, or enhancing or mimicking insulin's effects in suppressing liver glucose production and stimulating glucose uptake into peripheral tissues; some drugs such as nonselective β-adrenoceptor antagonists can block the warning symptoms or neuroendocrine counter-regulatory responses to hypoglycemia, thereby prolonging and intensifying hypoglycemic episodes.
GLP-1 receptor agonists such as exenatide, liraglutide, lixisenatide, dulaglutide, and semaglutide enhance insulin secretion and suppress glucagon secretion in response to elevated glucose levels, delay gastric emptying, and promote satiety. These medications not only lower blood glucose and reduce body weight but also show neutral or beneficial effects on cardiovascular outcomes and kidney health in patients with type 2 diabetes. They are typically administered via daily or weekly subcutaneous injections, while semaglutide is also available in an oral formulation. The oral version uses sodium hydroxybenzoylamino-caprylate (SNAC) to protect the peptide from degradation and facilitate absorption in the stomach. Despite lower bioavailability compared to the injectable form, the oral formulation achieves similar efficacy through higher dosing.
In individuals with diabetes, once abnormal urinary albumin excretion (UAE) has been detected, the albumin:creatinine ratio should be measured every 3 months, ideally on three consecutive mornings before a clinic visit, to distinguish true changes in UAE from day-to-day variation. Additionally, serum creatinine and estimated glomerular filtration rate (eGFR) should be measured every 3 to 6 months. As renal function declines, a linear relationship exists between eGFR or the inverse of serum creatinine, which helps assess the rate of glomerular filtration rate decline in response to therapy and estimate the time until an individual may reach end-stage renal disease (ESRD).
Hypoglycemic agents can influence triglyceride concentrations through insulin's peripheral actions on adipose and muscle tissue or via effects on lipoprotein lipase (LPL). In poorly controlled type 1 diabetes mellitus (T1DM) and diabetic ketoacidosis, hypertriglyceridemia and reduced HDL cholesterol are commonly observed, typically resolving with insulin therapy. In type 2 diabetes mellitus (T2DM), metformin, sulfonylureas, and acarbose lead to modest reductions in triglycerides that correlate with glycemic control. Thiazolidinediones generally have more favorable effects on lipid profiles compared to sulfonylureas or insulin, though pioglitazone and rosiglitazone differ in their lipid-related effects. Pioglitazone reduces triglycerides, does not significantly alter apolipoprotein B levels, decreases LDL particle concentration, and increases HDL cholesterol without affecting apolipoprotein AI levels. Rosiglitazone, on the other hand, raises triglycerides, increases both apolipoprotein B and LDL particle concentrations, and decreases apolipoprotein AI levels, with a greater increase in LDL cholesterol compared to pioglitazone. Both drugs increase HDL cholesterol, but their differing impacts on lipid profiles may contribute to variations in cardiovascular disease (CVD) outcomes. The RECORD trial found no increased cardiovascular event rate with rosiglitazone, while the PROACTIVE study showed that pioglitazone reduced major atherosclerotic events in patients with T2DM.
Pregnancy in women with diabetes historically had very poor outcomes, with perinatal fetal losses of 45–65% in most units by 1950, significantly higher than in the general population. Success in improving outcomes was linked to good diabetic control and care by an experienced multidisciplinary team including a physician, obstetrician, and pediatrician, as demonstrated by Priscilla White and Jorgen Pedersen, who achieved much lower fetal mortality rates. Pedersen's target of a 6% fetal mortality rate was not widely achieved in Europe or the US until the 1980s.
Complications of type 2 diabetes, such as neuropathy, vascular disease, and impaired vision, likely increase the risk of falling and thereby of fracture. Studies show that individuals with type 2 diabetes have a 22% higher risk of non-spine fractures compared to those without diabetes, with insulin-treated individuals having both a higher prevalence of complications and a greater fracture risk. In older adults with type 2 diabetes who experienced fractures, there was a higher prevalence of neuropathy, cerebrovascular disease, and falls compared to those without fractures. Risk factors for falls, including medication use associated with falls, are more common in people with type 2 diabetes, and low-impact falls are more frequent in those treated with insulin. However, adjusting for diabetes complications and falls risk does not fully explain the increased fracture risk in type 2 diabetes.
All forms of diabetes are characterized by hyperglycemia and a relative or absolute lack of insulin action, leading to diabetes-specific pathology in the retina, renal glomerulus, and peripheral nerves. Diabetes is the leading cause of new blindness in people aged 20–74 and the leading cause of end-stage renal disease (ESRD) in the developed world, with patients on dialysis having half the survival rate of non-diabetic individuals. Over 60% of diabetes patients develop neuropathy, including distal symmetrical polyneuropathy, mononeuropathies, and autonomic neuropathies that cause erectile dysfunction, urinary incontinence, gastroparesis, and nocturnal diarrhea. Diabetic lower extremity arterial disease combined with neuropathy accounts for 50% of all non-traumatic amputations in the USA. Diabetes and impaired glucose tolerance increase cardiovascular disease risk three- to eightfold, with over 40% of patients hospitalized for acute myocardial infarction having diabetes and 35% having impaired glucose tolerance. Additionally, diabetes impairs new blood vessel growth, resulting in reduced collateral vessel formation in ischemic hearts and non-healing foot ulcers. The microvascular complications of diabetes include retinopathy, nephropathy, and peripheral neuropathy.
Nodular glomerulosclerosis, as depicted in the figure, is a renal complication associated with diabetes, specifically reflecting the pathological changes in the kidney's glomeruli due to long-term diabetic damage.
Practical monitoring of diabetic control became feasible in the late 1970s with the introduction of test strips for measuring blood glucose at home. The discovery of hemoglobin A₁c led to glycated hemoglobin (HbA₁c) assays, providing an objective measure of overall glucose control. These advancements enabled the North American Diabetes Control and Complications Trial in 1993, which demonstrated that good control prevents and delays microvascular complications in type 1 diabetes. For type 2 diabetes, the UK Prospective Diabetes Study in 1998 showed that improved glycemic control benefits microvascular complications and emphasized the importance of treating hypertension. By the late 1990s, it was recognized that reducing glucose levels, high blood pressure, or cholesterol individually could lower the risk of heart disease and death, prompting investigation into multiple risk factor interventions. The Steno 2 study, starting in Denmark in 1992, found after 13 years that such interventions reduced the risk of death by 20% and the development of nephropathy, retinopathy, and neuropathy by 50% in patients with type 2 diabetes and microalbuminuria.
HHS (Hyperosmolar Hyperglycemic State) shares many features with DKA (Diabetic Ketoacidosis), but differs primarily by the absence of significant ketoacidosis, likely due to residual low-level insulin secretion that suppresses lipolysis enough to prevent ketogenesis but not hyperglycemia. Hyperosmolarity may also decrease lipolysis, limiting free fatty acids needed for ketogenesis. HHS accounts for 10–30% of hyperglycemic emergencies and is becoming more common as type 2 diabetes prevalence rises, increasingly affecting younger adults and teenagers. Up to two-thirds of HHS cases involve individuals previously undiagnosed with diabetes, and mortality rates range from 5–20%, which is 10-fold higher than DKA, rising with age, particularly over 70 years.
The genetic basis of type 1 diabetes involves numerous genetic variants identified through genome-wide association studies, with 78 significant regions reported from analyses of over 60,000 individuals. Some of these variants are particularly enriched in CD4+ effector T cells, highlighting their potential role in islet autoimmunity. To better understand disease heterogeneity, aetiology, and pathogenesis, these genetic variants have been combined into a genetic risk score. This score, incorporating 41, 61, or 67 genetic variants, aids in distinguishing type 1 diabetes from other forms such as monogenic or type 2 diabetes, and can identify neonates at high risk of developing islet autoantibodies and subsequent clinical diabetes. The use of PCR-based testing for this genetic risk score is cost-effective and holds promise for neonatal screening and accurate disease classification.
Adults with type 1 diabetes may experience impairments in cognitive domains such as attention, visual perception, processing speed, and executive function, although memory and learning may be spared. Type 2 diabetes is linked to declines in executive function, processing speed, memory, and language, particularly verbal fluency. Older individuals with diabetes should be screened for cognitive impairment using standardized tests, and a formal diagnosis of dementia is necessary to create a tailored management plan. Comorbid depression should also be evaluated in people with diabetes and cognitive decline. Those with declining cognitive function are at higher risk of hyperglycaemia and hypoglycaemia due to difficulties with learning, retaining information, and recognizing the importance of self-care. Glycaemic management plans should be reviewed annually, incorporating cognitive screening and lived experience. Polypharmacy is common in older adults with diabetes and dementia, increasing risks of drug interactions, medication errors, falls, and further cognitive impairment, making regular medication review and appropriate de-prescribing essential. Social isolation is a risk factor for cognitive decline and dementia, highlighting the importance of social support and caregiver education for individuals with diabetes and dementia.
Pioglitazone has been shown to reduce cardiovascular risk in people with type 2 diabetes and macrovascular disease, as demonstrated in the PROACTIVE trial involving 5238 participants who were treated with either pioglitazone 45 mg daily or placebo over three years. Although the primary endpoint, which included death, non-fatal myocardial infarction, stroke, acute coronary syndrome, leg amputation, coronary revascularization, and peripheral artery revascularization, showed non-significant risk reduction, a significant 16% reduction in the secondary endpoint of three-point major adverse clinical events (MACE) was observed with pioglitazone compared to placebo. Similar findings were seen in the IRIS trial, where 3876 individuals with prediabetes who had experienced an ischemic neurological event were treated with pioglitazone versus placebo, resulting in a significant 24% reduction in three-point MACE.
Individuals with diabetes have an increased risk for various infections, including tuberculosis, severe Gram-positive infections, hospital-acquired postoperative infections, urinary tract infections, and tropical diseases. This elevated risk is particularly significant in low- and middle-income countries where the burden of communicable diseases is high. Diabetes not only predisposes individuals to a higher risk of infections but also leads to poorer outcomes, including greater tuberculosis disease severity, treatment failure, relapse, and death. Observational studies show that infection-related hospitalizations are nearly four times higher in adults with diabetes compared to those without, with some infection types being up to 15.7 times more frequent. From 2000 to 2015, increasing rates of sepsis, influenza, kidney infections, osteomyelitis, and cellulitis were observed in people with diabetes, while rates of pneumonia, foot infections, and mycoses declined in those without diabetes but not in those with diabetes. Although COVID-19 does not appear to be more frequent in people with diabetes, mortality risks are doubled in type 2 diabetes and tripled in type 1 diabetes.
The genotype that confers the highest risk of type 1 diabetes mellitus (T1DM) involves heterozygosity for the high-risk HLA class II haplotypes DR3-DQ2 and DR4-DQ8, with one or both of these haplotypes found in more than 95% of individuals with T1DM under 30 years of age. These haplotypes are also present in 40–50% of the general population. The combination of high-risk alleles increases T1DM risk synergistically, as seen in the association of DQ8 with specific DRB1 variants such as DRB1*0401, DRB1*0404, and DRB1*0402, but not DRB1*0403, which has a negative association. DQ2 is most commonly inherited with DRB1*03, further highlighting the role of specific allele combinations in disease susceptibility.
Regular aerobic exercise training improves metabolic profiles and exerts anti-inflammatory effects in individuals with type 2 diabetes mellitus (T2DM), potentially reducing the risk of cardiovascular disease. Exercise can lead to favorable changes in blood lipid levels and may lower other risk factors for coronary heart disease such as hypertension, obesity, and coagulation abnormalities, although these benefits are not consistently observed across all studies. The effectiveness of exercise in preventing atherosclerosis appears to be more pronounced in younger, healthier individuals compared to older patients with advanced atherosclerosis, suggesting that the timing and health status at initiation of exercise play a role in its protective benefits.
GLP-1 receptor agonists, such as albiglutide and efpeglenatide, have been shown to reduce the risk of heart failure hospitalization in people with diabetes. In the Harmony Outcomes trial, albiglutide resulted in a 29% lower risk compared to placebo, while the AMPLITUDE-O trial found a 39% reduction with efpeglenatide. A meta-analysis of eight GLP-1 receptor agonist trials confirmed an 11% relative risk reduction in heart failure hospitalization with this medication class.
DPP-4 inhibitors are used in the treatment of type 2 diabetes to prevent the breakdown of endogenous incretins, particularly increasing GLP-1 concentrations. These medications include sitagliptin, saxagliptin, linagliptin, and alogliptin, which are taken once daily, and vildagliptin, taken twice daily. Additionally, once-weekly agents such as omarigliptin and trelagliptin are available in some regions, with other DPP-4 inhibitors under development offering similar properties to existing options.
In individuals with diabetes, once proteinuria develops, the untreated rate of decline in glomerular filtration rate (GFR) is approximately $10 - 12\mathrm{mL / min} / 1.73\mathrm{m}^2$, a decline that may be more pronounced in non-Europid populations. Additionally, rates of acceptance for renal replacement therapy (RRT) are higher among African-Caribbean and Indo-Asian individuals compared to Europid individuals with diabetes. Among the Pima Indians, the age- and sex-adjusted incidence of end-stage renal disease (ESRD) has decreased since 1990, indicating a potential slowing of disease progression.
WHO-PEN provides tools for managing diabetes in primary healthcare, including diagnostic tools such as glucometers, urine protein and ketone test strips, blood cholesterol assays, lipid profiles, serum creatinine assays, urine microalbuminuria test strips, and Semmes-Weinstein 10g monofilaments. Medicines listed for diabetes care include insulin, metformin, glibenclamide, and gliclazide.
Faster insulin aspart and insulin degludec are insulin analogues with pharmacokinetic properties that make them suitable for managing diabetes, particularly in pregnancy. Faster insulin aspart has a rapid onset of appearance in the bloodstream (approximately 4 minutes), which helps reduce post-prandial glycaemic excursions and has been shown to improve one-hour post-prandial glucose levels and significantly reduce HbA1c in non-pregnant adults with type 1 diabetes. Insulin degludec has a long half-life of 25 hours and, when combined with aspart, was associated with reduced nocturnal hypoglycaemia and lower HbA1c over 12 months compared to glargine/aspart in non-pregnant adults. Faster insulin aspart is considered safe in pregnancy, and a study evaluating the use of insulin degludec compared to insulin detemir, along with insulin aspart, in pregnant women with type 1 diabetes is currently ongoing.
Smart insulin pens, such as the NovoPen 6 and NovoPen Echo Plus, are designed to communicate with continuous glucose monitoring (CGM) systems and blood glucose meters, enabling integration of glucose monitoring and insulin dosing data. These devices have been studied for their impact on glycaemic management, particularly in adults with type 1 diabetes. In a non-interventional study involving nearly 100 adults in Sweden, use of the NovoPen 6 was associated with a significant increase in time in range (TIR) and a reduction in episodes of hyperglycaemia and mild hypoglycaemia (3.0–3.9 mmol/l). However, the study lacked a control arm, and participants had frequent healthcare professional visits (more than five in six months), which may have influenced the observed improvements in glycaemic control.
Global transcriptome profiling in tissues such as the pancreas has helped identify and catalog numerous transcription-based events involved in the development of type 2 diabetes. Combining genome-wide association study (GWAS) data with metabolomics has enabled the detection of strong links between single nucleotide polymorphisms (SNPs) and metabolic reactions that might otherwise be overlooked. Network- or pathway-based methods, such as those using KEGG and Gene Ontology, have also contributed to identifying disease-related genes. Integrating GWAS with other data types, including expression differences, co-expression patterns with known type 2 diabetes genes, and protein-protein interactions, has led to the discovery of new candidate genes for type 2 diabetes in studies of human islets. This multi-layered approach supports a systems-based understanding of the disease's underlying mechanisms.
Patients with type 1 diabetes typically exhibit classic symptoms and may occasionally develop diabetic ketoacidosis, while those with type 2 diabetes mellitus (T2DM) can be asymptomatic or present with similar classic symptoms. Advancing age is associated with an increased renal threshold for glucose and diminished thirst perception.
Cotton wool spots are whitish, localized lesions that develop on the retina due to arrested axoplasmic transport in the retinal nerve fibre layer, often seen in diabetic retinopathy. These lesions, typically located in arcuate areas where the retinal nerve fibre layer is thick, do not indicate a specific cause of retinal damage but may reflect disturbances such as unstable blood glucose regulation. Although they generally do not affect vision and have a dynamic cycle of appearance and resolution over weeks to months, the presence of multiple cotton wool spots alongside other retinopathy changes can signal a risk of progression to vision-threatening diabetic retinopathy.
Gestational diabetes mellitus (GDM) is influenced by multiple maternal demographic and biological risk factors, and its prediction may be improved through a risk engine approach that considers personalized composite risk scores. This approach could optimize antenatal interventions and help identify women who would benefit most from continued monitoring and treatment. The pathogenesis of GDM is likely heterogeneous, suggesting that different underlying mechanisms may be at play, and this heterogeneity should be considered in risk prediction models. Integrating healthcare databases with clinical and biochemical data may enhance GDM prediction and support resource allocation, particularly in low- and middle-income countries. Additionally, there is a need to account for differences in risk among ethnic groups and to understand how various predictors contribute differently to GDM outcomes and its complications.
The UK CEMACH study found that 61% of women with type 1 diabetes experienced recurrent hypoglycaemic episodes during pregnancy, and 25% had severe hypoglycaemia, while 21% of women with type 2 diabetes had recurrent episodes of severe hypoglycaemia; however, neither recurrent nor severe hypoglycaemia was linked to poor pregnancy outcomes, with odds ratios of 1.1 and 1.3 respectively, and confidence intervals indicating no statistically significant associations. Follow-up studies showed no apparent long-term effects of maternal hypoglycaemia on offspring up to 5 years of age.
Thiazolidinediones, such as pioglitazone and rosiglitazone, have been studied for their cardiovascular effects in patients with diabetes. Pioglitazone reduced a composite outcome of all-cause mortality, myocardial infarction, or stroke in the PROactive study, but did not significantly affect the primary composite outcome which included additional events such as acute coronary syndrome and vascular interventions. Rosiglitazone, in combination with metformin or sulfonylurea, was found to be non-inferior to metformin and sulfonylurea dual therapy in preventing major adverse cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in the RECORD trial. However, both thiazolidinediones were associated with a higher risk of heart failure compared to control groups.
Hyperglycemia in non-diabetic patients following acute stroke is associated with a significantly increased risk of in-hospital or 30-day mortality, with a relative risk of 3.07 (95% CI 2.50–3.79) for those with admission plasma glucose levels above 6–8 mmol/L, compared to a lower and non-significant risk in patients with known diabetes. Additionally, hyperglycemic non-diabetic individuals face a 1.41 relative risk (95% CI 1.16–1.73) of poor functional outcomes after stroke, suggesting that abrupt elevations in plasma glucose levels may impair tissue function more severely in those not accustomed to hyperglycemia.
Technology-based clinical support involves a nurse checking patients' self-monitoring of blood glucose (SMBG) data and sending this information, along with other patient data, to an endocrinologist who reviews the uploaded details and communicates messages back to the nurse, enabling the nurse to educate and manage the patients based on the endocrinologist's recommendations.
Most patients with type 1 diabetes mellitus (T1DM) and coexisting celiac disease (CD) are transglutaminase autoantibody-positive at initial screening, though new cases can develop during follow-up. Screening for immunoglobulin A (IgA) transglutaminase autoantibodies should occur at the onset of diabetes, and if negative and asymptomatic, should be repeated every other year. If autoantibodies are negative but symptoms or signs of CD are present, other causes such as poor glycemic control or food intolerance should be investigated. HLA-DQB1 typing and total IgA level measurement can be useful, and biopsy is recommended if DQB1*0201 is present, IgA is less than 10 mg/dL, and symptoms persist. Positive transglutaminase autoantibody findings should be confirmed due to possible fluctuation in levels. Strongly and persistently positive levels (radioimmunoassay index >0.5 or ELISA >60) warrant biopsy even in asymptomatic patients, whereas patients with low to moderate levels may have false-negative biopsies and require repeated transglutaminase autoantibody testing every 3–6 months as long as levels remain positive.
Sulfonylurea therapy should be initiated at a low dose with self-monitoring of blood glucose at least once daily during the first few weeks, particularly in patients at higher risk of hypoglycemia such as the elderly, those living alone, or individuals operating machinery or driving. Patients who have had a partial response to lifestyle measures and have mild fasting hyperglycemia are more prone to hypoglycemia when using sulfonylureas. Dosage increases should occur every 2–4 weeks as needed, though hypoglycemia or early hypoglycemic symptoms often limit dose escalation. If hypoglycemia occurs before reaching the glycemic target or if increasing the dose provides no additional glycemic benefit, it is advisable to revert to the previous dose or consider modifying the administration regimen or switching to another insulin secretagogue. When sulfonylureas are used as monotherapy and the glycemic goal is not met, adding an agent that reduces insulin resistance or an α-glucosidase inhibitor is typically recommended. The maximal glucose-lowering effect of sulfonylureas is generally achieved at doses below the recommended maximum, suggesting that insulin secretion has already been maximally stimulated.
Rare causes of diabetes include haemochromatosis, which may present with features such as a slatey grey skin tone, large liver, and a haemoglobin level of 190 g/l, and is treatable. Hyperglycaemia associated with the use of thiazide diuretics and beta blockers may improve with alternative medications. Cushing syndrome can also present with curable diabetes, while diabetes induced by systemic steroid therapy typically resolves or becomes easier to manage once the steroid course is completed.
Prevalence rates of type 2 diabetes mellitus (T2DM) and impaired glucose tolerance (IGT) are significantly higher in certain minority populations compared with the general population. For example, native Hawaiians had crude prevalence rates of T2DM and IGT at 20% and 16% respectively, with the age-adjusted rate for T2DM being four times higher than that observed in the US NHANES II study population. Similarly, second-generation Japanese-Americans had prevalence rates of 16% for diabetes and 40% for IGT in 1991, with high incidence rates persisting at 17.2 per 1000 person-years. This increased risk is attributed to higher visceral adiposity in populations with a predisposition to impaired β-cell function. Other Asian populations in the USA, such as Chinese-Americans, also show heightened susceptibility to diabetes, with linguistic barriers potentially hindering diabetes education and effective healthcare delivery.
Gatifloxacin-induced hyperglycemia occurs in approximately 1% of cases, with reported instances involving both new-onset diabetes and deterioration of glycemic control in individuals with pre-existing diabetes. The precise mechanism remains unclear, but animal studies suggest it may involve inhibition of insulin secretion or increased epinephrine release.
In people with type 2 diabetes, improved glycaemic management has limited evidence in slowing the progression of neuropathy, though the ACCORD trial showed a significant reduction in loss of sensation to light touch after five years of intensive glycaemic control (HbA1c < 6.5%, 48 mmol/mol), with this improvement observed in only one of four neuropathy endpoints. An intensive glucose-lowering regimen, however, was linked to increased overall mortality (hazard ratio 1.22, 95% CI 1.01 to 1.46, p = 0.04). Self-reported diabetic sensorimotor polyneuropathy also posed a higher mortality risk in the intensive glycaemic management group compared to those with higher HbA1c and those on aspirin.
CN (Charcot neuroarthropathy) typically presents in a well-perfused insensate foot, often seen in diabetic patients, with symptoms including a warm, swollen foot that may be painful or cause discomfort, and the affected individual is usually younger than typical patients with diabetic foot ulcers. Although trauma may be reported, it is usually not severe enough to explain the observed clinical findings. Research has linked the RANKL/osteoprotegerin (OPG) pathway to the development of acute CN, with studies showing increased osteoclast formation from peripheral blood monocytes of CN patients when cultured with macrophage colony-stimulating factor, suggesting a role for RANKL-mediated osteoclastic resorption in acute CN and potential future therapeutic approaches through RANKL inhibition.
Ceramides and diacylglycerols are lipid mediators that may contribute to insulin resistance, a key feature of type 2 diabetes mellitus (T2DM). Ceramides, which are sphingolipids dependent on saturated fatty acids, are required for insulin resistance caused by saturated fatty acids in skeletal muscle and accumulate in the liver during diets rich in tristearin but not triolein. They are also upregulated in skeletal muscle and adipose tissue of insulin-resistant individuals. Diacylglycerols activate protein kinase C (PKC) in the liver, which interferes with insulin signaling by inactivating the insulin receptor tyrosine kinase and decreasing downstream signaling through IRS-2, PI3 kinase, AKT2, GSK-3, and FOXO phosphorylation. This disruption reduces hepatic glycogen synthesis and enhances gluconeogenesis. In humans, diacylglycerol levels correlate with intrahepatocellular triglyceride content, and PKC activity is elevated in the liver of patients with T2DM.
CSII therapy, or continuous subcutaneous insulin infusion, has evolved with newer models being smaller, more portable, and equipped with advanced features like bolus calculators and integration with continuous glucose monitoring (CGM). Sensor-augmented pump therapy combines CSII with CGM to provide automated adjustments in insulin delivery based on glucose levels, and artificial pancreas or closed-loop systems represent the most advanced form of this technology.
HNF1B mutations or deletions can lead to diabetes, often alongside renal abnormalities, with a variable phenotype even among individuals with identical mutations, and approximately 32-58% of cases occurring de novo.
Women with type 1 or type 2 diabetes have a significantly increased risk of antenatal death in utero compared to the general population, with rates of 25.8 and 29.2 per 1000 births respectively, which is approximately three to five times higher than the background population. Fetal death in pregnancies complicated by diabetes is likely multifactorial, involving congenital anomalies, chromosomal abnormalities, infection, placental vascular issues, maternal hyperglycaemia in the third trimester, smoking, and pre-eclampsia. Increased maternal age and BMI are also risk factors for stillbirth in both diabetic and non-diabetic pregnancies, potentially explaining similar stillbirth rates between type 1 and type 2 diabetes. Macrosomic fetuses, characterized by birth weight above the 90th centile, may be particularly at risk due to increased oxygen requirements, mild acidaemia, and borderline placental vascular supply. Hyperglycaemia is associated with increased perinatal mortality, as indicated by a pooled odds ratio of 3.23 in a systematic review of four studies, although these studies had methodological limitations. Approximately one-quarter of stillbirths remain unexplained.
Diabetic thoracoabdominal neuropathy or radiculopathy typically affects middle-aged or older individuals and is marked by sudden onset of pain or dysaesthesia, sometimes with hyperaesthesia, where the pain can be described as burning, tearing, jabbing, or boring and tends to worsen at night. This condition is almost always unilateral, affecting the trunk in a root-like distribution, with peak pain occurring a few days after onset and potentially lasting weeks to months. The pain can be mistaken for pulmonary, cardiac, or gastrointestinal issues. Abdominal muscle herniation is a rare occurrence, primarily in middle-aged men, involving 3–5 adjacent nerve roots between T6 and T12. A significant weight loss of 7–18 kg in over 50% of cases has been recognized, which should prompt physicians to consider underlying malignancy. The prognosis for truncal neuropathy is generally favorable, with remission typically occurring within 16 weeks.
In patients with type 2 diabetes mellitus (T2DM) treated with a glitazone and metformin, exenatide reduced HbA1c levels by 1.0% (11 mmol/mol) and body weight by 1.6 kg compared to placebo, with no clinically significant episodes of hypoglycemia reported; however, the dropout rate in the exenatide group was twice that of the placebo group.
Patients with type 1 diabetes mellitus (T1DM) who have disease complications exhibit substantially higher risks of hip fracture compared to those without complications. Additionally, T1DM patients with neuropathy show lower cortical bone mass in the distal limbs than those without neuropathy, suggesting a negative impact of neuropathy on bone mineral density (BMD). Animal studies indicate that interrupting nerve supply to bone reduces regional bone mass independently of mechanical loading changes. This regional osteopenia likely increases the risk of distal limb and foot fractures in individuals with T1DM.
In insulin-resistant patients with type 2 diabetes mellitus (T2DM), the ability of insulin to stimulate tyrosine phosphorylation of the insulin receptor and IRS-1, along with IRS-1-associated PI kinase activity and GLUT-4 translocation, is subnormal. However, aerobic training has been shown to increase GLUT-4 content in skeletal muscle and enhance the expression and activity of glycogen synthase to a level comparable to that in normal subjects. This suggests that the signaling pathways through which exercise promotes glucose uptake remain functional in individuals with T2DM, indicating that the glycemic response to exercise is not impaired by insulin resistance.
Certain HLA class II and class I alleles are associated with type 1 diabetes mellitus (T1DM) risk, with some alleles conferring independent risk while others provide protection, potentially neutralizing high-risk alleles when inherited together. Protective haplotypes such as DQ6 $(DQA1^{*}0102 - B1^{*}0602$ and $DQA1^{*}0102 - B1^{*}0603)$, along with $DQA1^{*}0101 - B1^{*}0503$ and $DQA1^{*}0202 - B1^{*}0303$, are commonly identified, and associations with other HLA class II loci such as DPB1 are also under investigation in relation to T1DM.
ACE inhibitors such as ramipril, enalapril, captopril, lisinopril, and perindopril are suitable for use in people with diabetes, with enalapril, lisinopril, perindopril, and ramipril typically given once daily for hypertension. The initial dose should be low and taken at bedtime to reduce the risk of postural hypotension, especially in those on diuretics or a sodium-restricted diet, as well as in patients with autonomic neuropathy. Ramipril has been shown to reduce cardiovascular morbidity and mortality in high-risk diabetic patients, regardless of whether they have pre-existing ischemic heart disease.
Patients with diabetes often have involvement of the arteries in the calf, including the anterior and posterior tibial and peroneal arteries, especially in cases of critical ischemia. When presenting with symptoms, individuals with diabetes tend to have more distal vascular involvement, with open vessels up to the popliteal artery followed by occlusive disease in the calf vessels and sometimes arteries in the foot. Revascularization outcomes for patients with diabetes who have toe or foot ulcers are worse compared to the general population, partly because patency rates are better when lesions are more centrally located.
α-glucosidase inhibitors act by inhibiting carbohydrate digestion, and an example is Voglibose; insulin secretagogues stimulate insulin secretion, such as with Mitiglinide; insulin secretion potentiators enhance nutrient-stimulated insulin secretion and include GLP-1 analogs and DPP-4 inhibitors; insulin mimetics produce insulin-like effects on glucose metabolism, as seen with IGF-I; insulin action enhancers improve the actions of insulin and include selective PPAR modulators; counter-regulatory hormone inhibitors suppress the secretion or action of counter-regulatory hormones and include glucagon receptor antagonists, cellular glucocorticoid inhibitors, GG activators, and F16Pase inhibitors; direct glucose regulators increase glucose metabolism through mechanisms such as CPT-1 inhibition; lipid regulators inhibit fatty acid oxidation and include "Flozins"; SGLT2 inhibitors increase renal glucose elimination and are also referred to as "Flozins."
GAD65Ab are autoantibodies associated with high-risk HLA haplotypes DR4-DQ8 and DR3-DQ2, more commonly linked with the latter, and are relevant in the context of type 1 diabetes mellitus (T1DM). Anti-idiotypic GAD65Ab are less frequent in T1DM, and their absence is a stronger predictive marker than the presence of GAD65Ab. These autoantibodies can be detected using radiobinding assays and ELISA, methods that have been standardized through the Diabetes Antibody Standardization Program (DASP), demonstrating high performance in predicting and classifying T1DM as well as serving as screening tools for individuals at risk.
Insulin therapy is often used initially after diagnosis, but most patients with KCNJ11 and ABCC8 mutations can transition to sulfonylurea therapy, leading to improved glycemic control. Ninety percent of patients with KCNJ11 mutations can stop insulin use, with HbA1c levels showing a mean reduction from 65 to 6 mmol/mol (8.1% to 6.4%) within 12 weeks. Glibenclamide is commonly used due to its non-selective nature and availability, and it may be more effective than other sulfonylureas. The required doses for these patients are higher than those for type 2 diabetes, with a median of 0.45 mg/kg/day and up to 1.5 mg/kg/day in some cases. Diarrhea is a potential side effect, typically lasting 1–3 days. Neurological symptoms may also improve with sulfonylurea therapy even when initiated in adulthood.
The ADRA2A locus is associated with type 2 diabetes risk, as it is linked to impaired insulin granule docking and reduced β-cell exocytosis. Human carriers of the ADRA2A risk variant (rs553668) exhibit reduced fasting insulin and decreased insulin secretion due to increased ADRA2 receptor expression in pancreatic islets. Excess epinephrine, which suppresses insulin secretion, can contribute to diabetes. The α2A-adrenergic receptor antagonist yohimbine improves insulin release in vitro in islets from carriers of the risk allele, bringing it to levels similar to those of non-risk carriers. A clinical study using α2A-adrenergic receptor blockade in individuals with type 2 diabetes and the rs553668 variant showed that yohimbine administration enhanced insulin response and corrected the disposition index, making secretion comparable to that of low-risk individuals. These findings indicate that insulin secretion defects linked to the ADRA2A risk genotype can be addressed through α2A-adrenergic receptor antagonism, highlighting the potential for using genetic risk variants to guide targeted therapies in diabetes treatment.
Insulin resistance, measured by indicators such as HOMA-IR, correlates with visceral fat mass, total fat mass, BMI, and waist circumference, and plays a key role in linking obesity to type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease. NAFLD reciprocally contributes to both type 2 diabetes and obesity, and there is significant variation in insulin resistance, β-cell dysfunction, and inflammation among individuals with diabetes. This variability is influenced by genetic, epigenetic, environmental, and lifestyle factors, leading to suggestions of six diabetes subtypes, two of which are associated with high BMI. One subtype, severe insulin-resistant diabetes, is marked by late onset, high BMI, extreme insulin resistance, elevated liver fat, and a high fatty liver index and NAFLD fibrosis score, and carries the greatest risk for macroalbuminuria, chronic renal disease, and ischaemic heart disease and stroke.
Managing diabetes in end-of-life care involves adjusting glycaemic target ranges, addressing individual and carer expectations, minimizing risks of hyperglycaemia and hypoglycaemia, managing interactions with other medications like glucocorticosteroids, and tailoring diabetes treatments based on the stage of end-of-life. End-of-life care for people with diabetes is complex and extends beyond the simple choice of continuing or withdrawing treatment.
Glycated haemoglobin (HbA1c) has been used as a diagnostic test for diabetes since February 2011, but its low sensitivity (46.8%) can result in missing more than half of diabetes cases despite its high specificity (98.7%). In older individuals, HbA1c levels may increase due to non-glycaemic factors, such as age-related changes and iron-deficiency anaemia, which is common in this population. These factors can lead to overdiagnosis of diabetes in older people when HbA1c is used instead of glucose testing, and therefore, a second laboratory test should be used to confirm the diagnosis in the absence of diabetes symptoms, similar to the approach in younger individuals.
Clozapine, a second-line antipsychotic, is associated with higher rates of diabetes, though this may not be directly caused by the drug itself but rather by factors such as the underlying severity of mental illness in those who receive it, as individuals with treatment-resistant mental illness may already be at higher risk for diabetes. Additionally, increased screening for blood glucose abnormalities in people taking second-generation antipsychotics like clozapine may contribute to higher reported diabetes rates due to greater detection of previously undiagnosed cases, rather than a true increase in incidence caused by the medication.
Chronic emotional stress and low stress resilience are associated with an increased risk of developing type 2 diabetes, potentially through mechanisms such as unhealthy behaviours (e.g., physical inactivity, poor diet, sleep issues, smoking) and physiological changes like activation of the innate immune system, which may lead to insulin resistance. Studies have shown that individuals with low stress resilience are 51% more likely to develop type 2 diabetes compared to those with higher stress resilience, even after adjusting for family history and body mass index. While some personality traits like high hostility, neuroticism, or type D personality have been explored as potential risk factors for metabolic syndrome and type 2 diabetes, evidence remains conflicting, possibly due to publication bias. Ongoing and future research, such as the Maastricht Study, aims to further clarify the role of depression, anxiety, and personality traits in the development of type 2 diabetes by investigating both behavioural and physiological pathways linking stress to disease onset.
In diabetes, the brain establishes the lower boundary of blood glucose levels (BDL_G) by initiating counter-regulatory responses, such as adrenaline secretion and activation of the sympathetic nervous system (SNS) outflow to the liver and pancreas, which restore low blood glucose to baseline. The threshold at which these brain-driven responses are activated serves as a biomarker for the brain's perception of the lowest acceptable blood glucose level. Although this mechanism is rarely triggered in healthy individuals, it is considered an emergency response to severe hypoglycemia, a pathological state relevant to diabetes management.
GLP-1 receptor agonists improve glucose levels through several mechanisms: stimulating glucose-dependent insulin secretion, suppressing glucagon release, decreasing appetite and food intake, and slowing gastric emptying. These medications do not cause hypoglycemia unless combined with other therapies that increase hypoglycemia risk, such as sulfonylurea derivatives and insulin. Genetic variations influence the pharmacodynamic response to GLP-1 receptor agonists; for example, polymorphisms in the GLP-1 receptor gene (rs6923761) are linked to greater weight reduction with liraglutide, while the T allele of rs10305420, which causes an amino acid substitution from proline to leucine, is associated with less weight loss and reduced HbA1c response to exenatide.
Annual screening for kidney disease in diabetes is recommended, which includes measuring the estimated glomerular filtration rate (eGFR) to assess kidney function. Early detection and prevention of vascular complications are crucial in managing diabetes, as highlighted in guidelines adapted from Marshall SM and Flyvbjerg A.
GLP-1 receptor agonists are a class of medications used in the treatment of diabetes that mimic the action of the hormone glucagon-like peptide-1, helping to regulate blood glucose levels by stimulating insulin secretion and reducing glucagon release. Potassium ATP (KATP) channels play a role in insulin secretion from pancreatic beta cells, with their dysfunction contributing to impaired glucose homeostasis. Oral anti-diabetes drugs (OADs) are a category of medications taken orally to manage blood glucose levels in individuals with diabetes. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are another class of diabetes medications that lower blood glucose by increasing urinary glucose excretion.
Diabetes related knowledge points include different presentations and progression of hyperglycemia, where Glucokinase MODY typically presents with minimal increase in glycemia with age, mild fasting plasma glucose (FPG), and HbA1c close or just above normal, whereas Transcription factor MODY shows progressive deterioration of glycemia with age, potentially severe hyperglycemia, and variable HbA1c levels. Oral glucose tolerance tests reveal different patterns, with Glucokinase MODY showing FPG >5.5 mmol/L and a smaller increase in 2-hour glucose, while Transcription factor MODY often has FPG <5.5 mmol/L and a larger increase in 2-hour glucose. Microvascular complications are rare in Glucokinase MODY but frequent in Transcription factor MODY. Pathophysiologically, Glucokinase MODY involves a β-cell defect affecting glucose sensing, while Transcription factor MODY involves impaired insulin secretion during hyperglycemia despite normal secretion at normoglycemic levels. Treatment differs as Glucokinase MODY rarely requires pharmacologic intervention, while Transcription factor MODY is sensitive to sulfonylureas and may eventually need insulin therapy.
Liraglutide improves several cardiovascular risk factors including C-reactive protein, tumor necrosis factor α-induced plasminogen activator inhibitor 1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and B-type natriuretic peptide. Weight loss associated with liraglutide varies by baseline BMI, ranging from 0–2 kg in individuals with a BMI < 25 kg/m² to 1–4.5 kg in those with a BMI > 35 kg/m², with the greatest reduction seen when combined with metformin. Liraglutide also lowers systolic blood pressure, with reductions of 2.7–4.5 mmHg in general and up to 11 mmHg in patients with systolic blood pressure > 140 mmHg. Additionally, it enhances β-cell function as measured by homeostasis model assessment and the proinsulin:insulin ratio. Although thyroid C-cell neoplastic changes have been observed in rodents, they have not been reported in humans; however, five cases of pancreatitis were noted during phase 3 trials.
Semaglutide, approved in 2018 by the FDA and EMA, is a GLP-1 receptor agonist administered once weekly via subcutaneous injection for the treatment of type 2 diabetes. It is structurally similar to liraglutide but features a C-18 fatty acid chain and an alanine to α-aminoisobutyric acid substitution at position 8, which enhances albumin binding and reduces degradation by DPP-4. Clinical trials in the SUSTAIN program demonstrated that semaglutide, when titrated to a dose of 1 mg once weekly, was superior to placebo and several active comparators—including sitagliptin, canagliflozin, exenatide once weekly, dulaglutide, liraglutide, and insulin glargine—in reducing HbA1c and promoting weight loss. Exposure-response analyses revealed a correlation between plasma levels of semaglutide and reductions in HbA1c and body weight, as well as a link between plasma concentration and the occurrence of gastrointestinal adverse events such as nausea and vomiting. The prevalence of gastrointestinal side effects with once-weekly semaglutide was comparable to that of dulaglutide at full dose.
For individuals treated with insulin or hypoglycemic agents, proper matching of medication with the amount, type, and timing of carbohydrate intake is essential to prevent hypoglycemia and excessive postprandial hyperglycemia. Those on intensive insulin therapy should adjust premeal insulin doses based on the carbohydrate content of meals or snacks, as well as the glycemic index of the foods. Nutrition education programs for people with diabetes often incorporate this approach. Self-monitoring of blood glucose helps determine the best timing for meals and food choices. Individual preferences and treatment strategies largely dictate suitable meal frequency, portion sizes, and carbohydrate amounts. Additional carbohydrates may be necessary before exercise, though adjusting insulin dosage is often a preferred alternative for those on intensified regimens. Ongoing structured training and support from the diabetes care team are crucial to help individuals properly adjust insulin doses by considering blood glucose levels, carbohydrate intake, and physical activity levels.
Type 1 diabetes is characterized by β-cell autoimmunity involving an inflammatory response with progressive infiltration of immune cells such as CD4+, CD8+ T cells, macrophages, dendritic cells, and B cells within the pancreatic islets. This disease process begins years before clinical onset and shows heterogeneity in immunopathology, with children and adolescents typically exhibiting a more rapid and severe progression alongside a broader, more aggressive β-cell–specific T-cell response compared to adults. The imbalance between T-regulatory (Treg) cells and T-effector cells, along with dysregulation of antigen-presenting cells, contributes to proinflammatory conditions that drive naïve T cells toward pathogenic T-effector differentiation and directly contribute to islet inflammation and β-cell destruction through cytokines such as interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and interferon γ (IFNγ). Autoantibodies against targets like insulin (IAA), glutamate decarboxylase (GAD), islet antigen 2 (IA-2), and zinc transporter 8 (ZnT8) serve as disease markers but do not damage β cells. CD4 and CD8 T cells recognize the same epitopes, and β cells themselves appear to function as antigen-presenting cells, particularly in early-onset cases before age 7, contributing to disease progression through upregulation of HLA molecules, self-antigen presentation, and secretion of chemoattractants that attract cytotoxic T cells. This interaction leads to β-cell damage, potentially generating post-transcriptional or post-translational modified islet proteins that further activate T cells, perpetuating islet infiltration and β-cell destruction.
GLP-1 receptor agonists (GLP-1RAs) are associated with side effects such as nausea, vomiting, and diarrhea, which are linked to delayed gastric emptying and tend to diminish over time; dose-dependent symptoms can be mitigated through slow dose escalation and these agents should be avoided in individuals with gastroparesis. Compared to insulin, GLP-1RAs are more likely to cause local site reactions. Initial concerns regarding an increased risk of acute pancreatitis or pancreatic cancer have decreased, though animal studies suggest a possible link between certain GLP-1RAs and thyroid C-cell neoplasms, warranting avoidance in individuals with a history of medullary thyroid cancer or multiple endocrine neoplasia type 2. There may also be an association between GLP-1RAs and gallbladder-related adverse events, including acute cholecystitis, although the causal relationship remains uncertain.
Understanding carbohydrate content in foods is an important aspect of managing diabetes, as carbohydrates directly affect blood glucose levels. Carbohydrate awareness involves recognizing the amount and type of carbohydrates in meals, which helps individuals with diabetes plan their food intake and adjust insulin or medication accordingly. This practice is especially relevant for those using insulin therapy, as matching insulin doses to carbohydrate consumption can help maintain glycemic control.
Gliclazide, a sulfonylurea used in the management of type 2 diabetes, can cause hypoglycemia, especially in patients with impaired renal function, as the drug may accumulate. Hypoglycemia in such cases can be severe, leading to acute confusion and unresponsiveness, and may require intravenous glucose for reversal. However, administration of glucose can further stimulate insulin secretion, resulting in recurrent hypoglycemia that necessitates continuous intravenous glucose infusion. Elevated serum insulin and C-peptide concentrations during hypoglycemia indicate increased endogenous insulin secretion, which in this context is likely driven by the accumulated gliclazide. Renal impairment is an important risk factor for hypoglycemic episodes in patients treated with sulfonylureas.
Amyloid deposition in the islets of a patient with type 2 diabetes involves the accumulation of islet amyloid polypeptide (IAPP), which stains pink with Congo red, occupying more than 50% of the islet mass primarily in the central region. In these islets, insulin-containing β-cells, identified by brown immunoperoxidase labeling, are clustered toward the periphery and are markedly reduced in number.
Blood pressure control in people with type 2 diabetes mellitus (T2DM) has shown varying levels of achievement over time and across regions. Initially, with a target of ≤140/90 mmHg, approximately 40–60% of individuals with T2DM achieved this target, with some improvement seen in studies such as the Department of Veteran Affairs study in the USA, where the proportion achieving target increased from 40% to 52% between 1996 and 2000. The DiabCare studies in Asia reported that over 70% and 90% achieved systolic and diastolic targets of ≤140 mmHg and ≤90 mmHg respectively. As evidence emerged on the importance of tighter control, the target was revised to <130/80 mmHg, though this was not associated with further improvements in target achievement, with recent studies showing only about half of people with T2DM achieving this stricter target.
The prevalence of diabetes in China is increasing, driven largely by rising obesity rates, particularly among children and adolescents. Data from the 2002 National Nutrition and Health Survey showed that 4.1% of children aged 7–12 years and 5.6% of those aged 12–18 years were overweight, while obesity prevalence was 2.5% and 1.6%, respectively. In Hong Kong, a study of over 2000 adolescents aged 11–18 years found that 8–10% of those aged 12–13 years were obese. A national screening program in Taiwan from 1992 to 1999 reported new diabetes rates of 9.0 per 100,000 boys and 15.3 per 100,000 girls. Obesity was identified as the primary risk factor for type 2 diabetes mellitus (T2DM), with children having a BMI at or above the 95th percentile showing approximately a 19-fold increased risk compared to those below the 50th percentile.
GLP-1 receptor agonists such as liraglutide and exenatide once weekly are more effective than the DPP-4 inhibitor sitagliptin in reducing HbA1c and body weight in patients with diabetes. Liraglutide lowered HbA1c by 1.4% (14 mmol/mol) compared to 0.9% (10 mmol/mol) with sitagliptin, and reduced weight by -3.5 kg versus -0.9 kg. Exenatide once weekly decreased HbA1c by 1.7% (19 mmol/mol) versus 1.0% (11 mmol/mol) with sitagliptin, and reduced weight by 2.8 kg compared to 0.9 kg.
Hypoglycaemia in people with diabetes is associated with an increased risk of accidents leading to hospitalization, particularly in older individuals. In a study of people with diabetes aged approximately 60 years, 5.5% of those experiencing hypoglycaemia had accidents requiring hospital visits compared to 2.8% of those without hypoglycaemia. Hypoglycaemia significantly increases the hazard for any accident, including accidental falls and motor vehicle accidents. The risk of falls is twice as high in individuals aged 65 years or older compared to younger individuals, with hypoglycaemia contributing to a more than 50% increase in the hazard of falls. Additionally, hypoglycaemia raises the risk of fractures, which can lead to disability and frailty. In a study of over 360,000 Medicare-covered individuals with diabetes aged 65 or older, those with hypoglycaemic events had a significantly higher rate of fall-related fractures compared to those without (5.24% vs. 2.67%). Hypoglycaemic events increase the risk of falls and fractures by approximately 70%.
Low carbohydrate and low fat calorie-restricted diets may be effective for weight loss in diabetes over the short term, up to one year. While low carbohydrate, higher fat diets can lead to greater weight loss and more favorable changes in serum triglycerides and HDL cholesterol compared to high carbohydrate, lower fat diets, they also result in higher LDL cholesterol levels. The long-term metabolic and cardiovascular safety of low carbohydrate, high fat diets remains unclear, and such diets may lack important sources of fiber, vitamins, and minerals. Substituting monounsaturated fatty acids for carbohydrates is challenging due to limited food sources and current dietary habits. After initial weight loss, preventing weight regain is crucial.
Hypertension is associated with type 2 diabetes mellitus (T2DM), also known as insulin resistance syndrome X or metabolic syndrome, and can also occur in type 1 diabetes mellitus (T1DM) when nephropathy is present. Hypertension may coincide in patients with diabetes without a direct causal link, and can be classified as essential or isolated systolic hypertension. Renal scarring, such as from recurrent pyelonephritis, can contribute to hypertension in diabetic individuals. Certain antihypertensive drugs can be diabetogenic, including potassium-losing diuretics like chlorthalidone and high-dose thiazides, high-dose beta-blockers, and combinations of diuretics and beta-blockers. Some medications that lead to obesity, hypertension, and glucose intolerance include glucocorticoids, combined oral contraceptive pills, and antipsychotics. Endocrine disorders that can cause both hypertension and glucose intolerance include acromegaly, Cushing syndrome, Conn syndrome, and pheochromocytoma.
Gastrointestinal manifestations are not uncommon among patients with diabetes, particularly those with predominantly type 2 diabetes mellitus (T2DM), although in the general population, the prevalence of such symptoms is not substantially higher in people with diabetes compared to matched controls. This may be due to the relatively high prevalence of gastrointestinal symptoms, often related to functional gastrointestinal disorders like irritable bowel syndrome, among people without diabetes, which can approach 20%. In a specific population in Olmsted County, Minnesota, the age-adjusted incidence of definite gastroparesis from 1996 to 2006 was 2.4 per 100,000 person-years for men and 9.8 for women, while the age-adjusted prevalence as of January 1, 2007, was 9.6 per 100,000 persons for men and 37.8 for women.
Increased macrophage infiltration of white adipose tissue during obesity leads to higher lipolysis through the release of cytokines such as interleukin-6, contributing to fasting hyperglycaemia and insulin resistance. This process enhances hepatic gluconeogenesis by two mechanisms: first, elevated fatty acid delivery to the liver raises hepatic acetyl-coenzyme A levels, boosting pyruvate carboxylase activity, and second, increased glycerol delivery promotes its conversion to dihydroxyacetone (glyceraldehyde) 3-phosphate, which serves as a glucose precursor.
Hemoglobin A₁c (HbA₁c) is a key measure of mid to long-term glycemic control in diabetes, with elevated levels predicting an increased risk of both microvascular and macrovascular complications. In the Diabetes Control and Complications Trial (DCCT), an HbA₁c level of 53 mmol/mol (7.0%) in conventionally treated patients corresponded to a higher average blood glucose concentration of 192 mg/dL compared to 163 mg/dL in intensively treated patients, indicating that the same HbA₁c level can represent different average glucose levels depending on treatment intensity. This difference was associated with a higher risk of microvascular complications and hypoglycemia in conventionally treated individuals. HbA₁c should be used alongside assessments of hypoglycemia and quality of life as part of optimal diabetes management, with recommended testing frequencies of four to six times per year for younger children and three to four times per year for older children.
Improved glycemic control and management of risk factors such as blood pressure and lipid levels are linked to a reduced risk of late complications and better survival in diabetes patients. Trends in mortality for those with long-term type 1 diabetes appear to be improving, although there is limited data from large cohorts with long-term follow-up after the late 1980s. A significant issue remains the occurrence of deaths among undiagnosed type 1 diabetes cases and individuals lacking access to healthcare in developing regions.
In diabetes, elevated glucose levels contribute to the formation of advanced glycation end products (AGEs), which originate from early glycation products known as Schiff bases that convert into more stable Amadori products like 1-amino-1-deoxyfructose derivatives. These Amadori products undergo further modifications, producing reactive intermediates such as 3-deoxyglucosone and methylglyoxal. Methylglyoxal reacts with amino, sulfhydryl, and guanidine groups in proteins, leading to browning, denaturation, and cross-linking between lysine residues, which results in structural and functional damage to proteins. Methylglyoxal also generates hydroimidazolones, N-ε-(carboxyethyl) lysine, a homolog of carboxymethyl lysine (CML), and methylglyoxal lysine dimer. These AGE-based cross-links are resistant to degradation and accumulate over time, with their formation influenced by glucose concentrations, oxidative stress levels, and the duration of exposure to these conditions.
Improved multiple risk factor interventions in diabetes reduce mortality and cardiovascular events, as demonstrated by the Steno-2 study, which showed a composite endpoint of reduced death from cardiovascular causes, non-fatal myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, non-fatal stroke, amputation, or surgery for peripheral arterial disease.
In type 1 diabetes, the risk of premature mortality is significantly increased, with a 2- to 3-fold higher risk in those with moderately elevated albuminuria, a 9-fold increase in those with severely increased albuminuria, and an 18-fold increase in those with ESKD compared to people without diabetes. Cardiovascular disease (CVD) is also more common, being 1.2-fold higher in individuals with moderately increased albuminuria and 10-fold higher in those with severely increased albuminuria compared to those with normoalbuminuria. The cumulative incidence of CVD by the age of 40 years is 43% in people with type 1 diabetes.
Self-monitoring of blood glucose (SMBG) has been studied in randomized trials to assess its effectiveness in improving outcomes for people with diabetes, showing an overall decrease in HbA1c of 0.2% with SMBG use. However, trials that directly compared self-monitoring with no monitoring, while providing comprehensive patient education to both groups, did not demonstrate a significant benefit, and were limited by including a large proportion of patients with well-controlled diabetes. Some evidence suggests that SMBG may be more beneficial for patients with less well-controlled diabetes. In addition to potential glycemic benefits, concerns have been raised about adverse effects such as increased depression or anxiety associated with self-monitoring, as indicated by two recent trials.
The pancreatic $\beta$-cells play a critical role in maintaining glucose homeostasis and are uniquely responsible for insulin production, which is essential for their own growth, function, and survival. Under chronic physiological and immunological stress, $\beta$-cell mass and function must be preserved to prevent metabolic dysfunction, particularly in conditions like type 2 diabetes. The IRS2 signaling pathway is central to $\beta$-cell function, with its expression regulated by multiple transcription factors such as FOXO1/3, NFAT, and CREB$\bullet$CRTC2. Insulin and IGF-I inhibit FOXO-mediated transcription of IRS2 through the IRS2$\rightarrow$PI3K$\rightarrow$AKT cascade, while glucose-stimulated Ca²⁺ influx and cAMP production promote IRS2 expression by activating calcineurin and CREB$\bullet$CRTC2, respectively. These pathways help counteract $\beta$-cell failure during chronic nutrient excess, which is relevant in the context of insulin resistance and type 2 diabetes progression. Glucose, GLP-1, and other GPCR agonists enhance cAMP levels, further supporting IRS2 transcription and $\beta$-cell function. Maintaining IRS2 expression is crucial for preserving PDX1 activity, which is necessary for $\beta$-cell survival and function, and targeting IRS2 may offer therapeutic potential for treating $\beta$-cell dysfunction in type 2 diabetes.
High glucose concentrations in the body can cause irreversible damage to cellular proteins and lead to tissue damage, particularly evident in diabetes-related microvascular complications. To maintain glucose homeostasis, the body relies on a complex feedback system involving multiple organs such as the brain, pancreatic islets, and liver.
The prevalence of diabetes reflects the total burden of the disease globally, but it can be influenced by improved care and longer survival of patients, making incidence rates a more accurate measure of the risk of developing new-onset diabetes. Data on type 2 diabetes incidence are limited, though a systematic review from 1980 to 2017 showed that most studies reported rising incidence between 1990 and 2005, followed by stabilization or decline between 2006 and 2014. Recent data from 22 million diagnoses across 19 high-income and 2 middle-income countries suggest that diabetes incidence may be stabilizing or declining in high-income regions. Despite this potential trend, global increases in overweight and obesity continue to pose a risk, necessitating ongoing public health efforts to monitor and address diabetes and its associated burden.
Blood β-hydroxybutyrate measurement is preferred over urinary acetoacetate in diagnosing and monitoring diabetic ketoacidosis (DKA) as it provides a real-time quantitative indicator of the key metabolic product, allowing serial tracking of metabolic recovery during treatment. Blood gas analysis is crucial to confirm the presence of a raised anion gap metabolic acidosis, calculated as ([Na⁺] + [K⁺]) – ([Cl⁻] + [HCO₃⁻]), while also considering other potential causes of a raised anion gap such as salicylate poisoning. A transient hyperchloremic non-anion gap metabolic acidosis often develops during treatment, which, although not acutely harmful, may delay DKA resolution. Baseline assessments including electrolytes, hematology, and liver and kidney function are necessary, and additional investigations like blood cultures, cardiac biomarkers, chest X-ray, and ECG may be required to identify complications or comorbidities, particularly potassium-related cardiac disturbances.
Gene transfer techniques using adenoviral or AAV-mediated delivery of transcription factors such as Pdx-1, NeuroD, MafA, and Ngn3 have been explored to convert liver or pancreatic cells into insulin-producing cells for diabetes treatment. Adenoviral vectors, while typically supporting short-term transgene expression, have shown efficacy in liver cells where sustained insulin expression helped partially reduce hyperglycaemia, though full conversion into functional β cells was not achieved. In contrast, reprogramming cells from the exocrine pancreas led to the formation of cells that closely resembled native β cells in structure and function, forming islet-like structures and achieving long-term normalization of blood glucose levels exceeding one year.
Endothelin receptor antagonists have been studied in type 2 diabetes-related nephropathy, with some showing potential benefits. For instance, atrasentan, a more selective $\mathrm{ET_A}$ receptor blocker, has demonstrated a reduction in residual albuminuria in individuals with type 2 diabetes. Although $\mathrm{ET_A}$ receptor antagonism appears beneficial for diabetic nephropathy, there is currently no evidence supporting its protective effect on macrovascular disease in diabetes. Previous trials, such as with avosentan, were halted due to adverse effects like fluid retention, heart failure, and cardiovascular mortality, potentially linked to the antidiuretic effect of $\mathrm{ET_B}$ receptor activation. Whether the kidney-protective effects of these drugs translate into cardiovascular protection remains to be confirmed in long-term studies with predefined cardiovascular endpoints.
Anaemia is common in people with diabetes and CKD stage 3 or poorer, and is associated with higher mortality, higher rates of hospital admission with heart failure, and poorer quality of life; investigation of iron-deficiency anaemia may be needed to exclude non-kidney causes, and management includes repletion of iron stores with oral or parenteral iron as necessary, and erythropoietin replacement if indicated, though treatment of anaemia in people with type 2 diabetes and CKD has shown no benefit in renal or cardiovascular outcomes.
Exenatide is generally well tolerated but has higher dropout rates compared to placebo in phase 3 studies. It does not typically cause hypoglycemia when used alone or with metformin, but mild hypoglycemia occurs in 15–36% of patients when combined with sulfonylurea. GLP-1 or exenatide treatment allows appropriate glucagon responses, potentially protecting against severe hypoglycemia. Common side effects include nausea, which affects up to 57% of patients and usually subsides over time, as well as vomiting, headache, diarrhea, dizziness, and constipation. Around 40–50% of patients develop antibodies to exenatide, though they rarely affect glucose control except in cases of very high titers. Exenatide has been linked to acute pancreatitis, prompting recommendations to avoid its use in individuals at risk, such as those with alcoholism, cholecystolithiasis, or hypertriglyceridemia, and to discontinue the drug if pancreatitis is suspected.
Thiazolidinediones, a class of medications used in the management of diabetes, have adverse skeletal effects that involve complex mechanisms including direct inhibition of bone formation by diverting mesenchymal stem cells from the osteoblast to the adipocyte lineage, and by increasing or maintaining elevated bone resorption through direct actions on osteoclast development. Additionally, these drugs may indirectly contribute to skeletal deterioration by decreasing systemic and skeletal production of IGF-1, modulating adipokine production, and reducing levels of pancreatic β-cell hormones with skeletal activity. Preclinical studies in rodents show that thiazolidinediones decrease bone formation and bone mineral density (BMD) in vivo, and in humans, randomized controlled trials have demonstrated a reduction in BMD over 12–18 months with thiazolidinedione use, although the change is not markedly pronounced, and there is no consistent pattern in markers of bone turnover.
Lipopolysaccharide (LPS) infusion in mouse models has been shown to induce changes in insulin sensitivity and glucose levels, supporting a causal role for metabolic endotoxaemia in the development of type 2 diabetes. Chronic low-dose subcutaneous LPS infusion over four weeks led to increased fasting glucose, impaired glucose clearance following an oral glucose load, and increased hepatic gluconeogenesis, indicating a loss of glycaemic control. In healthy humans, acute intravenous LPS infusion during a euglycaemic hyperinsulinaemic clamp protocol resulted in significant reductions in glucose utilization, while subsequent studies reported decreases in insulin sensitivity and increased insulin resistance in response to low-dose LPS infusion, further implicating LPS as a causal factor in the development of insulin resistance.
Improved glucose control has been shown to delay the progression of microalbuminuria in patients with diabetes. In the ADVANCE study, a lower HbA1c level of 6.5% (48 mmol/mol) compared to 7.3% (56 mmol/mol) over 5 years was linked to a 21% relative risk reduction in the development of proteinuria. Additionally, a small study involving Japanese patients with type 2 diabetes demonstrated that those with normal urinary albumin excretion or microalbuminuria at baseline experienced a lower rate of nephropathy progression over 6–8 years with intensive glucose management.
Thiazolidinediones (TZDs) reduce insulin resistance by activating the peroxisome proliferator activated receptor γ (PPARγ), lowering glucose levels by 3–4 mmol/L and reducing HbA₁c by 5–15 mmol/mol (0.5–1.4%) as monotherapy. These medications do not cause hypoglycemia but are associated with mild edema, dilutional anemia in less than 5% of users, and weight gain, with a twofold increased risk of heart failure making them contraindicated in such cases. TZDs can be combined with metformin, sulfonylureas, and glinides, and pioglitazone may be used with insulin in the UK. Meta-analyses suggest rosiglitazone may increase the risk of myocardial infarction, though this has not been shown with pioglitazone. Both TZDs are linked to an elevated fracture risk, especially in women, and require caution in older individuals with osteoporosis. They are safe for use in mild to moderate renal impairment, and unlike troglitazone, which was withdrawn, rosiglitazone and pioglitazone do not cause liver damage, although regular liver function monitoring, particularly in the first 12 months of treatment, remains necessary.
Diabetes-related monogenic diseases include subtypes of neonatal diabetes and MODY, which involve genetic polymorphisms affecting β-cell function and insulin secretion. Neonatal diabetes subtypes such as those linked to 6q24, HNF1B, GCK, KCNJ11, ABCC8, and INS are characterized by abnormal β-cell function with impaired insulin secretion, and are treated with sulfonylurea derivatives or insulin. MODY subtypes, including MODY1 (HNF4A), MODY3 (HNF1A), MODY4 (PDX1/IPF1), MODY5 (HNF1B), MODY6 (NEUROD1), MODY7 (KLF11), MODY9 (PAX4), and MODY11 (BLK), are associated with pancreatic β-cell dysfunction and impairments in insulin secretion, with treatment options including sulfonylurea derivatives, insulin, GLP-1 RAs, and SGLT-2 inhibitors. MODY2 (GCK) involves a impairment in the glucose-sensing mechanism but typically does not require treatment. Protein misfolding disorders like MODY8 (CEL) and MODY10 (INS) affect both endocrine and exocrine pancreatic function and involve structurally defective insulin molecules, treated with OADs or insulin. Mutations in KATP channels, seen in MODY12 (ABCC8) and MODY13 (KCNJ11), lead to impairment in insulin secretion and are managed with sulfonylurea derivatives. Signal transduction errors such as MODY14 (APPL1) also result in impaired insulin secretion and are treated with OADs or insulin.
Elevated triglycerides in diabetes are linked to defects in insulin action and hyperglycemia, which can alter plasma lipoproteins. Some suggest that diabetes should be referred to as "lipidus" rather than "mellitus" due to the significant lipid disturbances. In type 2 diabetes mellitus (T2DM), obesity and insulin-resistant metabolic dysfunction may independently contribute to lipid abnormalities, separate from hyperglycemia. This connection between lipid and carbohydrate metabolism has led to a "lipocentric" perspective on the development of insulin resistance and T2DM. Fatty acids play a key role in insulin sensitivity, obesity, and T2DM, with the primary issue in lipoprotein metabolism being disturbances in triglyceride-rich lipoproteins due to problems in chylomicron synthesis and clearance.
Two companies have initiated clinical trials involving stem cell-derived beta cells for the treatment of type 1 diabetes. One trial, conducted by a European consortium, involves implanting encapsulated pancreatic progenitor cells (PEC-01) in a device that allows new blood vessel growth and uses both anti-inflammatory agents and standard immunosuppression. The Beta-Cell Therapy Consortium reported that VC-02m, derived from human-induced pluripotent stem cells, has been implanted in people with type 1 diabetes in Europe for the first time, showing that these cells can survive, engraft, differentiate, and mature into human islet-like cells when implanted subcutaneously. Vertex is also testing a new method using fully differentiated and functional stem cell-derived islet-like organoids (VX-880) delivered through the portal vein along with immunosuppression in humans.
Elevated free fatty acid levels in type 2 diabetes contribute to insulin resistance and impaired beta-cell function, a condition known as lipotoxicity, which leads to beta-cell dysfunction through multiple mechanisms such as intracellular triglyceride accumulation, increased expression of uncoupling protein 2, and activation of caspase-mediated apoptosis. Free fatty acids also impair insulin gene expression, disrupt insulin exocytosis by altering calcium channel complexes, induce endoplasmic reticulum stress, and dysregulate autophagy, all of which contribute to beta-cell dedifferentiation and loss of insulin-producing cells. Additionally, free fatty acids induce nitric oxide overproduction, which further impairs insulin secretion and promotes apoptosis through activation of stress-related kinases. These effects are compounded by increased cytokine release from expanded adipose tissue, including tumor necrosis factor-alpha and interleukin-6, which negatively affect beta-cell function and survival, while chronic inflammation and leptin signaling further inhibit insulin secretion and gene expression.
Studies have shown an association between diabetes and anxiety in children and adolescents, with young people with type 1 diabetes having a 2.5-fold increased risk of developing anxiety over 26 years. A systematic review found that 13.4% and 17% of participants with type 1 diabetes exhibited state and trait anxiety symptoms, respectively, while another review reported anxiety prevalence ranging from 15.5% to 32.1% in young people with type 1 diabetes compared to 0% to 8% in control groups.
Diabetic diarrhoea is managed symptomatically with loperamide, ideally taken 30 minutes before meals in a dosage range of 2–16 mg/day, and reducing intake of sorbitol-containing artificial sweeteners is advised. For refractory cases, clonidine at 0.1 mg orally or via patch may be used in individuals without significant postural hypotension, while amitriptyline can help alleviate intestinal cramping and transit due to its anticholinergic properties. Octreotide, administered subcutaneously at 25–50 µg before meals, delays small intestinal transit and may reduce secretory diarrhoea linked to rapid transit, although it may promote bacterial overgrowth by slowing transit. Improving stool consistency can aid faecal continence, and pelvic floor retraining with biofeedback therapy may enhance rectal sensation and coordination of the external anal sphincter contraction, though it is less effective in those with severely reduced rectal sensation. In severe cases of diarrhoea with faecal incontinence, a descending colostomy may be considered to improve quality of life.
Studies have shown that individuals with type 2 diabetes exhibit distinct alterations in gut microbial composition compared to those without diabetes, with consistent observations including an enrichment of opportunistic pathogens such as Eggerthella species, Escherichia coli, and Lactobacillus species, as well as a depletion of known butyrate-producing bacteria including Faecalibacterium prasnitzii, Roseburia species, and Eubacteria species. Metagenome analysis further reveals functional changes in the microbiome, such as decreased potential for butyrate biosynthesis, increased potential for membrane transport of sugars, and upregulation of genes involved in oxidative stress pathways in individuals with type 2 diabetes. Additionally, combinations of metagenomic markers have been used to successfully predict type 2 diabetes status, reinforcing the link between the gut microbiome and the risk of developing the condition.
Amylin, a 37-amino-acid polypeptide co-secreted with insulin by pancreatic beta cells, is the principal component of amyloid deposits in the islets of Langerhans in type 2 diabetes. Pancreatic amyloidosis is associated with beta-cell loss in both white European and Chinese individuals, and studies have shown correlations between body mass index and beta-cell volume, with amyloidosis, inflammation, and fibrosis as common pathological features. The formation of intracellular islet amyloid polypeptide oligomers leads to progressive beta-cell loss and hyperglycaemia. Genetic variants affecting amylin metabolism can cause structural changes in amylin, increasing its oligomerization and resulting in beta-cell death. One such variant, S20G of the amylin gene, enhances cytotoxicity and amyloidogenicity and is found in 2–3% of Japanese, Chinese, and Pacific Islanders with diabetes. In Taiwanese Chinese, normoglycaemic carriers of the S20G variant exhibit reduced early-phase insulin secretion, though family studies suggest this variant acts as a risk-modifying factor rather than a major diabetes gene.
GLP-1 therapy in patients with type 2 diabetes mellitus (T2DM) has shown beneficial effects including reductions in fasting and average plasma glucose concentrations by approximately 4–6 mmol/L, a 1.2% (13 mmol/mol) decrease in HbA1c, significant lowering of free fatty acids, and gradual weight loss of around 2 kg. Additionally, insulin sensitivity nearly doubled and insulin secretion capacity improved substantially. These improvements were observed with continuous subcutaneous infusion of GLP-1 over 6 weeks, with minimal side effects. The study supported the therapeutic potential of GLP-1, leading to further development of DPP-4 resistant analogs and DPP-4 inhibitors to enhance GLP-1's insulinotropic activity.
Limited care for diabetes refers to the minimum standard of care provided in settings with constrained resources, where access to standard medical facilities and fully trained professionals may be lacking. Despite these limitations, this level of care focuses on achieving a significant portion of the outcomes possible with recommended care by utilizing only low-cost or highly cost-effective interventions.
Gestational diabetes mellitus (GDM) can develop early in pregnancy, with studies showing that 15–70% of cases may be detectable before 24 weeks' gestation, and the overall prevalence of early GDM ranges from 0.8% to 22.9%. Women diagnosed with GDM before 24 weeks have a higher risk of perinatal mortality, neonatal hypoglycaemia, and requiring insulin treatment compared to those diagnosed later. Additionally, early-diagnosed GDM is associated with increased risks of pregnancy-induced hypertension, postpartum haemorrhage, and caesarean section, and the offspring have higher rates of macrosomia, prematurity, stillbirth, and need for neonatal intensive care, even with treatment.
Tighter glucose regulation in patients with type 2 diabetes mellitus (T2DM) has been studied in several trials, including the ACCORD, ADVANCE, and a study in American veterans. In ACCORD, intensive glucose control leading to an average HbA1c of 46 mmol/mol (6.4%) was associated with excess cardiovascular mortality, while the ADVANCE study did not show such excess mortality despite similar HbA1c reductions. Neither study demonstrated a benefit in reducing cardiovascular outcomes in the intensive control groups. A study in American veterans with T2DM, where the average HbA1c in the intensive group was 52 mmol/mol (6.9%), also failed to show cardiovascular benefits at this commonly targeted HbA1c level. Across all studies, hypoglycemia occurred significantly more often in the intensive treatment groups.
When carbohydrate requirements for exercise exceed 60g/hr, adjustments to insulin doses are recommended, and carbohydrate intake beyond the maximum rate of enteral glucose absorption (1g/min) would require a combination of glucose and fructose.
Healthy eating, regular physical activity, and daily self-monitoring of blood glucose are essential for managing diabetes, helping individuals understand how food, activity, and medications affect their blood glucose levels. Diabetes education classes support patients in developing skills related to food choices, activity planning, and problem-solving. Medication, determined by a healthcare team, works alongside lifestyle changes to lower blood glucose and reduce complications. Effective diabetes management also involves risk reduction strategies such as smoking cessation, regular eye, foot, and dental exams, blood pressure monitoring, and aspirin use. Psychosocial factors influence health and quality of life, with successful self-management depending on individual motivation, achievable goal setting, and ongoing support.
Islet transplantation was first attempted in the 1970s, with limited success in achieving insulin independence. By 1998, around 260 patients with type 1 diabetes mellitus (T1DM) had undergone islet transplantation, but only 12% remained insulin-independent for more than a week. In 1989, two patients in Edmonton received approximately 260,000 islets during renal transplantation and were managed with intravenous insulin and intensive glucose monitoring for 14 days to maintain euglycemia, potentially preserving β-cell function. Their immunosuppressive regimen included corticosteroids, azathioprine, cyclosporine A (CsA), and Minnesota antilymphocyte globulin. Both patients showed positive C-peptide levels post-transplant but developed cytomegalovirus infection, leading to loss of islet mass and failure to achieve insulin independence.
Quality targets for HbA₁c measurement are critical because the range distinguishing low risk for diabetes from diagnostic levels is very narrow, sometimes as small as 42–48 mmol/mol. Small biases or imprecision in measurement can significantly affect clinical diagnosis; for instance, a true HbA₁c value of 45 mmol/mol with a bias of ±2 mmol/mol and 3% imprecision could result in readings that cross into either the diagnostic or low-risk range for diabetes. To ensure accuracy, performance goals based on sigma metrics have been established, and global monitoring through External Quality Assessment schemes, such as the EurA₁c trial, helps identify areas for targeted quality improvement.
Whole pancreas transplantation does not typically improve or reverse retinopathy, especially in individuals with diabetes who often have pre-existing retinopathy at the time of transplant, with most having laser-treated or proliferative retinopathy. Studies show that in nearly 80% of cases, retinopathy remains stable following transplantation, though 92% of those who experience progression do so within the first year. Factors associated with early worsening include the baseline severity of retinopathy, recent photocoagulation treatment, and PTA. Long-term graft survival (>25 years) after SPK transplantation is associated with retinopathy stabilization in about 90% of individuals, highlighting the importance of close initial and ongoing retinopathy monitoring post-transplant.
Recent studies have challenged established models of glucagon's role in glucose and lipid metabolism, suggesting that signaling through $\mathrm{G}_{\mathrm{i}}$ may contribute to glycogenolysis and gluconeogenesis, rather than the traditionally emphasized $\mathrm{G}_{\mathrm{S}} / \mathrm{AMP}$ signaling. Additionally, research in mice indicates that glucagon may not be essential for ketosis caused by starvation or SGLT-2 inhibitor treatment, and that hepatic glucagon receptor signaling might enhance insulin-stimulated glucose uptake in skeletal muscle and brown fat, pointing to a broader and more complex role for glucagon in glucose regulation. These findings highlight gaps in understanding glucagon's actions and suggest potential new avenues for diabetes research and therapy.
GAD65Ab and IA-2A autoantibodies have equal predictive value for diabetes in both the general population and first-degree relatives (FDR) siblings, with higher cumulative risk observed for each individual autoantibody among siblings. Double autoantibody positivity confers a similar cumulative risk in both groups, and the levels of these autoantibodies provide additional predictive information. In school children, multiple autoantibodies have a positive predictive value of 25–75% and a sensitivity of 58–100% for diabetes, without considering HLA genotypes.
The addition of bedtime NPH insulin is effective for improving fasting glycemic control in patients no longer controlled by oral agents alone, particularly those who do not consume large evening meals and thus do not require short-acting insulin at suppertime. Clinical trials have demonstrated that combining bedtime NPH insulin with daytime oral agents can achieve glycemic control comparable to other insulin regimens, with the added benefit of less weight gain. Better glycemic control is observed when bedtime NPH insulin is used with a sulfonylurea compared to insulin alone, and evening NPH insulin also lowers free fatty acids more effectively than daytime insulin. Patients typically start with a low dose of NPH insulin, around 10 units, and adjust the dose based on fasting glucose levels, often reaching a total daily dose of 30–50 units or approximately 0.4–0.5 units/kg body weight. The target fasting glucose level is often individualized but may align with ADA recommendations of 90–130 mg/dL. Consistent wake times and breakfast consumption are important, and oral agents are continued, with sulfonylureas usually taken only with the first meal. A randomized trial found that metformin combined with bedtime NPH insulin resulted in the least weight gain, while hypoglycemia was a limiting factor when glyburide was used.
Preserving β-cell function is crucial in preventing the progression of type 1 diabetes to its clinical stage, though improving insulin sensitivity may also play a significant role in disease management. Evidence from teplizumab studies suggests that enhanced C-peptide capacity does not always correlate with reduced HbA1c levels, indicating limited metabolic benefits in some cases. Observational data show that treatment with abatacept in individuals with rheumatoid arthritis led to a significant improvement in insulin sensitivity as measured by the Matsuda Insulin Sensitivity Index (ISI) after six months. These findings support the exploration of combined interventions targeting different aspects of diabetes pathology. Ongoing studies such as AbAte (teplizumab/antiCD3), T1DAL (alefacept/CTLA4Ig), and EXTEND (tocilizumab/IL-6 blockade), with a total of 80 participants, are examining long-term effects and combinations of therapies in type 1 diabetes, with recruitment currently underway.
Time in range (70–180 mg/dL) is a key metric for glucose control, with greater than 70% of readings within this range considered beneficial, while time below 70 mg/dL should remain less than 4% and below 54 mg/dL less than 1%. Elevated glucose levels above 180 mg/dL should be less than 25% and above 250 mg/dL less than 5%. Each 5% increase in time within the target range provides clinical benefits. Average glucose was measured at 173 mg/dL and the glucose management indicator (GMI) was 7.6%, reflecting overall glycemic control. Glucose variability was reported at 49.5%, indicating fluctuations in blood sugar levels.
The National Urban Diabetes Survey conducted in six cities in 2001 found an age-standardized prevalence rate of 12% for diabetes with a slight male predominance, and 14% for impaired glucose tolerance, with younger individuals (≤40 years old) showing rates of 5% for diabetes and 13% for impaired glucose tolerance. Diabetes was independently associated with increasing age, BMI, waist/hip ratio, family history of diabetes, higher monthly income, and physical inactivity, while impaired glucose tolerance was linked to age, BMI, and family history of diabetes. Later studies indicated rising prevalence, including 14.3% in the Chennai Urban Rural Epidemiology Study (CURES-17) and 18.6% in Chennai in another study. The ICMR-INDIAB study across 188 urban and 175 rural sites in four regions reported diabetes prevalence rates of 10.4% in Tamil Nadu, 8.4% in Maharashtra, 5.3% in Jharkhand, and 13.6% in Chandigarh, leading to an estimated 62.4 million people with diabetes and 77.2 million with pre-diabetes in India in 2011.
Infants of mothers with hyperglycaemia during pregnancy, whether preexisting or gestational diabetes, are more likely to be born large for gestational age (LGA) due to excessive fetal growth and adiposity, with the HAPO study demonstrating a linear association between maternal glycaemia and increased odds of LGA birth weight, showing an odds ratio of 1.38 for each standard deviation increase in maternal fasting glucose, and this risk is independent of maternal obesity or excessive gestational weight gain, which also contribute to the likelihood of LGA birth.
The diagnostic criteria for diabetes were established based on observations of bimodality in glucose levels among high prevalence groups like the Pima Indians, along with considerations of risk for retinopathy. In 1979 and 1980, NDDG and WHO recommended a 75-g glucose load dissolved in 300 mL of water to be consumed over 5 minutes. NDDG set fasting and 2-hour venous plasma thresholds at 140 mg/dL (7.8 mmol/L) and 200 mg/dL (11.1 mmol/L), respectively, while the WHO slightly rounded these values to 8 mmol/L and 11 mmol/L. Impaired glucose tolerance (IGT) was defined as a fasting venous plasma level below 8 mmol/L with a 2-hour value between 8 and 11 mmol/L. In 1985, the WHO revised its criteria to align exactly with NDDG's original values.
Autoantibodies to insulinoma-associated protein 2 (IA-2), a non-functional member of the protein tyrosine phosphatase family, are present in about 70% of children with type 1 diabetes mellitus (T1DM) at the onset of the disease; these autoantibodies target intracellular protein domains and are expressed in both islet alpha and beta cells, though the exact function of IA-2 remains unknown despite its localization to secretory vesicle membranes in endocrine and neuronal cells.
Group art therapy in young adults with type 1 and type 2 diabetes showed improved social support and reduced diabetes distress despite poor attendance. Group diabetes education for teenagers with type 1 diabetes significantly improved self-management and transition readiness. The use of a smartphone application for carbohydrate counting demonstrated improved accuracy and positive acceptability. Peer mentorship trials are ongoing to assess effects on glycaemic levels, time to first adult visit, and frequency of blood glucose monitoring. Mobile applications such as MyT1DHero and iSpy are being tested for their impact on glycaemic levels, diabetes knowledge, and carbohydrate counting accuracy. Trials evaluating the impact of pet ownership and video games on diabetes management are ongoing or have results pending.
Elevated blood glucose levels in gestational diabetes mellitus (GDM) typically appear later in pregnancy, which is why screening is most effective at 24–28 weeks' gestation. Women who are predisposed to GDM may not have sufficient β-cell response when insulin resistance becomes too high. The risk of recurrence of GDM in subsequent pregnancies is variable, influenced by differences in insulin resistance between pregnancies. South Asian and Hispanic populations have higher rates of GDM, consistent with their higher background prevalence of type 2 diabetes mellitus (T2DM). Detecting and treating GDM is important as fetal growth rates in GDM are similar to those observed in type 1 (T1DM) and T2DM pregnancies. Early diagnosis of GDM provides benefits for both mother and child. Women with a history of GDM have a risk of developing subsequent diabetes ranging from 2.6% to 70%, depending on follow-up duration. According to NICE guidelines (March 2008), fasting plasma glucose should be measured at 6 weeks postpartum and repeated annually in women with prior GDM; however, this approach may miss some cases of impaired glucose tolerance. A diagnosis of GDM should prompt lifestyle modifications, particularly weight loss.
Some skin manifestations are more common in individuals with diabetes and can be categorized into metabolic, vascular, infectious, and iatrogenic types, with considerable overlap. Acanthosis nigricans, characterized by pigmented papillomatous overgrowth of the epidermis in flexures, is linked to hyperinsulinaemia. Metabolic skin changes in diabetes are often due to the glycation of structural proteins, leading to thickening, loss of elasticity, and yellowing of the skin from glycated collagen and elastin. Necrobiosis lipoidica, frequently observed in type 1 diabetes, commonly appears on the shins in women and is difficult to treat.
Poor perception of hypoglycaemia in individuals with diabetes can be dangerous, particularly when drivers overestimate their blood glucose levels and drive while hypoglycaemic. Impaired awareness of hypoglycaemia, often linked to frequent severe episodes, poses a significant risk and is a common reason for losing a driving licence. However, it is not an absolute contraindication to driving if individuals demonstrate prolonged freedom from hypoglycaemia through frequent self-monitoring.
Certain antiretroviral medications used in the treatment of HIV, including protease inhibitors (PIs) and some nucleoside reverse-transcriptase inhibitors (NRTIs) such as zidovudine, stavudine, and didanosine, are associated with hyperglycaemia and diabetes. These drugs can cause insulin resistance, lipodystrophy, and pancreatitis, with PIs also shown to reduce insulin secretion in vitro. PI-induced lipodystrophy often presents as central obesity with or without peripheral fat loss and is linked to metabolic complications such as dyslipidaemia, further increasing the risk of cardiovascular events. The American Diabetes Association's 2021 Standards of Medical Care in Diabetes include HIV as a risk factor for diabetes, recommending screening with fasting glucose tests before starting or switching antiretroviral therapy, and again three to six months later, with annual checks thereafter if initial results are normal. The incidence of diabetes and prediabetes in individuals on antiretroviral therapy is estimated at 13.7 and 125 per 1000 person-years, respectively, with additional risk factors including age, obesity, family history, lipodystrophy, and specific antiretroviral regimens.
In type 1 diabetes and advanced type 2 diabetes, the loss of glucagon response to hypoglycaemia is linked to β-cell failure, where intra-islet insulin, along with other β-cell secretory products, normally regulates α-cell glucagon secretion; as β-cell function declines—whether through T-cell-mediated autoimmune destruction in type 1 diabetes or gradual β-cell loss in advanced type 2 diabetes—the absence of intra-islet insulin signalling impairs the glucagon response to hypoglycaemia. Research by Heller et al. supported this intra-islet hypothesis in humans by showing that during hypoglycaemia induced by tolbutamide, which increases portal insulin concentrations, the glucagon response was reduced, indicating that intra-islet insulin plays a key role in regulating glucagon release during hypoglycaemia.
New onset of unexplained weight loss in a patient with type 2 diabetes mellitus (T2DM), despite insulin therapy and good glycemic control, along with symptoms such as back pain or jaundice, should raise suspicion for pancreatic carcinoma.
The India Diabetes study involved 421 men and 110 women with impaired glucose tolerance, with a mean age of $45.9 \pm 5.7$ years and a mean BMI of $25.8 \pm 3.5 \, \mathrm{kg}/\mathrm{m}^2$, who were randomized into four groups. Group 1 served as the control, Group 2 received advice on lifestyle modification, Group 3 was treated with metformin, and Group 4 received both lifestyle modification and metformin. The lifestyle advice given was less intense compared to that in the American and Finnish prevention studies. Participants in the lifestyle modification group were instructed to increase their daily activity to 30 minutes; if they were already meeting this target, they were encouraged to maintain it, though exercise was not supervised. Diet modification was also recommended for each participant.
Insulin pumps offer greater flexibility and responsiveness in managing glycaemia throughout the day and night by allowing adjustments to basal insulin infusion rates hourly, which helps mimic a more physiological insulin profile compared to long-acting basal insulins. They are particularly beneficial for individuals with pronounced diurnal variations in insulin sensitivity, such as the dawn effect or those engaging in intensive physical exercise. Insulin pumps are increasingly used in specific populations like children and women planning pregnancy or who are pregnant, aiming to achieve tight glycaemic control. Newer closed-loop and smart pump systems automatically adjust basal insulin delivery based on glucose levels from connected sensors, proving especially helpful during nighttime. Pumps also facilitate administering correction boluses and adjusting mealtime boluses according to anticipated carbohydrate intake using built-in calculators. However, using these systems requires more active involvement from the person with diabetes, and some may prefer not to use an external device with a catheter. Additionally, insulin pump systems tend to be more expensive.
Pioglitazone, a thiazolidinedione and peroxisome proliferator-activated receptor-γ (PPARγ) agonist, is used as a second-line therapy in the treatment of type 2 diabetes. However, its use has raised safety concerns due to findings from pre-clinical studies showing an increased risk of bladder cancer in male rats exposed to pioglitazone. A large European randomized controlled trial, PROactive, observed a non-significant increase in bladder cancer incidence among pioglitazone-treated patients. Subsequent analyses, including a 10-year observational cohort study mandated by the US Food and Drug Administration (FDA), indicated that two or more years of cumulative exposure to pioglitazone were associated with an increased risk of bladder cancer. A similar risk increase was also noted in a French cohort, leading to the drug's withdrawal in France and Germany.
Persistent hyperglycaemia in diabetes leads to excessive activation of certain protein kinase C (PKC) isoforms, primarily β and δ, in vascular cells, retina, and glomeruli, contributing to microvascular complications. This activation occurs through increased de novo synthesis of diacylglycerol from glucose, enhanced by elevated intracellular glucose levels, and can also result from interactions between advanced glycation end products (AGEs) and their receptors. Other PKC isoforms such as α and ε in the retina, and α and δ in the glomerulus, have also been found to increase in diabetic conditions, suggesting a broad role of PKC activation in diabetic tissue injury.
Glycemic control should be monitored regularly in all patients with diabetes, with HbA1c measurement being the optimal method for assessing the risk of long-term complications; if unavailable, a series of blood glucose measurements, including fasting tests, may offer some guidance. Management of therapy depends on the clinical setting and the type and stage of diabetes. Patients with non-insulin-treated diabetes generally have limited ability to adjust therapy based on routine self-monitoring of blood glucose (SMBG), though some may benefit from assessing glycemic variability, self-titrating glucose-lowering medications, or checking for symptoms related to low blood glucose. For adults with type 1 diabetes and pregnant women on insulin, regular blood glucose testing, including continuous glucose monitoring, is strongly supported to achieve intensive control through insulin dose adjustments related to lifestyle. There is also strong evidence supporting the routine use of SMBG for insulin-treated patients with type 2 diabetes. However, rigorous trials in well-controlled non-insulin-treated patients show no significant clinical benefit from SMBG, and it should be used only when the information can actively adjust treatment, improve diabetes understanding, and evaluate the effectiveness of the management plan on glycemic control.
Pioglitazone treatment in individuals with type 2 diabetes and NASH has been associated with greater resolution of NASH and improvement in liver histological scores, including fibrosis, compared to placebo, and this benefit extends to individuals with NASH regardless of their type 2 diabetes status. However, its use is limited by concerns such as weight gain, peripheral edema, and increased risk of distal bone fractures, particularly in postmenopausal women.
In individuals with diabetes and one other cardiovascular disease (CVD) risk factor, treatment with ACE inhibitors such as fosinopril or perindopril, often combined with a diuretic like indapamide, has been shown to significantly reduce the risk of various cardiovascular outcomes, including combined cardiovascular events, cardiovascular mortality, myocardial infarction, and stroke. Clinical trials such as MICRO-HOPE, FACET, EUROPA, QUIET, and ADVANCE demonstrated relative risk reductions ranging from 7% for revascularization procedures to 37% for cardiovascular mortality. A meta-analysis of these trials confirmed that ACE inhibition leads to a 14% reduction in all-cause mortality and myocardial infarction, and a 23% reduction in stroke compared to placebo.
Increasing dietary fibre intake by approximately $18\mathrm{g / d}$ up to a total of $50\mathrm{g / d}$ can reduce fasting plasma glucose by $0.7 - 0.9\mathrm{mmol / l}$ and lower $\mathrm{HbA_{1c}}$ by $4\mathrm{mmol / mol}$ $(0.3\%)$, indicating a beneficial effect on glucose homeostasis. However, the American Diabetes Association states there is insufficient evidence to recommend fibre intake beyond the current recommended daily allowances for people with diabetes, emphasizing that meeting the existing minimum fibre recommendations should be a dietary priority.
In type 2 diabetes mellitus (T2DM), the progression of nephropathy shares similarities with type 1 diabetes mellitus (T1DM), though there are key differences. At the time of T2DM diagnosis, urinary albumin excretion (UAE) may be elevated but often returns to normal with effective glycemic control; however, microalbuminuria persists in 10–48% of cases. Persistent elevation of UAE suggests that diabetes was likely present for some time before diagnosis, with established kidney changes already occurring. The prevalence of hyperfiltration at diagnosis varies across studies, which may be due to undiagnosed diabetes and the presence of comorbidities such as preexisting hypertension.
Glibenclamide (glyburide) has been studied for the management of hyperglycaemia during pregnancy, particularly in women with fasting hyperglycaemia uncontrolled by diet. In a large randomized trial, glibenclamide was found to have similar glycaemic control and neonatal outcomes compared to insulin, with only 4% of women requiring insulin addition. However, subsequent smaller randomized controlled trials indicated higher risks with glibenclamide, including increased rates of neonatal hypoglycaemia, macrosomia, and intrauterine growth restriction (IUGR). Observational studies also reported associations with pre-eclampsia, lower Apgar scores, lower ponderal index, need for phototherapy, stillbirth (particularly with early gestational use), and neonatal intensive care unit (NICU) admission. Approximately 20% of women on glibenclamide required a switch to insulin therapy.
Meglitinides reduce hepatic metabolism, an effect that can be influenced by enzyme induction such as with rifampicin, and may interact with gemfibrozil.
SGLT-2 inhibitors, which promote glycosuria and lower blood glucose levels, can lead to a pseudo-fasted state and reduce insulin production while increasing glucagon release. During intercurrent illnesses or metabolic stress, when insulin resistance rises due to counter-regulatory hormones, a mismatch between insulin demand and supply can occur. This relative insulin deficiency may trigger lipolysis, ketosis, and acidosis, resulting in euglycaemic diabetic ketoacidosis (DKA), particularly when medication is not appropriately discontinued during periods of stress such as surgery, infection, or reduced oral intake.
High glucose levels, with or without a prior diagnosis of diabetes, are associated with increased in-hospital mortality and subsequent heart failure in acute coronary syndromes, particularly when blood glucose exceeds 120 mg/dL (6.1 mmol/L). In the setting of ST-segment elevation myocardial infarction (STEMI), the DIGAMI 1 study demonstrated that the use of intravenous insulin in the first 24 hours followed by intensified subcutaneous insulin for 3 months led to a 29% reduction in mortality at 1 year, although other trials such as DIGAMI-2 and CREATE-ECLAT have not confirmed these results.
Pioglitazone, a member of the thiazolidinediones class, activates PPAR-γ receptors primarily in adipocytes and skeletal muscles, enhancing glucose oxidation for cellular energy and leading to a durable reduction in HbA1c levels. It is particularly beneficial in patients with severe insulin resistance or non-alcoholic steatohepatitis (NASH), and does not cause hypoglycaemia. However, it is associated with weight gain, fluid retention due to increased sodium reabsorption, and an increased risk of bladder cancer and fractures. The drug may also precipitate or worsen heart failure, especially when used with insulin, but could potentially reduce the incidence of cardiovascular events.
National and international diabetes associations have contributed significantly to diabetes care by supporting research, offering patient assistance, and advocating for policy changes. The first such organization, the Portuguese Association for the Protection of Poor Diabetics, was founded in 1926 with the goal of providing free insulin and education. This was followed by the establishment of the Diabetic Association in the UK in 1934, which later became Diabetes UK. Similar organizations were subsequently founded in France (1938), the USA (1940), and Belgium (1942), and such groups now exist in most countries worldwide.
Hyperthyroidism can impair glucose tolerance in about one-third of individuals and may lead to diabetes in an additional 8% of patients, primarily due to insulin resistance, especially in overweight individuals, though insulin secretion can also be affected. Excess thyroid hormones enhance glucose production and increase expression of the hepatocyte glucose transporter 2 (GLUT-2) protein. Insulin resistance improves with restoration of normal thyroid function even if body mass index rises. In patients with diabetes who develop hyperthyroidism, glucose control worsens and insulin requirements increase in about half of cases, with these effects reversing after treating hyperthyroidism. Additionally, hyperthyroidism alters the response to oral glucose tolerance tests due to faster intestinal glucose absorption.
Painful diabetic peripheral neuropathy (DPN) can be managed with controlled-release oxycodone, a pure μ-agonist, in patients whose pain is not adequately controlled by standard treatments such as antidepressants and anticonvulsants, with studies showing significant pain relief and improved quality of life. Combination therapy with gabapentin and morphine may offer better efficacy and lower maximum tolerable doses compared to monotherapy, indicating an additive interaction between the drugs. Opioids should be considered for painful DPN only after careful patient selection, regular monitoring, appropriate dose titration, and management of opioid-specific issues like misuse, addiction, tolerance, and opioid-induced hyperalgesia. Clinical skills in risk assessment and management are essential for safe and effective opioid prescribing, and opioid agonists should generally be reserved for patients who do not respond to or cannot tolerate first-line medications.
DPP-4 inhibitors, including sitagliptin, linagliptin, and alogliptin, are rapidly absorbed and achieve maximum concentration within 2 hours, with most producing over 90% inhibition of DPP-4 activity for 24 hours. Vildagliptin has a shorter elimination half-life and requires twice-daily dosing. Most DPP-4 inhibitors are eliminated via the kidneys, necessitating dose adjustments in those with moderate renal impairment, except linagliptin, which is primarily excreted via the bile and can be used without dose adjustment in moderate to severe renal impairment.
Islet cell transplantation aims to address problematic and recurrent hypoglycaemia in individuals with diabetes, rather than solely focusing on insulin independence or reduction. A key measure of success is the abrogation or minimization of severe hypoglycaemic episodes, with over 90% of individuals experiencing complete abrogation of such episodes at 5 years post-transplant, and 80–100% at 10 years in some reports. Restoration of hypoglycaemia awareness is another important outcome, though there is ongoing debate regarding the extent of recovery of counter-regulatory hormonal responses and symptom recognition after the procedure. More recent studies have shown significant improvements in hypoglycaemia awareness following islet cell transplantation. Additionally, the procedure contributes to improved glycaemic control, with composite outcomes showing absence of severe hypoglycaemic episodes and HbA1c levels below 6.5% (48 mmol/mol) or 7.0% (53 mmol/mol) reported in 62.5–87.5%, 58.3–71.0%, 35–55%, and 21.9–36.3% of patients at 1, 2, 5, and 10 years post-transplant, respectively. Most studies also indicate a substantial and sustained improvement in overall glycaemic management following the procedure.
Inappropriately timed insulin or oral hypoglycemic therapy in relation to meals or enteral feeds can lead to dysglycemia, including both hyperglycemia and hypoglycemia, which may result in adverse outcomes such as metabolic instability, increased risk of complications, and impaired recovery.
In type 2 diabetes, MBL is strongly predictive of worsening urinary albumin excretion and mortality, with several studies confirming its utility in predicting the development of nephropathy. Research has shown that certain MBL2 polymorphisms, such as the GA and AA genotypes of rs1800450, are associated with type 2 diabetes, though not directly with diabetic nephropathy. However, individuals with the GG genotype of rs1800450 and the CC genotype of rs11003125 exhibit high serum MBL levels, and elevated serum MBL has been linked to nephropathy in type 2 diabetes.
In patients with diabetes, the renin-angiotensin system (RAS) plays a role in influencing the number of regenerative endothelial progenitor cells, which help maintain vascular endothelium integrity. Increased levels of these cells are linked to better cardiovascular outcomes in individuals with coronary artery disease. In patients with type 2 diabetes mellitus (T2DM), treatment with an angiotensin receptor blocker (ARB), specifically olmesartan, has been found to increase the number of regenerative endothelial progenitor cells, potentially contributing to the positive cardiovascular effects associated with AT1 receptor blockade.
Nasal insulin has been investigated for its potential to prevent type 1 diabetes mellitus (T1DM) by inducing autoimmune tolerance. Studies such as the Intranasal Insulin Trial (INIT) phases I and II and the Type 1 Diabetes Prediction and Prevention trial (DIPP) have explored this approach. INIT-I, conducted in Australia with T1DM first-degree relatives (FDR), showed some indications of mucosal tolerance to insulin but no significant effect on beta-cell function. INIT-II (NCT00336674) is an ongoing trial assessing the effects of nasal insulin at doses of 1.6 or 16 mg on islet autoimmunity. The DIPP study in Finland tested nasal insulin in children with genetic risk and positive islet cell autoantibodies (ICA) and insulin autoantibodies (IAA), but found no protective effect after daily administration of short-acting insulin or placebo in 224 participants.
Studies have shown that MASP-1 and MASP-2 levels are significantly higher in both adults and children with type 1 diabetes compared to age-matched controls, while MASP-3 levels do not differ between those with and without diabetes. Furthermore, HbA1c levels correlate with MASP-1 and MASP-2, and improved glycaemic management leads to a decrease in these MASP levels. However, no studies have yet been published on MASP levels in type 2 diabetes.
The first candidate gene associated with type 2 diabetes is PPARG, which encodes the PPAR-γ receptor, a target for thiazolidinediones, a class of insulin-sensitizing drugs. Genome-wide association studies (GWAS) in 2007 identified several genes linked to type 2 diabetes, including TCF7L2, FTO, CDKAL1, HHEX, SLC30A8, IGF2BP2, and CDKN2A/2B, most of which have modest effects. A variant in TCFCB4 in Greenland showed a strong association with glucose tolerance. Most type 2 diabetes risk variants influence β-cell function, as seen with TCF7L2, CDKAL1, and SLC30A8. Monogenic forms of diabetes, such as MODY, result from highly penetrant mutations in over 10 genes, while only a few rare variants, such as those in PAM and PDX1, are linked to type 2 diabetes. Protective variants have also been found, including in SLC30A8 and TCF2, and understanding their mechanisms could aid in drug development. A comprehensive understanding of type 2 diabetes genetics will require a systems approach integrating GWAS, epigenetic modifications, and multi-omics expression data.
Inhibition of hepatic glucose production pathways such as gluconeogenesis and glycogenolysis can lower blood glucose levels, but these interventions are limited by counter-regulatory mechanisms that prevent excessive hypoglycaemia. Glycogen phosphorylase inhibitors have shown glucose-lowering effects in pre-clinical studies, though clinical results have been limited in efficacy or duration. Glucose 6-phosphatase inhibitors block the final step of both gluconeogenesis and glycogenolysis, but their prolonged action increases the risk of hypoglycaemia. Fructose 1,6-bisphosphatase inhibitors target an earlier step in gluconeogenesis and can partially reduce hepatic glucose output, though compensatory glycogenolysis may occur; clinical studies on these inhibitors are ongoing.
Supporting a relative with diabetes is perceived as a considerable burden by 35% of family members, with 40% experiencing high levels of distress related to concerns about their relative's condition, and 61% expressing significant worry about hypoglycaemia in their family member with diabetes.
People with diabetes may experience increased oxidative stress, leading to investigations into the benefits of antioxidant vitamin intake, though studies have not shown clear advantages, and routine supplementation with vitamins E, C, and carotene is not advised due to long-term safety concerns. The effectiveness of folate supplementation in reducing cardiovascular events remains unclear and requires further study. Diabetes associations do not currently recommend supplements or functional foods, as most fiber-enriched products, plant sterol-containing margarines, and supplements with n-3 fatty acids, minerals, trace elements, or herbs lack sufficient evidence from clinical trials to support their use. Vitamin or mineral supplementation should only be used therapeutically in cases of proven deficiency. Given the role of vitamin D in bone health and the skeletal complications associated with diabetes, monitoring dietary vitamin D intake, sunshine exposure, and vitamin D levels is important. Nutrition education to support healthy eating and meet dietary recommendations is essential for individuals with both type 1 and type 2 diabetes.
Sulfonylureas are commonly used in elderly individuals with diabetes who do not respond adequately to diet alone due to their general tolerability, though their primary risk is hypoglycemia, especially with glibenclamide, which is associated with more fatalities and should be strictly avoided in older adults. Glipizide can cause prolonged hypoglycemia and has been linked to hypoglycemic deaths in the elderly, whereas gliclazide has a lower risk of hypoglycemia and may be less likely to cause weight gain, making it a safer alternative to glibenclamide. A modified-release once-daily formulation of gliclazide is now available. Tolbutamide poses the lowest hypoglycemia risk and can be used in individuals with mild renal impairment defined as serum creatinine less than 150 μmol/L or eGFR less than 42 mL/min/1.73 m² based on a 75-year-old non-black male. Glimepiride may be beneficial for patients with uncertain compliance as it is taken as a single daily dose before breakfast, although there are no strong comparative studies between glimepiride and gliclazide.
Painful neuropathy in diabetes may remit with improved metabolic control, especially when symptoms are of recent onset, while chronic pain lasting more than six months typically requires specific therapy. Treatment options include topical capsaicin cream $(0.075\%)$ for localized pain, which works by depleting substance P in pain fibers, as well as tricyclic antidepressants like amitriptyline and antiepileptics such as carbamazepine and gabapentin, the latter being licensed for this indication. Additional approaches include transcutaneous nerve stimulation and acupuncture.
Incretin mimetics, including glucagon-like peptide 1 (GLP-1) receptor agonists such as exenatide and liraglutide, and dipeptidyl peptidase 4 (DPP-4) inhibitors like sitagliptin, saxagliptin, alogliptin, and vildagliptin, offer new options for combination therapy in diabetes management. Exenatide, an injectable synthetic analog of a salivary protein from the Gila monster, closely resembles GLP-1 and activates GLP-1 receptors to mimic the effects of natural GLP-1 when administered at doses of 5 or 10 micrograms twice daily. Clinical trials lasting 30 weeks evaluated exenatide in patients whose diabetes was inadequately controlled by oral agents such as sulfonylureas, metformin, or both. After a 4-week placebo period, participants were randomly assigned to receive either placebo or exenatide at 5 micrograms twice daily for the first month, with the option to increase to 10 micrograms twice daily thereafter, while continuing their existing oral diabetes medications.
Variants of the TCF7L2 gene, involved in the regulation of β-cell function, are associated with a worse response to sulfonylurea derivatives in individuals with type 2 diabetes, with those carrying the homozygous TT genotype for SNP rs1225372 being twice as likely to fail to achieve an HbA1c goal of <7% within one year of treatment. Variants in KCNJ11 and ABCC8 genes, which encode components of the sulfonylurea receptor, are linked to an increased glycemic response to these drugs, with specific variants such as Ser1369Ala in ABCC8 and rs5210 and E23K in KCNJ11 predicting a greater response. Additionally, the Arg972 variant of IRS-1, involved in insulin signaling, is associated with treatment failure, and risk alleles in NOS1AP are related to a reduced response to glibenclamide.
Monogenic diabetes results from single-gene mutations leading to β-cell dysfunction or insulin resistance, accounting for 1–2% of diabetes cases and often misdiagnosed. It should be suspected in atypical presentations, with autosomal dominant or maternal inheritance patterns, characteristic features like deafness or fat loss, or diabetes diagnosed within the first 6 months of life. Glucokinase gene mutations cause mild fasting hyperglycemia with minimal glycated hemoglobin changes and rarely lead to complications. Mutations in HNF1A and HNF4A cause progressive hyperglycemia and symptomatic diabetes in youth, with high sensitivity to sulfonylureas. Mitochondrial mutations may result in maternally inherited diabetes with hearing loss. Neonatal diabetes before 6 months suggests a genetic cause even in adults. Sulfonylureas are effective for mutations in β-cell potassium channels like Kir6.2 and SUR1. Acanthosis nigricans in non-obese patients indicates insulin resistance and possible genetic causes such as lipodystrophy from LMNA or PPARG mutations, or insulin receptor mutations when lipodystrophy is absent.
Gestational diabetes mellitus (GDM) is a risk factor for subsequent type 2 diabetes, metabolic syndrome, and increased cardiovascular risk. Women with a history of GDM should undergo postnatal testing to detect unrecognized type 2 diabetes or pre-diabetes, and if suspected, rule out type 1 diabetes and genetic types of diabetes. The postnatal visit offers an opportunity for lifestyle advice, cardiovascular risk factor screening, counseling on contraception, and early referral for future pregnancies. Despite these recommendations, only 58% of women in the UK underwent any glucose testing and even fewer had lipid testing within the first year after a GDM pregnancy. While the risk of developing type 2 diabetes is well recognized and incorporated into the QDiabetes-2018 risk prediction algorithm, this information has not been integrated into cardiovascular disease risk calculators.
Integrated approaches to adopting the Chronic Care Model (CCM) have been explored in the USA, particularly in Pennsylvania, where insurers provide reimbursement and incentives for primary care practices to improve diabetes care. Learning collaboratives and practice coaches support clinicians and staff in implementing the CCM, with clinics reporting clinical outcomes and care changes monthly. Payers fund necessary practice changes, such as case management, aiming to control rising healthcare costs. Similar initiatives are being implemented or explored in Australia, Canada, Denmark, the Netherlands, New Zealand, and other regions.
Planning pregnancy is important for individuals with impaired glucose tolerance (IGT) or diabetes due to the increased risks associated with uncontrolled blood sugar levels during pregnancy, which can affect both maternal and fetal health.
Fasting glucose, two-hour post-challenge glucose, and HbA₁c are equally effective in predicting future microvascular complications of diabetes and can serve as diagnostic and screening tools. Impaired fasting glucose, defined with a cutoff of 5.5 mmol/L, provides a straightforward method to identify or rule out dysglycemia. Urinalysis for glycosuria is highly specific (96–100%) but poorly sensitive (16–43%), while random blood glucose testing is specific but lacks sensitivity.
Psychologic traits such as personality, temperament, and coping style can directly influence self-care behaviors and emotional state, which in turn may affect metabolic control in diabetes. Psychological states, particularly stress, can impact metabolic control both directly through the autonomic nervous system and indirectly by impairing diabetes management. Family interactions and functioning, including conflicts and cohesiveness, influence emotional states and self-care behaviors, which are critical for effective diabetes management. Self-care behaviors—such as medication use, diet, exercise, and monitoring—are the primary determinants of glycemic control, though their relationship with metabolic outcomes can be confounded by physiological factors like intercurrent illness or hormonal changes during puberty.
During illness, blood glucose levels should be monitored every 3–4 hours, especially when outside the target range of 80–200 mg/dl (4.4–11.1 mmol/l), and ketone testing should be done at least twice daily, increasing frequency if ketones are elevated or blood glucose exceeds 300 mg/dl (17.6 mmol/l). Blood ketone testing, particularly for β-hydroxybutyrate using devices like the Precision Xtra®/Xceed Pro® meter, offers a more accurate and timely assessment of ketosis compared to urine testing, and the presence of ketones with persistently elevated blood glucose above 200 mg/dl (11.1 mmol/l) indicates the need for additional insulin and fluids.
ACE inhibitors may be used in diabetic hypertension as they can interfere with local angiotensin action in specific target tissues, even when the general renin-angiotensin system (RAS) is not activated. However, when used alone, these agents have limited hypotensive effectiveness in many black patients, who typically exhibit suppressed RAS activity.
The age-adjusted prevalence of type 2 diabetes in Fergana, Uzbekistan, was estimated to be 8% in both urban men and women, with impaired glucose tolerance affecting 5% of men and 6% of women. In Sirdaria province, Uzbekistan, the age-adjusted prevalence rates of diabetes were 10% in men and 7.5% in women, while impaired glucose tolerance was higher at 14% in women and 11% in men. In Russia, diabetes prevalence was estimated at 6% in men and 7% in women, with impaired glucose tolerance at 6% and 13%, respectively, and diabetes was associated with clustering of hyperlipidaemia, obesity, hypertension, and low 10-year survival. A survey in Moscow reported a low incidence of diagnosed diabetes at 2%, supported by self-reported doctor diagnoses, and underdiagnosis, undertreatment, and infrequent insulin use were noted as contributors to diabetes-related morbidity. Prevalence data from Poland showed an increase in type 2 diabetes from 3.7% to 10.8% between 1986 and 2000, with impaired glucose tolerance rising from 2.9% to 14.5%, influencing estimates for other eastern European countries.
Pramlintide has been shown to improve glycemic control in individuals with type 2 diabetes, particularly by reducing postprandial glucose excursions and the 24-hour glucose profile, likely through delayed gastric emptying. In a 52-week trial involving 656 participants with type 2 diabetes and baseline HbA1c levels ≥8%, treatment with pramlintide twice daily led to a greater reduction in HbA1c compared to placebo, with a mean change of -0.62% versus -0.25% respectively. Additionally, pramlintide was associated with sustained weight loss, with the 120μg twice daily dose resulting in an average weight reduction of -1.4kg compared to +0.7kg in the placebo group. A pooled post hoc analysis of over 1155 participants with type 2 diabetes and BMI >25kg/m² further confirmed significant reductions in HbA1c (-0.43%) and body weight (-2.0kg) at week 26 with adjunctive pramlintide therapy. These findings indicate that adding pramlintide to insulin therapy can yield further improvements in glycemic control and promote weight loss in individuals with type 2 diabetes.
In individuals with type 1 diabetes and moderately elevated albuminuria, treatment with angiotensin-converting enzyme (ACE) inhibitors reduces the risk of progression to severely increased albuminuria with an odds ratio of 0.35 and increases the likelihood of regression to normoalbuminuria with an odds ratio of 3.07 compared to placebo. After two years, ACE inhibition results in a mean 50% reduction in urinary albumin excretion (UAE), particularly in those with the highest baseline levels, although the treatment effect plateaus over time, indicating a delay rather than prevention of disease progression.
Commercially available insulin was initially extracted from porcine and bovine pancreases, resulting in insulin with a purity of 80–90%, with contaminants including pancreatic polypeptides and glucagon. This insulin was effective but often caused immune-mediated side effects such as lipoatrophy and antibody-mediated insulin resistance, which affected insulin action. The introduction of recombinant DNA technology in 1980 enabled the production of human insulin with a purity of 99.5–99.9%, virtually eliminating these immune-related complications.
Metformin is effective and safe for treating gestational diabetes mellitus (GDM) when diet alone is insufficient, with most women continuing metformin until birth. When metformin alone does not achieve glycemic targets, insulin can be added. Fasting blood glucose levels are similar between metformin and insulin treatments, but 2-hour postprandial glucose levels are lower with metformin. Women treated with metformin experience less weight gain in late pregnancy and greater postpartum weight loss compared to those on insulin alone. Perinatal complications are largely similar between the two treatments, though infants of mothers on metformin have a lower risk of severe hypoglycemia. A majority of women on metformin prefer to use it again in future pregnancies compared to those on insulin.
Several prevention and intervention trials with long follow-up durations, some involving combinations of therapies, are ongoing or planned for type 1 diabetes mellitus (T1DM). These trials aim at different stages of prevention: primary prevention seeks to stop the triggering of autoimmunity, secondary prevention focuses on halting β-cell destruction, and tertiary prevention aims to preserve remaining β-cells and enhance their regeneration. The chapter provides an evidence-based review of the main ongoing drug clinical trials in individuals at risk for or with newly diagnosed T1DM.
GLP-1 is an incretin hormone produced by the enteroendocrine L cells that enhances peripheral insulin action, slows gastric emptying, and inhibits glucagon secretion, making it relevant to diabetes management. Due to its short half-life and rapid deactivation by DPP-4, synthetic, degradation-resistant GLP-1 receptor agonists (GLP-1RAs) have been developed. These include exenatide, liraglutide, lixisenatide, dulaglutide, exenatide extended release, semaglutide, and an oral formulation of semaglutide, all of which are administered either once daily or once weekly via subcutaneous injection or orally.
Type 2 diabetes is a key focus in several major clinical trials, including UKPDS, ACCORD, ADVANCE, and VADT, which differ in participant characteristics and outcomes. UKPDS involved newly diagnosed patients with type 2 diabetes, while ACCORD enrolled individuals aged 40–79 with a history of cardiovascular disease (CVD) or additional risk factors such as atherosclerosis, albuminuria, or left ventricular hypertrophy. ADVANCE included participants with type 2 diabetes diagnosed after age 30 or those over 55 with macro- or microvascular disease, and VADT selected those with inadequate response to maximum oral agent or insulin therapy. Mean age across studies ranged from 60.5 to 66 years, with diabetes duration at entry varying from newly diagnosed to an average of 11.5 years. Cardiovascular outcomes differed across trials: UKPDS showed cardiovascular benefit, ACCORD indicated potential harm, and ADVANCE and VADT found no significant benefit. Hypoglycemia rates were higher with intensive therapy in all studies, ranging from 16.2% in ACCORD to 53% in ADVANCE, compared to standard therapy.
People with diabetes, particularly type 1 diabetes, face significantly higher risks of hospitalization and mortality due to infections compared to those without diabetes. Studies show that individuals with type 1 diabetes have higher incidence rate ratios for hospitalization related to any infection and death due to infection than those with type 2 diabetes. For example, hospitalization rates for infections are 3.7 times higher for type 1 diabetes and 1.9 times higher for type 2 diabetes, while death due to infection is increased 7.7-fold for type 1 diabetes and 1.9-fold for type 2 diabetes. Specific infections such as pneumonia, osteomyelitis, and sepsis show significantly elevated mortality ratios in type 1 diabetes, with respective increases of 5.8-fold, 29.6-fold, and 9.9-fold compared to people without diabetes, whereas type 2 diabetes shows smaller increases of 1.2, 3.3, and 1.9-fold. Evidence also indicates that diabetes worsens outcomes from infections, as seen in a Danish study where diabetes increased the risk of death at 90 days by 10% among people hospitalized with pneumonia, and a UK study that found a twofold increase in infection-related deaths after adjusting for confounding variables.
Upper body obesity is associated with insulin resistance, potentially due to visceral fat accumulation and increased lipolysis in omental and mesenteric adipocytes, which may release excessive amounts of NEFA into the portal vein, contributing to hepatic insulin resistance. However, evidence supporting this "portal theory" is limited, as NEFA and glycerol concentrations in the portal vein are similar to those in arterial plasma, and tracer studies indicate that NEFA from the splanchnic bed contribute only about 10% of total NEFA delivery to the liver. Additionally, in women with upper body obesity, increased NEFA turnover appears to originate from subcutaneous fat rather than visceral fat.
Studies have evaluated the effects of statins in diabetes, including the Collaborative Atorvastatin Diabetes Study (CARDS) and the Heart Protection Study (HPS), which demonstrated that statin therapy reduces LDL cholesterol and cardiovascular events in diabetic patients. CARDS, involving individuals with diabetes and additional risk factors but no prior cardiovascular disease, showed a 40% reduction in LDL cholesterol and a 37% reduction in cardiovascular endpoints, leading to early termination due to significant benefits. Similarly, HPS, the largest statin study, included a substantial subgroup of patients with diabetes and found a 33% reduction in LDL cholesterol and a 31% decrease in cardiovascular events. However, the ASPEN study found a non-significant 15% reduction in events with atorvastatin, and in end-stage diabetes with renal failure, aggressive LDL cholesterol reduction resulted in only a non-significant 8% decrease in events despite a 41% drop in LDL cholesterol, suggesting that statin benefits are most pronounced early in the course of diabetes.
In patients treated with insulin for more than five years, the prevalence of severe hypoglycemia is 7% and 25%, with incidences of 10 and 70 episodes per 100 patient-years, respectively. The incidence of iatrogenic hypoglycemia is relatively low in the early stages of insulin treatment for type 2 diabetes mellitus (T2DM), but the risk increases significantly over time, approaching the levels seen in type 1 diabetes mellitus (T1DM).
Patients with diabetes and peripheral arterial disease (PAD) have a significantly higher risk of amputation at the level of the transmetatarsal bones or above, being 8 times greater compared to the non-diabetic population. Additionally, the presence of diabetes further doubles the already elevated mortality risk associated with PAD.
Candidate genes selected for their plausible role in glucose homeostasis or insulin secretion have been studied in diabetes research, but no genes with a moderate or major effect on polygenic forms of diabetes have been identified, possibly due to either the absence of such genes or incomplete understanding of the pathophysiologic mechanisms of type 2 diabetes mellitus (T2DM) and the genes involved.
Teplizumab, a CD3 blocking agent, was evaluated in the AbATE study involving 52 individuals with newly diagnosed type 1 diabetes (aged 8–30 years) who received a cumulative dose of 11.6 mg or 12.4 mg at baseline and after one year, compared to 25 placebo recipients. At 24 months, the intervention group showed 75% higher mean C-peptide AUC levels than the control group, though no difference in HbA1c levels was observed at that time point. Among responders—45% of the intervention group who retained more C-peptide than controls—lower HbA1c at study entry was noted. These findings were corroborated in the Protégé study with over 500 participants. Additionally, one-year responders from the 2013 Herold et al. study maintained higher C-peptide levels at seven years compared to placebo, again without differences in HbA1c.
Mild elevations of plasma glucose during pregnancy can be harmful to the fetus, even at levels below those causing osmotic symptoms. The Hyperglycaemic and Pregnancy Outcome (HAPO) study involving over 23,000 women demonstrated a continuous linear relationship between maternal glucose levels and fetal growth, with no clear threshold for diagnosing gestational diabetes mellitus (GDM). This supports the need for screening for GDM, which is typically conducted through universal screening programs as recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG) consensus panel. However, implementation of the one-step 75g oral glucose tolerance test (OGTT) recommended by international consensus faces practical challenges, and there is a lack of high-quality health economic analyses evaluating the costs and benefits of lifestyle and pharmaceutical interventions for GDM.
Increased glucose levels activate the hexosamine pathway, leading to the formation of O-linked N-acetylglucosamine, which plays a significant role in hyperglycemia-induced and fat-induced insulin resistance. The conversion of glucose to glucosamine is regulated by the enzyme glutamine: fructose-6-phosphate amidotransferase (GFAT), and inhibiting this enzyme prevents hyperglycemia-induced increases in the transcription of TGF-α and TGF-β1.
Pre-mixed insulin combinations, such as 70/30 insulin (70% NPH and 30% Regular), are used with the evening meal and may be more effective for obese patients (BMI >30 kg/m²) when combined with morning sulfonylureas like glimepiride, allowing for faster glycemic control compared to insulin alone. In a multicenter study, patients self-titrating 70/30 insulin while continuing glimepiride reached fasting plasma glucose targets of 140 mg/dL (7.8 mmol/L) more quickly, with HbA1c decreasing from nearly 10% (86 mmol/mol) to 7.6% (60 mmol/mol). Insulin doses averaged 49 units in the combination group versus 78 units in the insulin-only group, with more patients in the insulin-only group needing over 100 units daily. A smaller study showed better glycemic control with evening 70/30 insulin plus glyburide once daily compared to insulin alone, and premixed rapid analogs like lispro or aspart may offer more convenient meal timing. Administering 70/30 aspart mix at meal times once, twice, or thrice daily reduced HbA1c by 1.4% (15 mmol/mol), 1.9% (21 mmol/mol), and 1.8% (20 mmol/mol) respectively in patients not controlled by oral agents or basal insulin. Insulin pens are often preferred for convenience, especially for those eating away from home, and pre-mixed insulins are typically given twice daily, though frequency may vary, sometimes causing confusion with dose adjustments.
Bariatric surgery leads to marked and sustained weight loss, which is associated with improvement or remission of obesity-related comorbidities such as type 2 diabetes. The surgery induces significant changes in eating behavior, including reduced hunger, increased satiety, altered food preferences away from energy-dense foods, and changes in smell and taste perception, all contributing to reduced energy intake and weight loss. These physiological changes following bariatric surgery support weight loss maintenance and offer insights into the development of new strategies for managing obesity and its related conditions, including type 2 diabetes.
Diabetes develops when the β-cell area declines by approximately 65%, though a mere reduction in β-cell mass may not be sufficient to cause glucose intolerance, as evidenced by the large overlap in β-cell mass between individuals with and without diabetes. Hemi-pancreatectomy in normal individuals does not typically lead to major disturbances in insulin secretion, suggesting that β-cell function may be more critical than β-cell mass alone. The insulin content per β-cell tends to increase despite a decline in β-cell mass over the course of the disease, raising questions about whether β-cell number or insulin content is more important in diabetes progression. The progressive loss of β-cells is likely exacerbated by mild elevations in plasma glucose levels and increased secretory demand due to insulin resistance, especially in genetically predisposed β-cells. Animal studies show that a 60% pancreatectomy in dogs does not alter insulin secretion unless plasma glucose levels are elevated, a finding supported by limited human studies where pre-existing defects in β-cell function, such as reduced first-phase insulin secretion and glucose sensitivity, predicted the risk of developing hyperglycemia after partial pancreatectomy, highlighting the importance of β-cell dysfunction in the pathogenesis of type 2 diabetes.
Women with diabetes, particularly those participating in the TODAY study, faced significant risks related to unplanned pregnancies, with 10% becoming pregnant despite mandatory contraception use. Among these pregnancies, 26.4% resulted in miscarriage, stillbirth, or intrauterine demise if not electively terminated, and 21.5% of live births involved major congenital anomalies. A separate Canadian study indicated that girls with type 2 diabetes were more likely to become pregnant during the transition period compared to those with type 1 diabetes. This highlights the importance of comprehensive counselling on family planning and contraception during the transition to adult care to reduce adverse maternal and fetal outcomes.
DPP-4 inhibitors, also known as gliptins, work by inhibiting the enzyme DPP-4, which degrades the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). By preventing their degradation, these inhibitors enhance the activity of endogenous incretins. GLP-1 receptor agonists, such as exenatide, are also used therapeutically in the management of diabetes through subcutaneous injection.
Glycemic control in people with HbA1c higher than 9%, blood pressure control in individuals with pressure exceeding 160/95 mmHg, and foot care for those at high risk of ulcers are all cost-saving interventions for diabetes management. Lifestyle interventions, metformin use, and screening for undiagnosed diabetes are additional strategies for preventing and managing type 2 diabetes. Other cost-saving or cost-effective measures include preconception care, annual eye examinations, influenza vaccinations among the elderly, smoking cessation, ACE inhibitor use, cholesterol control for those with total cholesterol above 200 mg/dL, intensive glycemic control for individuals with HbA1c higher than 8%, and annual screening for microalbuminuria. These interventions vary in feasibility and implementation priority but collectively contribute to diabetes care and prevention.
Hyperglycemia-induced increases in polyol pathway flux are thought to contribute to tissue damage in diabetes through several mechanisms, including sorbitol-induced osmotic stress, decreased cytosolic Na/K+-ATPase activity, increased cytosolic NADH/NAD+ ratio, and decreased cytosolic NADPH. Although early theories suggested that intracellular accumulation of sorbitol could cause osmotic damage, current evidence shows that sorbitol levels in diabetic nerves and blood vessels are too low to induce such effects. Another early hypothesis proposed that increased polyol pathway activity reduced phosphatidyl-inositol synthesis, leading to inhibition of Na/K+-ATPase activity. However, recent findings indicate that the decrease in Na/K+-ATPase activity observed in diabetes is actually due to hyperglycemia-induced activation of PKC, which promotes the production of two inhibitors of this enzyme: arachidonate and prostaglandin E2.
Managing type 1 diabetes in young children and young people involves addressing unique challenges such as balancing the risk of hypoglycaemia, which is complicated by factors like the child's developmental stage, unpredictable dietary intake, irregular activity levels, emotional maturity, and behaviour.
Reactions to insulin were previously common due to impurities from cow or pig proteins, preservatives, or additives, but the use of human and analogue recombinant insulin has reduced the incidence of insulin allergy to less than 1% of people with insulin-treated diabetes. Allergic reactions can be immediate-local, general, delayed, or biphasic. Immediate-local reactions occur within minutes of injection and involve erythema and urticaria, potentially Ig-mediated, and can be managed by switching to a more purified insulin product. Systemic reactions include generalized urticaria and rarely anaphylaxis, with generalized urticarial reactions to purified insulins being uncommon, though some individuals sensitized to animal insulins may experience anaphylaxis with human insulin. Delayed hypersensitivity reactions are the most frequent, appearing around two weeks after starting insulin therapy and manifesting as itchy nodules at injection sites 4–24 hours post-injection. Biphasic responses, involving immediate urticaria followed by a delayed reaction, are considered Arthus-immune complex reactions, and hypersensitivity may be triggered by insulin itself or preservatives such as aminobenzoic acid or zinc. Management options for allergic reactions include antihistamines, glucocorticoids, discontinuation of insulin therapy, or changing the insulin delivery system.
Iatrogenic hypoglycemia, often underestimated due to missed asymptomatic episodes and poor recall of symptomatic ones, is a common complication in diabetes management. Symptomatic episodes may not be recognized as hypoglycemia, leading to underreporting. Severe hypoglycemia, although a small fraction of total hypoglycemic events, is more reliably reported because it involves dramatic incidents requiring assistance from another person. Population-based prospective studies focusing on hypoglycemia provide more accurate estimates of severe hypoglycemia frequency.
Hepatic insulin resistance is associated with NAFLD in lean individuals, particularly in young, healthy Asian Indian men who have a higher risk of hepatic steatosis. Certain polymorphisms (rs2854116 and rs2854117) in the ApoC3 gene predispose lean individuals of Asian descent to insulin resistance and NAFLD by increasing fasting plasma apolipoprotein C3 and triglyceride levels. Apolipoprotein C3 inhibits LPL activity, reducing triglyceride clearance and causing post-prandial hypertriglyceridemia and increased chylomicron remnants. This mechanism was observed in transgenic mice with hepatic overexpression of human ApoC3 fed a high-fat diet. The gene-environment interaction involving ApoC3 and hepatic steatosis occurs only in males, likely due to the protective effect of estradiol in females, and is not seen in individuals with obesity, where the dominant effects of obesity and insulin resistance overshadow this genetic influence.
During mild to moderate exercise under conditions of low insulin and normal blood glucose, individuals with type 1 diabetes (T1DM) can exhibit fuel selection patterns similar to those without diabetes, with a progressive increase in fat utilization as exercise continues. However, elevated insulin levels can cause muscle, fat, and liver cells to take up glucose for storage instead of making it available for active muscles. Although individuals with T1DM can still produce glucagon, the glucagon-to-insulin ratio in the portal vein may not be sufficient to support adequate liver glucose production. Compared to people without diabetes, those with T1DM may rely less on liver glycogen stores during low-intensity aerobic activity. If glucose appearance in the bloodstream cannot meet demand, blood glucose levels may fall, increasing the risk of hypoglycemia.
In Singapore, the prevalence of diabetes has increased significantly from 2% in 1975 to 9% by 1998, with more recent data suggesting a stabilization in the rate of rise. Certain ethnic groups, particularly Malays (especially women) and Indians, exhibit the highest diabetes rates, ranging from 14.3% to 16.7%, and also show the highest rates of obesity. Additionally, approximately 15% of adults in Singapore have impaired glucose tolerance (IGT). The rise in diabetes prevalence is closely linked to obesity and the adoption of a westernized diet and lifestyle. Type 2 diabetes mellitus (T2DM) in children has also emerged as a growing concern.
Glucagon and glucagon-like peptides are differentially processed in various tissues through the action of prohormone convertases (PC), with PC2 being the major convertase in pancreatic α cells responsible for glucagon release, while intestinal L cells primarily use PC1/3 to generate GLP-1, oxyntomodulin, and GLP-2. GLP-1 is particularly relevant in diabetes due to its role in glucose regulation, and there is increasing evidence for GLP-1 production by pancreatic islets. Additionally, glucagon has been reported to be produced by enteroendocrine cells after bariatric surgery, highlighting the complexity of proglucagon processing and its potential impact on diabetes management. Other proglucagon-derived peptides such as oxyntomodulin, glicentin, and major proglucagon fragment may also have signaling properties relevant to metabolic regulation.
Metformin, a drug commonly used in the context of severe mental illness (SMI), has been associated with a mean reduction in body weight of 3.3 kg over 3–6 months, although its long-term effectiveness for weight loss remains unclear; while metformin has minimal impact on body weight in the general population, it is the most extensively studied drug for managing weight in individuals with schizophrenia receiving antipsychotics, but no pharmacological diabetes-prevention trials in this population have been reported.
Glycemic control using continuous subcutaneous insulin infusion (CSII) pumps has been shown to be more effective than multiple daily insulin injections (MDI) in patients with type 1 diabetes mellitus (T1DM), resulting in 0.4–0.5% (5–6 mmol/mol) lower HbA1c levels. The improvement in glycemic control is more pronounced in individuals with initially poorer control. While earlier studies compared CSII with MDI regimens using NPH or ultralente insulins, more recent trials indicate that CSII remains superior even when MDI uses newer long-acting insulin analogs. However, complications of pump therapy such as ketoacidosis, device malfunction, and infusion site issues are not consistently reported in randomized trials, with historical data suggesting an increased risk of ketoacidosis linked to CSII, mainly from the 1980s.
Ethnicity may influence the impact of behavioural and demographic factors on physical activity and sedentary behaviour in people at high risk of type 2 diabetes, highlighting the need to adapt screening and lifestyle interventions to ethnic minority groups such as South Asians, though this is challenging due to low recruitment, retention, and follow-up in research trials, with community and faith centre-based approaches showing promise in reducing type 2 diabetes risk among South Asians in the UK.
Metformin decreases glucose levels by 10%, has a diabetes risk reduction of 45-48%, and reduces cardiovascular disease risk by 35%. Sulfonylureas (SU) show no glucose decrease and have an unknown diabetes risk reduction, with a 20% reduction in cardiovascular disease risk. Thiazolidinediones (TZD) reduce glucose by 8%, have a high diabetes risk reduction of 51-58%, and show variable cardiovascular disease risk reduction ranging from -10 to +43%. Statins do not affect glucose levels, reduce diabetes risk by 0-14%, and reduce cardiovascular disease risk by 20-55%. Fibrates reduce glucose by up to 6%, reduce diabetes risk by 0-23%, and reduce cardiovascular disease risk by 10-34%. Niacin increases glucose by 5%, has an unknown diabetes risk reduction, and reduces cardiovascular disease risk by 22-31%. Orlistat decreases glucose by 4%, reduces diabetes risk by 43%, and has an unknown effect on cardiovascular disease risk. Sibutramine decreases glucose by 4%, has unknown effects on diabetes and cardiovascular disease risk reduction.
Patients with diabetes are twice as likely to be admitted to hospital and stay twice as long, often due to diabetes mismanagement resulting from poor staff knowledge and lack of education; involvement of specialist diabetes teams, particularly diabetes inpatient specialist nurses, significantly reduces length of stay and insulin errors while improving patient experience, highlighting the importance of effective communication between patients, diabetes specialists, and non-specialist teams to ensure timely intervention and prevent glycemic deterioration during hospitalization.
Our understanding of the genetic basis of type 2 diabetes mellitus (T2DM) has advanced through genome-wide association (GWA) studies, which hold potential for improving diagnostics and therapeutics. However, many genes contributing to T2DM risk remain unidentified, as current findings explain only part of the familial inheritance of the condition. Most GWA studies are based on the "common disease/common variant" hypothesis, but an alternative "allelic heterogeneity" hypothesis suggests that rare variants with large effects may also play a role in disease susceptibility. Detecting such rare variants would require deep resequencing of known and novel T2DM loci in both diabetic and normoglycemic individuals, a process becoming more feasible with improved sequencing technologies. Additionally, structural variants like copy number variations, insertions, deletions, and duplications may contribute to genetic risk beyond single nucleotide polymorphisms. Emerging approaches involving epigenetics, multi-tissue gene expression, metabonomics, and metagenomics are expected to further expand our knowledge of T2DM in the coming years.
Fasting glucose can be affected by drugs, coexisting conditions, or improper fasting, making it less reliable in some cases. The oral glucose tolerance test (OGTT) is known to vary significantly within the same person over time and is especially unreliable when individuals are near the diagnostic threshold for diabetes. Despite these limitations, OGTT has historically been considered the gold standard for diagnosing diabetes, largely due to tradition and the lack of better alternatives. These issues have gained importance as more screening programs aim to identify people with asymptomatic diabetes.
In 2007, genome-wide association studies identified multiple genetic loci associated with type 2 diabetes mellitus (T2DM), including variants within or near SLC30A8, HHEX, CDKAL1, CDKN2A/2B, IGF2BP2, and JAZF1, with at least 15 loci consistently linked to T2DM risk. Among these, TCF7L2 was confirmed as the strongest genetic risk factor for T2DM in European populations. A significant single nucleotide polymorphism (SNP) within SLC30A8, which encodes a zinc transporter (ZnT8) highly expressed in pancreatic islets, was also identified. Overexpression of ZnT8 in cell lines leads to increased intracellular zinc accumulation and enhanced insulin secretion in β-cells, while not increasing sensitivity to zinc toxicity but rather conferring resistance to apoptosis after zinc depletion. A specific non-synonymous polymorphism in SLC30A8 causing an arginine to tryptophan substitution at position 325 is associated with an increased risk of T2DM and impaired β-cell function in vivo, potentially due to reduced zinc availability for insulin co-crystallization in secretory vesicles.
In the context of painful diabetic neuropathy, tramadol has been studied in a 6-week multicenter trial involving 131 patients, showing a 44% pain relief rate compared to 12% on placebo, with a maximum daily oral dose of 400 mg and a mean dose of 210 mg. Common adverse events included nausea and constipation, and the NNH of 7.8 for dropouts due to adverse events suggested notable toxicity. Additionally, in a 4-week study involving patients with neuropathy of various origins, including diabetes, tramadol demonstrated significant pain relief (NNT 4.3) and reduced mechanical allodynia. Possible mechanisms for its effectiveness include hyperpolarization of postsynaptic neurons via opioid receptors or a reduction in central hyperexcitability through monoaminergic or combined opioid and monoaminergic effects.
Hypertriglyceridemia is the most frequent lipoprotein abnormality found in uncontrolled diabetes, resulting from increased production or absorption of triglycerides or reduced catabolism due to decreased activity of lipoprotein lipase (LPL). In type 2 diabetes mellitus (T2DM), liver apolipoprotein B production, the major protein component of VLDL and LDL, is increased, indirectly caused by increased lipolysis in adipose tissue due to insulin resistance or insulin deficiency. This increased lipolysis leads to higher fatty acid release from fat cells and increased transport of fatty acids to the liver, which in turn modulates liver apolipoprotein B secretion, as suggested by studies in tissue cultures, animal experiments, and humans.
HbA1c upper target levels for diabetes management vary by country, with the USA and Australia recommending less than 7.0% (DCCT) or less than 53 mmol/mol (IFCC), while the UK suggests a target of less than 6.1% (DCCT) or less than 43 mmol/mol (IFCC) if safely possible.
A raised blood glucose has been the hallmark of diabetes mellitus for over 100 years, with the oral glucose tolerance test (OGTT) becoming widely used as methods for measuring blood glucose improved. The first WHO Expert Committee on Diabetes noted that glycosuria was an unsatisfactory diagnostic test, recommending instead the use of the 50-g or 100-g OGTT. They suggested that a fasting venous blood glucose level over 130 mg/dL (7.2 mmol/L), equivalent to about 150 mg/dL (8.3 mmol/L) in plasma, indicated the likelihood of diabetes, though at the time most blood glucose tests overestimated true glucose by at least 20 mg/dL (1.1 mmol/L). The committee placed most reliance on the OGTT, determining that the 2-hour value after the glucose load was sufficient for diagnosis, setting the threshold at 130 mg/dL (7.2 mmol/L) for venous whole blood, regardless of whether a 50-g or 100-g glucose load was used. They also introduced the concept of "borderline" diabetes, the precursor to impaired glucose tolerance (IGT), where 2-hour values were above normal but below the diagnostic threshold for diabetes, specifically between 110 mg/dL (6.1 mmol/L) and 129 mg/dL (7.2 mmol/L) for venous whole blood.
Recommendations for monitoring hyperglycaemia, weight gain, and dyslipidaemia were first published in 2004 by several medical associations, emphasizing regular screening for glucose and lipid abnormalities. Guidelines suggest obtaining personal and family history of diabetes, dyslipidaemia, hypertension, obesity, and cardiovascular disease, along with baseline measurements of glucose, lipids, blood pressure, and body mass index, followed by periodic reassessment. Fasting plasma glucose should be monitored at 12 weeks and then annually. If a person gains ≥5% of their baseline weight during treatment, switching to another second-generation antipsychotic is advised, with studies showing improved glucose levels after switching from olanzapine to aripiprazole.
Amyloid deposits are a pathological feature in people with diabetes and those with insulinomas, and amylin, isolated from these deposits, may have significant endocrine effects. Amylin is stored and secreted with insulin from beta cells, and type 1 diabetes is considered an amylin-deficient state due to beta-cell destruction, with both hormones playing complementary roles in regulating plasma glucose. Amylin physiologically inhibits appetite and gastric emptying and may suppress glucagon secretion after meals. Amylin analogues are developed to provide clinical benefits in managing glycemic levels, particularly postprandially, and body weight in diabetes treatment.
Patients with diabetes may be underrepresented or poorly defined in clinical trials related to congestive heart failure (CHF), leading to potential issues such as hidden diabetes, unclear glucose-lowering therapies, and selection biases that favor less severe cases. Despite these limitations, current data suggest that the efficacy of treatments is proportionately similar in patients with and without diabetes. However, because the overall prognosis is worse for those with diabetes, the absolute benefit of therapy, measured by the number of patients needed to treat to prevent an event like hospitalization for CHF or death, is lower in diabetic patients compared to non-diabetic individuals.
Subcutaneous or intravenous injection of adrenal gland extract in various animals can cause glycosuria lasting 48 to 72 hours, and this condition is accompanied by hyperglycemia, distinguishing it from renal diabetes or phlorizin-induced diabetes. This form of diabetes, referred to as adrenal diabetes, resembles true diabetes in nature but differs in the duration of its existence and lacks a tendency to progress, meaning it never reaches the terminal stage typical of severe human diabetes. The glycosuria caused by adrenal extracts has been regarded by some as a benign toxic glycosuria rather than a serious pathological condition.
α-glucosidase inhibitors are associated with gastrointestinal side effects, particularly when the dosage is too high relative to the amount of complex carbohydrate in a meal, leading to undigested oligosaccharides passing into the large bowel where they are fermented, causing flatulence, abdominal discomfort, and sometimes diarrhoea, though these symptoms often improve with slower titration and time. In the STOP-NIDDM trial, 31% of acarbose-treated participants discontinued treatment early compared to 19% on placebo. Hypoglycaemia is uncommon with these inhibitors, and there are no clinically significant drug interactions, although their use with agents affecting gut motility or cholestyramine is not recommended.
Elevated and fluctuating blood glucose levels contribute to the development of microvascular complications through several mediating pathways, including metabolic factors, haemodynamic factors, growth factors/cytokines, and intracellular factors. The innate immune system also plays a significant role in this process. These systems interact in complex ways, as illustrated in a schematic diagram, and are involved in the pathogenesis of diabetes-related complications such as kidney disease. Additionally, incretin drugs and sodium-glucose cotransporter 2 (SGLT-2) inhibitors may offer renoprotective effects in the treatment of type 2 diabetes.
Adipose tissue functions as a secretory organ that produces various factors contributing to insulin resistance and other health risks, with tumor necrosis factor α (TNF-α) being a key mediator in this process. TNF-α is a multifunctional cytokine expressed in adipose tissue, and its two receptor subtypes are overexpressed in obese individuals. The elevated TNF-α system impairs insulin signaling, inhibits glucose uptake, suppresses GLUT 4 expression, reduces lipoprotein lipase activity, and increases lipolysis. Additionally, TNF-α activates the NF-κB pathway in adipose tissue, leading to increased production of proinflammatory proteins such as interleukin 6 (IL-6), IL-8, and monocyte chemotactic protein 1 (MCP-1), which further contribute to the development of type 2 diabetes mellitus (T2DM).
TLK16998, a nonpeptide molecule that does not bind to the insulin receptor α-subunit, enhances insulin-induced phosphorylation of the insulin receptor β-subunit and potentiates β-subunit phosphorylation initiated by L-783,281. In cultured mouse 3T3-L1 adipocytes, low μmol/L concentrations of TLK16998 increase insulin-induced phosphorylation of IRS-1 and PI3K, promote translocation of GLUT-4 glucose transporters to the plasma membrane, and enhance glucose uptake during submaximal insulin stimulation. Additionally, TLK16998 administered at 30 mg/kg intraperitoneally lowers glucose concentrations in insulin-resistant obese-diabetic db/db mice.
Hyperglycemia activates the hexosamine pathway, leading to increased O-GlcNac modification of various proteins, including transcription factors like Sp1, which may alter the expression of glucose-responsive genes such as TGF-β1, PAI-1, and acetylcoenzyme A carboxylase. This post-translational modification can interfere with normal protein function and regulation, as seen in the inhibition of eNOS activity by O-GlcNacylation at the Akt site, potentially affecting vascular function in diabetes. Additionally, elevated glucose levels increase GFAT activity in aortic smooth muscle cells, further contributing to protein dysfunction through O-GlcNac modifications.
Fasting hyperglycaemia in women with GCK MODY is difficult to correct due to increased counterregulation, which causes them to stop producing insulin and instead produce counter-regulatory hormones when blood glucose is lowered to normal levels. This makes blood glucose control with insulin challenging, often requiring large insulin doses and leading to frequent hypoglycaemic symptoms even at non-hypoglycaemic glucose concentrations. Fetal genotype significantly influences birth weight, and when the fetus inherits the genetic variant, intensive insulin treatment may result in a low-birth-weight child, especially if the mother is normoglycaemic.
Gestational diabetes mellitus (GDM) and obesity frequently coexist, but most studies have failed to adequately control for population heterogeneity, screening, and treatment. The HAPO study, involving 23,000 untreated pregnant women, found that 16.1% had GDM by IADPSG criteria and only 25% of those with GDM also had obesity. Maternal BMI and glycaemia have similar independent and additive associations with adverse pregnancy outcomes, and maternal BMI is strongly related to fetal adiposity and hyperinsulinaemia even after adjusting for maternal glycaemia. Other factors such as triglycerides, free fatty acids, amino acids, and total caloric intake, as well as adipocytokines, inflammatory markers, and physical activity, may also influence fetal size and adiposity. Both maternal BMI and glucose levels are associated with increased frequency of caesarean section. Additionally, the effects of gestational weight gain on fetal outcomes are observed independently of HbA1c in pregnancies of women with type 1 diabetes and type 2 diabetes.
In individuals with overweight, initiating oral glucose-lowering therapy with metformin was associated with a 39% reduced risk of myocardial infarction compared to conventional treatment, and this benefit did not depend on the metformin dosage or its glucose-lowering effect. Metformin has also been shown to improve atherothrombotic risk markers, including reduced carotid intima-media thickness, increased fibrinolysis, and decreased levels of plasminogen activator inhibitor-1, independent of its effects on blood pressure or plasma lipids.
Excess delivery of fatty acids to muscle, which exceeds mitochondrial oxidation or storage capacity, contributes to obesity and lipodystrophy-associated muscle insulin resistance, a key factor in the development of type 2 diabetes. Activation of PKCε and PKCθ by plasma membrane-bound sn-1,2-DAG impairs insulin signaling by phosphorylating proteins involved in insulin action, such as the insulin receptor, IRS-1, and p70S6K, leading to insulin resistance. This resistance redirects ingested carbohydrates away from muscle glycogen storage toward hepatic de novo lipogenesis, promoting NAFLD, metabolic syndrome, and type 2 diabetes. In later stages of obesity, macrophage infiltration into white adipose tissue increases cytokines like TNF-α and IL-6, enhancing lipolysis and increasing fatty acid and glycerol flux to the liver. Elevated hepatic acetyl-CoA and pyruvate carboxylase activity, along with increased glycerol availability, amplify hepatic gluconeogenesis. This increased glucose production, combined with peripheral insulin resistance, leads to β-cell exhaustion, likely due to glucose toxicity, resulting in impaired glucose tolerance and progression to type 2 diabetes.
Long acting hypoglycaemic agents and metformin must be stopped, while short acting sulphonylureas such as glipizide and gliclazide may be started, and short acting insulin is effective for controlling blood sugar in cases of renal failure.
Several non-insulin parenteral therapies for type 2 diabetes are based on glucagon-like peptide-1 (GLP-1), a glucose-lowering and satiety-promoting hormone secreted by intestinal enteroendocrine L cells. GLP-1 receptor agonists (GLP-1RAs) are used in treatment algorithms for type 2 diabetes, addressing multiple aspects of its pathophysiology by improving glycemic control, reducing hunger, food intake, and body weight. The structural differences, pharmacokinetics, and size of various GLP-1RAs influence their effects on glycated hemoglobin (HbA1c), body weight, dosing frequency, and tolerability.
Diabetes in animals and humans, as well as hyperglycemia in cells, reduces the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis, particularly in cell types that experience intracellular hyperglycemia. This inhibition of GAPDH leads to an accumulation of upstream glycolytic intermediates, including glyceraldehyde-3-phosphate, which activates the AGE pathway by increasing the non-enzymatic formation of methylglyoxal, a major intracellular AGE precursor. Hyperglycemia-induced methylglyoxal formation has been shown to increase the expression of RAGE and its activating ligands S100 calgranulins and HMGB1. Preventing mitochondrial overproduction of superoxide, for example by UCP-1 or MnSOD, can block the inhibition of GAPDH by hyperglycemia.
Patients with diabetes have an increased risk of cancer, particularly pancreatic, hepatocellular, endometrial, breast, and colorectal carcinoma, which may be partly due to shared risk factors like obesity and diet; however, studies also show that cancer risk rises with higher fasting glucose levels, indicating a direct association.
Managing diabetes involves targeting specific glycemic, blood pressure, and lipid goals to reduce the risk of complications associated with the disease. Achieving optimal levels in each of these areas helps prevent both microvascular and macrovascular complications, such as retinopathy, nephropathy, neuropathy, heart disease, and stroke. Glycemic control is typically measured using HbA1c levels, with a commonly recommended target of less than 7% for many adults, though individualized goals may vary based on patient factors. Blood pressure management is crucial, with a general target of below 140/90 mmHg for most patients, as hypertension significantly increases cardiovascular risk. Lipid management focuses on controlling low-density lipoprotein (LDL) cholesterol, with a recommended target generally below 100 mg/dL, though more stringent goals may apply for high-risk individuals. Lifestyle modifications, including diet, physical activity, weight management, and smoking cessation, are foundational to achieving these targets, while pharmacologic therapy may be required to meet individualized goals. Regular monitoring and a multidisciplinary approach are essential for effective diabetes management.
Adiponectin, a hormone produced by adipocytes, enhances insulin sensitivity by promoting insulin receptor tyrosine phosphorylation and activating AMPK, while also exhibiting anti-inflammatory properties and improving vascular reactivity. Lower adiponectin levels are associated with increased adipose mass, and strategies to increase its levels, including analogs and receptor agonists, are being explored. The insulin-sensitizing effects of thiazolidinediones may be partly due to their ability to increase adiponectin production.
The prognosis for people with type 1 diabetes mellitus (T1DM) has improved significantly over the past 50 years, with median life expectancy increasing by over 15 years, largely due to reduced rates of diabetic nephropathy. Life insurance considerations for individuals with T1DM have shifted focus toward the risk of developing diabetic nephropathy, and a model has been proposed to calculate insurance terms based on factors such as current age, age at diagnosis, sex, presence of nephropathy or proliferative retinopathy, and other pre-existing conditions. As the risk of nephropathy declines after 25 years of diabetes duration, individuals who reach age 50 without nephropathy may qualify for reduced insurance premiums, a practice adopted by many insurance companies in Nordic and some other European countries.
Hypoglycaemia is more common in older individuals with diabetes due to factors such as comorbidities, geriatric syndromes, polypharmacy, long-standing diabetes, and increased prevalence of liver and kidney dysfunction. The incidence of severe hypoglycaemia varies in research findings, influenced by differing definitions and study population ages. A US retrospective study of over 19,000 Medicaid beneficiaries aged 65 years or older found an incidence of 1.23 episodes per 100 person-years among those using sulfonylureas and 2.76 episodes per 100 person-years for those on insulin therapy. However, the strict definition of severe hypoglycaemia as requiring hospitalization or resulting in death likely underestimates its actual occurrence, and the data were collected before evidence emerged in 1998 regarding the benefits of tight glycaemic control in type 2 diabetes.
Antidiabetic drugs include insulins and sulfonylureas such as glimepiride, as well as repaglinide, which are used to manage blood glucose levels. Certain medications can interact with sulfonylureas to enhance their effects, potentially increasing the risk of hypoglycemia. Some other drugs, such as quinolone antibacterials like levofloxacin and gatifloxacin, corticosteroids, aspirin in overdosage, ethanol, and non-selective β-adrenoceptor antagonists, can also influence blood glucose control. Additionally, drugs such as imatinib, pentamidine, and valproate in specific contexts may affect glucose metabolism or interact with diabetes management strategies.
Replacement of saturated fat with polyunsaturated fat is linked to a reduced risk of diabetes according to cohort studies, with stronger evidence for polyunsaturated fats compared to monounsaturated fats, potentially due to the association of monounsaturated fats with saturated fats in Western diets and better biomarker availability for polyunsaturated fat intake. Randomized controlled trials show inconsistent effects of saturated fat on insulin sensitivity, possibly due to variations in study design such as sample size, duration, and the macronutrient used to replace saturated fat.
CGM devices are categorized into real-time, intermittently scanned, and professional types, each measuring glucose levels continuously but differing in how and when data is displayed or accessed. Real-time CGM provides continuous display of glucose levels, intermittently scanned CGM shows values only when accessed by a reader, and professional CGM is used in a provider's office for assessing glycemic patterns over a set period. The recommended goal for time in range (70–180 mg/dL; 3.9–10.0 mmol/L) is over 70%, with less than 4% time spent in hypoglycemia (<70 mg/dL; <3.9 mmol/L). An increase in time in range by 5% is linked to meaningful improvements in diabetes outcomes.
GLP-1 analogs such as exenatide and liraglutide are used in the treatment of diabetes, with liraglutide being resistant to DPP-4 degradation due to its palmitoyl fatty acid moiety binding to albumin, thereby prolonging its activity. DPP-4 normally cleaves N-terminal dipeptides from GLP-1 and GIP, which contain alanine or proline residues at the N2 position, reducing their effectiveness.
Genetic testing is recommended for neonatal diabetes to determine whether it is transient or permanent, particularly for cases diagnosed before 6 months of age, and optionally between 6 and 9 months. Testing focuses on genes such as KCNJ11, ABCC8, and INS using Sanger sequencing, with next-generation sequencing used if no variant is found. Identifying specific genetic variants influences treatment decisions. A genetic cause involving KCNJ11 or INS is found in approximately 7% of cases diagnosed between 6 months and 1 year, especially when autoantibody tests are negative. Early diagnosis and very low birth weight suggest the 6q24 locus. New screening methods, including dried blood spot cards to measure glucose, have been developed to detect hyperglycaemia and aid in early identification of neonatal diabetes.
Assessment of insulin secretion in vivo requires complex methods and sophisticated modeling analysis. Homeostasis model assessment B (HOMA-B) is a model-derived parameter reflecting β-cell function in the basal state and has been instrumental in describing the natural history of β-cell dysfunction in type 2 diabetes, particularly in the UK Prospective Diabetes Study (UKPDS). Individuals with type 2 diabetes already have significantly reduced β-cell function at diagnosis, which declines in a nearly linear manner over a 10-year follow-up period regardless of pharmacological treatment. This linear decline suggests that β-cell dysfunction may precede the development of hyperglycaemia by many years. The Belfast Diet Study also used HOMA-B to describe β-cell dysfunction in individuals who eventually developed diabetes.
The prevalence of diabetes varies globally, with rates in Western Europe at approximately 6–7%, rising to 10.5–11.1% in North America and the Caribbean, and reaching as high as 33% in some areas of the USA. Diabetes significantly increases the likelihood of hospitalization, with affected individuals having longer hospital stays and higher mortality rates compared to those without the condition. The presence of diabetes in hospitals is notable, with prevalence ranging from 8.3% to 31%, and a mean of 18.1% in the UK according to the 2019 National Diabetes Inpatient Audit. The economic burden of diabetes is substantial, accounting for over 10% of the UK's National Health Service budget in 2010, with hospital-related excess costs amounting to between 573 million and 686 million GBP annually. In the USA, diabetes accounted for 25% of the healthcare budget in 2017, representing 327 billion USD, a 25% increase from 2012 after adjusting for inflation.
JNK activity is increased in insulin-resistant states and during cellular stress responses such as endoplasmic reticulum stress, and has been implicated in the pathogenesis of insulin resistance in the metabolic syndrome and type 2 diabetes mellitus (T2DM). Evidence includes findings that high-fat diets increase Ser307 phosphorylation of IRS1 in wild-type mice but not in JNK1-/- mice, with JNK1-/- mice showing decreased adiposity, increased insulin receptor signaling, and improved insulin sensitivity.
Android obesity, characterized by upper body (truncal) adiposity and greater overall muscular development, is associated with an increased risk of developing diabetes, along with hypertension, atherosclerosis, and gout.
In individuals with type 1 diabetes mellitus (T1DM), plasma glucose levels remain low but there is no corresponding decrease in insulin, no increase in glucagon, and only an attenuated increase in epinephrine. In early type 2 diabetes mellitus (T2DM), plasma glucose is low with a decrease in insulin, an increase in glucagon, and an increase in epinephrine, similar to non-diabetic individuals. However, in late T2DM, plasma glucose remains low without a decrease in insulin, without an increase in glucagon, and with only an attenuated increase in epinephrine, resembling the hormonal responses seen in T1DM.
Men with type 2 diabetes and obstructive sleep apnea (OSA) have a higher prevalence of coronary artery diseases (61% and 44%, respectively) compared to those with type 2 diabetes without OSA (38% and 27%, respectively), and the prevalence of stroke is also higher in men with type 2 diabetes and OSA (15%) compared to those with type 2 diabetes and no sleep disorder (8%).
GLP-1 analogs are beneficial in treating type 2 diabetes mellitus (T2DM) as their regulation of insulin and glucagon secretion is glucose-dependent, thereby reducing the risk of hypoglycemia, particularly when used in combination with metformin or a glitazone. These analogs also promote weight loss, which is advantageous for many individuals with T2DM who are obese. Additionally, they require minimal self-monitoring of blood glucose compared to insulin therapy. However, it remains uncertain whether GLP-1 analogs can prevent β-cell failure or sustain significant weight loss over time.
Real-world evidence for DIY-APS (Do-It-Yourself Artificial Pancreas Systems) has shown overwhelmingly positive results, with studies reporting a mean time in range (TIR) of 77.5% and only 4.3% of time below 3.9 mmol/l among 80 OpenAPS users, although these findings are limited by small, self-selecting populations and subjective outcome measures. Users of DIY systems have also reported improved quality of life, with qualitative analyses of over 3000 tweets from 328 individuals or caregivers indicating reduced diabetes-related burden and distress. However, challenges remain, including technical and hardware limitations of older or out-of-warranty insulin pumps and concerns regarding the use of unregulated, unapproved algorithms. Healthcare professionals often hesitate to support DIY-APS users due to lack of familiarity with the systems or concerns about liability, although a recent UK survey found that 97% of practitioners believe they should learn more about DIY-APS to better support users.
Insulin glargine offers an alternative for initiating insulin therapy with an evening injection, as demonstrated in a 1-year European study comparing it to NPH insulin. In this study, subjects continued oral therapy while receiving bedtime insulin, aiming for a fasting blood glucose target of less than 120 mg/dL (6.7 mmol/L). The average insulin doses were similar between the two groups (23 units for glargine and 21 for NPH), and both achieved comparable HbA1c levels (8.3% or 67 mmol/mol for glargine and 8.2% or 66 mmol/mol for NPH). However, insulin glargine was associated with significantly lower rates of hypoglycemia, both overall (33% vs. 51%) and specifically at night (13% vs. 28%). Glargine also provided better glucose control in the afternoon and evening, likely due to its longer duration of action compared to NPH insulin.
The AACE/ADA recommends maintaining blood glucose levels between 140-180 mg/dL (7.8-10 mmol/L) for managing hyperglycemia in hospital settings, with potential benefits observed at the lower end of this range; however, targets below 110 mg/dL (6.1 mmol/L) are not generally recommended due to insufficient evidence, though they may be considered in specific patient groups under specialized care with adequate support.
Baseline hyperglycemia is linked to a higher risk of symptomatic intracranial hemorrhage after intravenous thrombolysis, with a dose-response relationship between serum glucose levels and hemorrhage likelihood, particularly evident when glucose levels exceed 11.1 mmol/L (200 mg/dL), resulting in a 25% incidence of symptomatic hemorrhage. When analyzing the presence of diabetes instead of glucose levels, diabetes was associated with an odds ratio of 3.61 for all hemorrhages and 7.46 for symptomatic hemorrhage.
Self-monitoring of blood glucose in individuals with non-insulin-treated type 2 diabetes is not consistently supported due to limited evidence of its effectiveness and cost-effectiveness, with guidelines advising against routine use. While some evidence suggests that glucose testing may improve glycaemic control in certain individuals, there is also evidence indicating that the data obtained are often not utilized effectively, and the benefits do not generally outweigh the costs. Blood glucose monitoring remains recommended in specific situations, such as when there are concerns about hypoglycaemia—particularly in those using sulfonylureas—or when HbA1c measurements are not feasible or do not accurately reflect glycaemic status.
Necrobiosis lipoidica diabeticorum (NLD) is a rare condition occurring in approximately 0.3% of diabetic populations, and while it is significantly more prevalent in individuals with diabetes, the exact relationship and etiology remain unclear. Early studies suggested that around two-thirds of patients with NLD had diabetes, typically type 1 diabetes mellitus (T1DM), with an additional 12–15% having abnormal glucose tolerance tests, although this may be an overestimation due to patient selection. More recent data from a retrospective study of 65 NLD patients showed that 11% had diabetes and another 11% had impaired glucose tolerance. NLD generally manifests in young adulthood or early middle age but has also been reported in childhood, and it affects women three times more frequently than men.
The prevalence of type 2 diabetes mellitus (T2DM) in China has increased rapidly, particularly due to urbanization, with historically low rates rising significantly over a short period. In the Da Qing area, diabetes prevalence increased from 1.0% in 1986 to 3.5% by 1994, and a 1994 survey across 19 provinces found an overall prevalence of 2.3% for diabetes and 2.1% for impaired glucose tolerance (IGT). Community-based studies between 1995 and 1997 showed age-standardized prevalence rates of 3.2% for diabetes and 4.8% for IGT, with higher rates in urban areas compared to rural regions. By 2000–2001, the prevalence of both diagnosed and undiagnosed diabetes reached 5.5%, with an additional 7.3% affected by IGT. A significant proportion of diabetes cases remain undiagnosed, with only 30% of the estimated 20 million diabetic individuals in China previously identified. Individuals with IGT or impaired fasting glucose (IFG) have an 11.7-fold increased risk of developing diabetes compared to those with normal glucose tolerance, highlighting the importance of early detection and intervention.
Reduced microbial exposure in recent decades has been linked to an increased incidence of immune-mediated diseases, including type 1 diabetes, according to the hygiene hypothesis. Some infections and microbial agents have been shown to reduce the incidence of autoimmune diabetes in experimental animals, and daycare attendance, which increases microbial exposure, has been associated with a lower risk of type 1 diabetes in early childhood, although findings are not entirely consistent. Enterovirus infections, which have become less frequent due to improved hygiene, are thought to potentially offer protection against type 1 diabetes, with decreasing maternal antibodies possibly contributing to the rising incidence of the disease. While most studies have not found a strong link between antibiotic use and type 1 diabetes risk, some suggest a weak association, particularly with broad-spectrum antibiotics and in children born by caesarean section. The gut microbiota is considered a potential influencing factor in type 1 diabetes, based on small studies, though larger research has found limited significant evidence.
Metformin, a medication used in the treatment of diabetes, is absorbed from the intestine into enterocytes via transporters such as organic cation transporter (OCT)-3, and then transferred into the bloodstream primarily through OCT-1 located on the basolateral side of the enterocytes. In the liver, metformin is taken up by hepatocytes via OCT-1 and OCT-3, and is excreted into bile through multidrug and toxin extrusion (MATE)-1 transporters. In the kidneys, OCT-2 facilitates the uptake of metformin from the blood into the tubular cells, while MATE-1, MATE-2, and OCT-1 are involved in its secretion into urine. Genetic polymorphisms in these transporters can influence the pharmacokinetics of metformin, potentially affecting its efficacy and safety in diabetes management.
The ADOPT study evaluated the effectiveness of three monotherapies—glyburide, metformin, and rosiglitazone—in maintaining fasting glycemia in patients with diabetes, showing that rosiglitazone was more effective than metformin, which was more effective than glyburide in maintaining HbA1c levels. Despite this, most patients in all three groups failed to maintain their HbA1c goals within four years, necessitating progression to combination therapy. The analysis was based on the time until the mean HbA1c within each treatment group exceeded 7% (53 mmol/mol) using a repeated measures mixed model.
Higher rates of incident ischaemic heart disease have been observed independently of the onset of type 2 diabetes, and women with prior gestational diabetes mellitus (GDM) have 1.95-fold higher odds of developing cardiovascular disease compared to those without GDM. The lifetime risk of cardiovascular disease following GDM is most significant in women who progress to overt type 2 diabetes, with a hazard ratio of 2.82, but an increased risk is also present in those who do not progress, with a hazard ratio of 1.41. Additionally, women with hyperglycaemia not meeting diagnostic thresholds for GDM still show a higher risk of cardiovascular disease, possibly due to meeting more stringent criteria such as IDAPSG/WHO guidelines.
Gliptins (sitagliptin, vildagliptin, and saxagliptin) act as prandial insulin secretagogues by increasing the levels of endogenous incretin hormones, particularly glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, which enhance nutrient-stimulated insulin secretion but are normally degraded by dipeptidyl peptidase 4, an enzyme inhibited by gliptins. These medications are weight neutral and have a low risk of interprandial hypoglycemia when used alone, and are commonly combined with metformin or a thiazolidinedione in the treatment of diabetes.
Sulfonylureas are commonly used in the treatment of diabetes, either as monotherapy or in combination with other antidiabetic agents such as metformin, thiazolidinediones, or α-glucosidase inhibitors. They can also be combined with incretins, DPP-4 inhibitors, or insulin in certain cases. Combining sulfonylureas with other glucose-lowering medications typically results in additive efficacy in lowering blood glucose levels, although this effect may diminish over time and is associated with an increased risk of hypoglycemia. The effectiveness of combining a sulfonylurea with another insulin secretagogue depends on their differing mechanisms of action on the β-cell. However, meglitinides, which are prandial insulin secretagogues acting via the SUR1 complex similar to sulfonylureas, generally do not provide additional benefit beyond adjusting the dose of sulfonylureas, except in specific situations involving unusual meal patterns where timing of the two agents may be optimized.
High glucose concentrations in cultured rodent embryos lead to decreased inositol uptake and inositol deficiency, which can result in malformations. Supplementing inositol in high glucose environments or adding it to the diet of diabetic pregnant rodents helps protect against glucose-mediated malformations. Inhibiting inositol uptake in rodent embryos causes inositol deficiency and developmental abnormalities, but these effects can be reversed by adding inositol. Antioxidants reduce embryonic malformations caused by both hyperglycemia and inositol uptake inhibitors, indicating a potential connection between oxidative stress and diabetes-related developmental issues.
In type 2 diabetes mellitus (T2DM), microalbuminuria increases the risk of complications two- to fourfold, while proteinuria increases the risk ninefold. When serum creatinine levels become abnormal, cardiovascular risk rises exponentially. The prognosis for individuals with T2DM who develop end-stage renal disease (ESRD) is poor, with approximately 20–25% dying within the first year of dialysis and nearly all within 4–5 years.
In type 2 diabetes mellitus (T2DM), the secretion of incretins such as glucagon-like peptide 1 (GLP-1) in response to meals is reduced. Supraphysiologic levels of GLP-1, achieved through intravenous infusion or subcutaneous injection, lower both fasting and postprandial glucose concentrations in individuals with T2DM. This effect occurs through increased insulin secretion, inhibition of glucagon secretion, and delayed gastric emptying. However, GLP-1 does not appear to affect insulin action or glucose effectiveness in T2DM.
ACE inhibitors may be used in diabetes-related hypertension, even in cases where the general RAAS is not activated, as the drugs may interfere with local angiotensin action in specific target tissues.
During exercise in children without diabetes, there is a decrease in pancreatic insulin secretion and an increase in counter-regulatory hormones, which raises liver glucose production and matches skeletal muscle glucose uptake, maintaining stable blood glucose levels. In children with type 1 diabetes, the lack of pancreatic insulin regulation and possible impaired counter-regulation increase the risk of both hypoglycaemia and hyperglycaemia during exercise. Managing exercise in type 1 diabetes involves tracking insulin doses, exercise details, blood glucose levels, snacks, and hypoglycaemic episodes. Factors influencing the glycaemic response to exercise include duration, type, intensity, and timing of activity, overall glucose control, insulin type and timing, food intake, muscle mass and conditioning, and stress levels.
Patients with proliferative diabetic retinopathy exhibit increased psychiatric symptomatology compared to those without retinopathy, and this may be influenced by both the level of visual acuity and the duration of the condition.
The HYPO score and lability index (LI) are tools used to assess the severity of hypoglycemia and glycemic lability in patients with diabetes. The HYPO score incorporates both self-monitored glucose levels over four weeks and patient-reported hypoglycemic episodes from the past year, assigning higher scores for more severe episodes such as those with lower glucose values, absence of symptoms, neuroglycopenic symptoms, or the need for external assistance. The LI is derived from glucose readings over four weeks, factoring in the number of readings, glucose values, and time intervals between measurements. These scores are used in evaluating candidates for transplant and monitoring patients post-transplant. The Clarke score is another commonly used measure, where a score of four or higher suggests hypoglycemia unawareness.
Anxiety disorders in individuals with diabetes have shown mixed associations with glycaemic management. While some studies indicate no direct link between anxiety and glycaemic levels, others that use diagnostic interviews reveal a connection between anxiety and hyperglycaemia. Stress and anxiety are frequently tied to less effective diabetes self-management, and high anxiety levels are linked to perceived poor glycaemic control, more diabetes complications, and reduced quality of life. Research also shows that generalized anxiety disorder and panic disorder can be associated with persistent hyperglycaemia, though findings are inconsistent across studies. Methodological issues such as using self-report measures or cross-sectional designs may explain discrepancies. Longitudinal research found no direct impact of generalized anxiety disorder on BMI, HbA1c, smoking, or blood glucose monitoring, but lifetime anxiety disorder was connected to a higher risk of worsening depressive symptoms. A four-year follow-up study indicated that a notable proportion of those with anxiety disorders experience increased depressive symptoms over time.
Viral infections have been suggested as environmental triggers for type 1a (autoimmune) diabetes, with enteroviruses such as coxsackie B4, rubella, mumps, rotavirus, parvovirus, and cytomegalovirus being implicated. Although a direct causal link has not been definitively established, correlations exist between diabetes onset and prior viral infections, possibly involving mechanisms like molecular mimicry and Toll-like receptor activation. A dominant CD4 T-helper type 1 immune response may contribute to the diabetogenic process, whereas a T-helper type 2 response may offer protection. Reduced exposure to infections in early childhood, particularly in developed regions, may weaken the innate immune system's ability to regulate autoimmune responses, potentially explaining the rising prevalence of type 1 diabetes and supporting the "hygiene hypothesis."
During illness, blood glucose levels should be monitored more frequently, at least every 3–4 hours, and more often if they fall outside the target range of 80–200 mg/dL; urinary or blood ketones should be checked at least twice daily, especially when blood glucose exceeds 300 mg/dL (17.6 mmol/L), with blood ketone testing (β-hydroxybutyrate, using Precision Xtra/Exceed meter) preferred over urine testing for its greater specificity and timeliness in detecting ketosis.
Wnt/β-catenin signaling regulates IRS1 transcription, with Wnt3A or active β-catenin increasing IRS1 gene and protein expression, while suppressing this pathway decreases IRS1 levels. TCF4, part of the TCF/LEF family, binds to the IRS1 promoter to stabilize Wnt/β-catenin signaling, and TCF/LEF response elements in the IRS1 promoter region mediate this regulation. Inhibiting TCF4 reduces IRS1 mRNA and protein levels, indicating that the β-catenin/TCF4 pathway controls IRS1 at the transcriptional level. Since Wnt signaling influences IRS1 expression in perivenous hepatocytes involved in lipogenesis, Wnt agonists may offer a therapeutic approach to modulate glucose homeostasis in type 2 diabetes.
The regulation of human β-cell function involves islet α cells and δ cells through multiple communication mechanisms, including gap junctions, cell-surface adhesion molecules such as E-cadherin and ephrins, and interactions with the extracellular matrix via integrins, all of which influence β-cell gene expression, proliferation, survival, and function. Additionally, intra-islet paracrine and autocrine effects mediated by substances like insulin, glucagon, somatostatin, neurotransmitters, peptides such as kisspeptin, GLP-1, and Ucn3, as well as adenine nucleotides and divalent cations co-released with insulin, contribute to β-cell regulation. These complex interactions are essential for coordinating hormone secretion in response to physiological conditions, although current experimental models using isolated islets may not fully represent the in vivo environment due to the absence of microcirculation.
Rapid-acting insulin analogues are more effective than soluble human insulin in insulin pumps, as they better mimic the first-phase insulin release after meals and reduce the risk of post-prandial hypoglycaemia. However, these analogues still require administration at least 10–15 minutes before meals to effectively control post-prandial glucose levels, with a longer lead time needed if pre-prandial blood glucose exceeds 150 mg/dl (8.3 mmol/l). Challenges in adherence include difficulties in timing insulin with meals, particularly in young children, picky eaters, and individuals with poor organization skills, often leading to issues such as infrequent blood glucose testing, failure to respond to high blood glucose, incorrect carbohydrate counting, or missed boluses. To address unpredictable meal sizes, a split bolus approach may be used, delivering half the usual bolus before the meal and the remainder afterward if needed.
Increased physical activity is linked to fewer diabetes-related complications in individuals with type 1 diabetes, although its effects may vary by complication and gender, as physical activity in men has been inversely associated with the risk of nephropathy and neuropathy but not retinopathy, and a retrospective analysis of the DCCT trial found no significant impact of baseline physical activity on the progression of retinopathy, nephropathy, or neuropathy after 6.5 years of follow-up.
Activation of FFAR1 (GPR40) and GPR119 receptors enhances insulin secretion through different mechanisms: FFAR1 agonists increase cytosolic Ca²⁺ to initiate and potentiate insulin release, while GPR119 signals via adenylate cyclase to raise cAMP and boost nutrient-induced insulin secretion. These receptors are also expressed in enteroendocrine cells, where their activation increases the incretin effect by promoting secretion of GIP, GLP-1, and PYY, which enhances satiety. FFAR1 activation on pancreatic α cells may reduce glucagon secretion, whereas GPR119 agonists can increase glucagon levels. FFAR4 (GPR120) agonists improve insulin sensitivity, glucose tolerance, and reduce ectopic fat, making them a potential therapeutic target for diabetes. However, the widespread expression of fatty acid receptors complicates targeting their effects to specific tissues.
Late diagnosis of diabetes is more common in ethnic minority groups, particularly among South Asians, and is associated with higher glycated haemoglobin (HbA₁c) levels. Among individuals with known diabetes, Pakistanis, Indians, and Bangladeshis tend to have higher glycaemic levels.
Bariatric surgery can improve type 2 diabetes management by increasing circulating glucagon-like peptide 1 (GLP-1) levels, which decrease appetite, slow gastric emptying, and enhance insulin sensitivity and glycaemic control. Current guidelines suggest that bariatric surgery may be a therapeutic option for individuals with type 2 diabetes and severe obesity (BMI >35 kg/m²), and should be considered for those with a BMI between 30 and 35 kg/m² when diabetes is poorly controlled by medical treatments or when multiple cardiovascular disease risk factors are present. However, the decision to perform bariatric surgery should take into account potential complications, patient acceptance, service availability, and cost.
HbA1c levels are influenced by glucagon, insulin, peptide YY, oxyntomodulin, gastrin, CCK, and xenin, with glucagon and gastrin showing an upward effect while insulin decreases HbA1c. Insulin also maintains β-cell mass and regulates glucagon secretion, and its deficiency leads to increased glucagon levels. Body weight is reduced by GLP-1 and oxyntomodulin, whereas gastrin and CCK promote weight gain. Energy expenditure is enhanced by glucagon, gastrin, and CCK, but GLP-1 has a neutral effect. Food intake is suppressed by GLP-1 and possibly by insulin, while GIP may influence it through other mechanisms. Pramlintide and ghrelin have uncertain effects on HbA1c and β-cell mass, respectively.
People with type 2 diabetes who have overweight or obesity often have comorbid non-alcoholic steatohepatitis (NASH), which is the most common liver disorder in Western countries and a leading indication for liver transplantation in the USA. Insulin resistance is a shared characteristic of type 2 diabetes and obesity and is considered a key pathogenic driver of NASH. Management of NASH is largely based on lifestyle modification and treatment of metabolic syndrome components due to the lack of disease-specific interventions to prevent progression to liver fibrosis and cirrhosis. Emerging evidence suggests that certain anti-diabetes drugs, including pioglitazone, GLP-1 receptor agonists (GLP-1RAs), and to a lesser extent SGLT-2 inhibitors, may have beneficial effects on NASH. Pioglitazone has been associated with reductions in hepatic steatosis and lobular inflammation but not fibrosis improvement. Liraglutide and semaglutide have shown histological resolution of NASH and halted fibrosis progression. Magnetic resonance-based studies suggest potential benefits for dulaglutide and SGLT-2 inhibitors like canagliflozin, dapagliflozin, empagliflozin, and ipragliflozin. The American Association of Clinical Endocrinology recommends pioglitazone or GLP-1RAs for people with type 2 diabetes and biopsy-proven NASH, and these drug classes, along with SGLT-2 inhibitors, may offer cardiometabolic benefits in those with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).
In type 2 diabetes, statins have more modest effects on atherogenic dyslipidaemia, reducing triglycerides by up to 30% and increasing HDL cholesterol by less than 10%. Despite challenges in distinguishing individual benefits of interventions affecting multiple lipid fractions, a residual benefit of 9% per 1 mmol/l reduction in triglycerides has been observed after excluding the effects of omega-3 fatty acids.
Elderly diabetics often suffer from poor eyesight, sensory loss, and limited mobility due to arthritis, making it difficult for them to monitor their foot health. Approximately 20% of diabetic hospital admissions are due to foot-related complications. Preventive foot care education can significantly lower the risk of amputation. Those with visual impairments, peripheral and autonomic neuropathy, and peripheral atherosclerotic vascular disease are especially vulnerable to diabetic foot symptoms, with recurrent foot ulcers being a common issue.
Hyperglycemia-induced activation of PKC contributes to microvascular complications in diabetes by promoting the accumulation of extracellular matrix proteins such as TGF-β1, fibronectin, and type IV collagen in mesangial cells and glomeruli. This effect is associated with the inhibition of NO production by PKC. Additionally, PKC activation is linked to increased expression of plasminogen activator inhibitor 1 (PAI-1) and the activation of NFκB in endothelial and vascular smooth muscle cells, which may further exacerbate diabetic vascular pathology.
Skin reactions are commonly reported in individuals with type 1 diabetes using continuous subcutaneous insulin infusion (CSII) therapy, with itching being the most frequent issue, often leading to greater disease burden and emotional distress; these reactions are frequently attributed to adhesive tapes in insulin infusion sets, and may include complications such as erythema, pruritus, pain, scars, or lipohypertrophy, which can be exacerbated by inadequate disinfection of the insertion site or infrequent changing of the infusion set.
Environmental factors such as diet and exercise may influence DNA methylation and gene expression, though evidence linking this to the development of type 2 diabetes remains limited. Epigenetic mechanisms, however, could contribute to disease progression by inducing glucotoxicity in islets and increasing the risk of diabetes-related complications. Elevated glucose levels are essential for this process, as cells can retain a memory of glucose concentration changes. Long-term benefits of early metabolic control have been demonstrated in large studies like the UK Prospective Diabetes Study and the Diabetes Control and Complications Trial, showing reduced complication rates decades later. This phenomenon is explained by the advanced metabolic memory hypothesis, which suggests that glucose can trigger histone modifications in endothelial cells that persist over time, influencing the long-term course of the disease.
Inhibiting DPP-4 can enhance incretin action by preventing the rapid degradation of GLP-1 and GIP, leading to improved glycemic control. Although the increase in circulating GLP-1 agonist activity with DPP-4 inhibition is less pronounced than with receptor agonists like exenatide and liraglutide, the glucose-lowering effect of DPP-4 inhibitors such as sitagliptin and vildagliptin is comparable to that of injectable agonists. For instance, adding vildagliptin 50 mg once daily to metformin in patients with inadequate glycemic control (baseline HbA1c 7.7% [61 mmol/mol]) resulted in a significant reduction in HbA1c of -1.0 ± 0.2% (11 mmol/mol, P < 0.001) after 52 weeks compared to placebo.
ACE inhibitors such as Enalapril are beneficial in patients with diabetes and hypertension, showing equivalent blood pressure-lowering effects compared to other antihypertensive drugs. These inhibitors improve insulin sensitivity and glycemic control, reduce microalbuminuria and nephropathy in both normotensive and hypertensive individuals, and are also helpful in managing heart failure. However, they should be avoided in patients with renal artery stenosis, and may cause side effects such as cough, skin rash, angioedema, and rarely, postural hypotension especially in volume-depleted patients.
In diabetes, the lack of insulin leads to reduced translocation of GLUT4 to the plasma membrane, along with decreased mRNA levels and activity of hexokinase II (HKII) in muscle cells, impairing the ability of skeletal muscle to take up and utilize glucose after meals. To address this issue, a gene therapy approach has been developed that involves the co-expression of insulin and glucokinase genes in muscle cells, aiming to improve glucose disposal and counteract hyperglycemia.
Recognition and diagnosis of anxiety in diabetes are essential for effective management due to its prevalence, persistence, and negative impact. Although routine screening for anxiety in people with diabetes has not been evaluated, regular screening is recommended because effective treatments are available. The American Diabetes Association suggests screening at diagnosis, during periodic intervals, and when there is a change in disease status, treatment, or life circumstances, with inclusion of caregivers and family members in the assessment.
Psychological treatments such as cognitive behavioural therapy, problem-solving, and psychodynamic techniques have been used to address depression in individuals with diabetes, often delivered through in-person, web-based, or telephone-based formats. These interventions have primarily involved people with type 2 diabetes, with no trials focusing exclusively on type 1 diabetes. Meta-analyses indicate that psychological treatments are effective for depression with large effect sizes, and some evidence suggests they may also improve glycaemic control. Reported reductions in HbA1c levels are around 0.6% (6 mmol/mol), though other studies show less consistent effects with standardized mean differences ranging from 0.40 to −1.40. More recent findings indicate a small to moderate effect size (0.607; 95% CI 0.15 to 1.1) of psychotherapy on glycaemic levels in those with both depression and diabetes.
Tighter glycaemic targets have led to more frequent hypoglycaemic episodes, with insulin being the second most common medication associated with adverse events reported to the US Food and Drug Administration, showing a threefold increase in reported events from 1998 to 2005. Insulin was also the second most frequent medication linked to emergency department visits in individuals aged 65 years and older, with 95.4% of episodes related to hypoglycaemia, 24.1% involving loss of consciousness or seizure, and 25.1% requiring hospitalization. A prospective study of 3347 people with diabetes in Germany found an annual incidence of hypoglycaemia of any severity at 14.1%.
Trend arrows are used to guide insulin dose adjustments for people with diabetes, though recommendations vary. The Juvenile Diabetes Research Foundation (JDRF) and the Diabetes Research in Children Network Study Group (DirecNet) advise adjusting insulin doses by a percentage based on trend arrows, with a maximum adjustment of 20%. However, studies show that individuals often make larger adjustments, sometimes increasing insulin doses by over 100% when glucose levels are rising, while reducing doses by no more than 50% when levels are falling. Another method suggests adding or subtracting a fixed amount of glucose from the current reading to calculate a correction bolus, but this requires strong numeracy skills and may increase the cognitive burden on the person managing diabetes.
Hypoglycemia is the most common acute complication in the treatment of type 1 diabetes mellitus (T1DM) and accounts for a significant proportion of deaths in people with diabetes under 40 years of age. It is defined as plasma glucose below 70 mg/dL (4 mmol/L), while severe hypoglycemia, involving seizures or loss of consciousness, typically occurs with prolonged exposure to glucose levels of 40–50 mg/dL (2.2–2.7 mmol/L) or lower. On average, one in five children with diabetes experiences severe hypoglycemia annually, with 80% of such events occurring in 20% of children who have recurrent episodes. Risk factors include younger age, longer diabetes duration, barriers to care, and the presence of psychiatric disorders or a chaotic family environment. Although lower HbA1c levels are generally associated with increased hypoglycemia risk, appropriate intensive insulin therapy can reduce this risk by better aligning insulin administration with food intake and physical activity.
Absolute or relative insulin deficiency in type 1 diabetes mellitus (T1DM) leads to increased free fatty acid (FFA) availability for oxidation, which impairs peripheral glucose uptake and can acutely stimulate endogenous glucose production. Elevated FFA levels also promote ketogenesis, contributing to ketoacidosis. Insulin normally counteracts the lipolytic effects of other hormones such as growth hormone and cortisol, but when insulin levels are low, these hormones can significantly increase lipolysis. Similarly, catecholamines have a reduced lipolytic effect under hyperinsulinemic conditions but an enhanced effect during hypoinsulinemia. While glucagon does not directly affect systemic FFA availability, its elevated levels in uncontrolled diabetes may promote hepatic ketogenesis.
Stress hyperglycemia, often resulting from elevated catecholamine and cortisol levels, can complicate presentations similarly to established diabetes, particularly in the context of acute myocardial infarction (AMI), where both conditions are associated with increased mortality. In a study of patients with AMI, 3-year mortality was 52% in those with stress hyperglycemia (defined as admission blood glucose >7.0 mmol/L) compared to 42% in those with established diabetes, while those with normal glucose levels had a 3-year mortality rate of 24%. A meta-analysis confirmed these findings, showing a 3.9-fold increased risk of death with stress hyperglycemia and a 1.7-fold increased risk with established diabetes. The DIGAMI study demonstrated that reasonable glycemic management (blood glucose <10 mmol/L) in patients with no prior insulin therapy and low coronary risk factors led to a 52% improvement in mortality, a group that likely included individuals with stress hyperglycemia. However, the study found no significant benefit of acute blood glucose control for individuals previously treated with insulin.
Early studies indicated that achieving normoglycaemia after successful pancreas transplantation with bladder drainage (PTA) could reverse histological lesions in established diabetic nephropathy over 10 years. Subsequent studies comparing PTA with intensive insulin therapy demonstrated improvements in proteinuria without significant changes in creatinine clearance, which is considered a positive outcome especially under immunosuppression. A large case series by Boggi et al. found that 54% of individuals with macroalbuminuria at baseline experienced a reduction to either microalbuminuria (18%) or normal levels (36%) after PTA. Those with an estimated glomerular filtration rate (eGFR) greater than 90 ml/min at baseline showed a faster decline in renal function (~ -4.9 ml/min/yr) compared to those with an eGFR below 90 ml/min (~ -2 ml/min/yr), likely due to the correction of hyperfiltration. Regarding the progression to end-stage renal disease (ESRD) after PTA, large studies reported five-year cumulative incidences of 3.5%, 12.2%, and 26.0%, and ten-year cumulative incidences of 21.8%, 29.9%, and 52.2% for individuals with baseline eGFRs of >90, 89–60, and <60 ml/min/1.73 m² respectively.
The ADVANCE trial evaluated the effect of a fixed dose of perindopril and indapamide on macrovascular and microvascular outcomes in individuals with type 2 diabetes, showing that the treatment group had a mean reduction in systolic and diastolic blood pressure of 5.6 and 2.2 mmHg respectively, which was associated with an 18% reduction in cardiovascular deaths and a 14% reduction in coronary events compared to the control group. No lower limit for blood pressure reduction appears to exist at which benefits related to cardiovascular outcomes are not observed, with a similar pattern reported for renal disease. The ACCORD trial tested the effects of lowering blood pressure below 140/90 mmHg on cardiovascular outcomes, aiming to determine if a systolic blood pressure reduction to 120 mmHg would further reduce cardiovascular events. In the ADVANCE-ON trial, after six years of follow-up, benefits on cardiovascular outcomes were still present among those originally assigned to blood pressure-lowering therapy, but there was no evidence that glucose lowering had long-term benefits with respect to mortality or macrovascular events.
Metformin reduces hyperglycaemia by decreasing hepatic glucose production, increasing peripheral glucose uptake, and enhancing glucose turnover, while also improving insulin resistance through enhanced receptor and postreceptor insulin signaling. It lowers hyperinsulinemia by reducing both fasting and post-prandial insulin levels, and may help stabilize body weight in obese individuals. Metformin decreases the progression of impaired glucose tolerance to type 2 diabetes and offers modest benefits in dyslipidaemia by lowering VLDL-TG and LDL while increasing HDL, although it may decrease free fatty acid oxidation. Additionally, it exerts antithrombotic effects by reducing fibrinogen, PAI-1, and platelet aggregation, improves endothelial function by decreasing vascular adhesion molecules, and has anti-atherogenic properties associated with reduced myocardial infarction, stroke, and carotid intima-media thickness, along with improved vascular reactivity and increased life expectancy.
Pregnancy alters insulin requirements due to changes in insulin sensitivity and glucose levels, necessitating frequent insulin dose adjustments and daily blood glucose monitoring. During the first trimester, insulin sensitivity is increased and glucose levels are lower, often leading to reduced insulin needs, which can be further influenced by pregnancy-related sickness and altered hypoglycemic awareness. From around 16 weeks onward, insulin resistance rises, causing a linear increase in total daily insulin doses by approximately 5% per week until 36 weeks, often doubling the daily dose compared to pre-pregnancy levels, and correlating with weight gain. In women using insulin pumps, both basal and bolus doses increase, with a greater proportional rise in bolus doses. Insulin needs typically stabilize toward the end of pregnancy, but a sudden decrease may signal placental insufficiency and could warrant early delivery. After childbirth, insulin requirements drop rapidly, with type 1 diabetic women requiring about two-thirds of their pre-pregnancy dose or one-third of the late-pregnancy dose by the third postpartum day, returning to pre-pregnancy levels by the end of the first postpartum week. For most women with type 2 diabetes or gestational diabetes mellitus who started insulin during pregnancy, insulin can be discontinued after delivery.
Blood glucose meters are more reliable at higher glucose levels, where small differences between values like 11 mmol/L and 14 mmol/L are less critical, and the goal is to significantly reduce plasma glucose. However, at lower glucose levels, particularly within the target range of 4–6 mmol/L, a 15% measurement imprecision can have greater consequences, with most readings below 4 mmol/L likely due to measurement variance rather than an actual hypoglycemic event.
Charcot joint is a destructive arthropathy that most commonly affects people with diabetes, particularly those with severe peripheral neuropathy, occurring in 0.1–0.4% of individuals with diabetes and potentially leading to severe foot deformity, disability, ulceration, and limb amputation. The condition progresses through several stages, beginning with an acute inflammatory phase marked by swelling, warmth, erythema, and sometimes pain despite sensory neuropathy, followed by progressive bone resorption, fracture, dislocation, and midfoot deformity known as the rocker-bottom foot. Early diagnosis may require MRI or bone scintiscan as plain radiographs can appear normal initially, but later stages show osteolysis and architectural disruption on imaging. The acute phase lasts 2–6 months, and the reparative phase, involving coalescence and reconstruction of bone, can last up to 24 months, during which abnormal load bearing from deformity may result in skin ulceration and secondary osteomyelitis.
Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous disorder accounting for 1–5% of all diabetes cases and is often undiagnosed. It can be identified through clinical factors and biomarkers such as age of onset, family history of diabetes in three consecutive generations, absence of insulin resistance and obesity, negative auto-antibodies, and C-peptide levels. Establishing an early molecular diagnosis helps tailor treatment to optimize blood glucose control and prevent long-term complications. Around 14 different genetic mutations are involved in MODY, with varying clinical presentations, extra-pancreatic features, complication risks, and treatment responses. The most common types are transcription factor-linked MODY (HNF1A, HNF4A, and HNF1B-MODY) and enzyme-linked MODY (GCK-MODY).
Type 1 diabetes and type 2 diabetes are two extremes of the diabetes spectrum, sharing similarities such as hyperglycaemia, insulin deficiency, and development of complications, but differing significantly in genetic factors. Notable genetic loci associated with both include PPARG Pro12Ala variant, MTNR1B, HNF1A, GLIS3, 6q22.32, and loci near the MHC involving HLA class II genes linked to about half the type 1 diabetes risk. Mechanisms underlying both types are intrinsically distinct, with type 2 diabetes risk SNPs being mostly randomly distributed in type 1 diabetes, except for the TCF7L2 gene SNP, which may protect against type 1 diabetes. Type 1 diabetes risk variants in BCAR1, GLIS3, and RAD51L1 are protective for type 2 diabetes, while those in C6orf173, COBL, and C10orf59 have concordant effects. APOC3 haplotypes increase the risk of type 1 diabetes and type 2 diabetes in lean individuals, but protect against type 2 diabetes in overweight individuals. Common variants in SLC30A8 increase the risk of type 2 diabetes, with rare variants offering protection, and SLC30A8 also acts as a major autoantigen in new-onset type 1 diabetes, eliciting 60–80% of autoantibodies.
Diabetes during adolescence and emerging adulthood presents unique challenges, including frequent alterations in glucose levels, expanding needs for self-care, and balancing diabetes care with schoolwork and social interests. Adolescents may experience body image concerns related to wearing diabetes devices and worries about peer awareness and comments. Psychosocial challenges include diabetes-related family conflict, disordered eating, depressive symptoms, and fear of hypoglycaemia or hyperglycaemia. As individuals transition into emerging adulthood, they face additional complexities such as understanding exercise and diabetes needs, possible gaps in medical insurance, recreational substance use, and negotiating diabetes tasks in new environments like college or first jobs. Maintaining consistent diabetes management becomes more challenging when moving away from family homes, and there is an increased need for self-advocacy and awareness of diabetes impact on relationships, family planning, and career development. Ensuring proper support from school staff, lecturers, and co-workers during emergencies remains important throughout these developmental stages.
Chinese patients with both chronic HBV infection and type 2 diabetes mellitus (T2DM) have a higher likelihood of developing end-stage renal disease compared to those with T2DM alone, with an 8.7% incidence versus 6.4% and a hazard ratio of 4.5, independent of other confounding factors; additionally, HBV-infected patients experience earlier onset of diabetes and a higher frequency of diabetic retinopathy at 28%.
Increased skeletal fragility in diabetes is associated with several mechanisms, including reduced bone mineral density, impaired bone microarchitecture, decreased bone formation, and increased bone resorption. Additionally, diabetes-related complications such as diabetic neuropathy and retinopathy contribute to an increased risk of falls and fractures. Advanced glycation end products accumulate in bone tissue, further compromising bone strength and elasticity.
SGLT-2 inhibitors such as dapagliflozin and empagliflozin have shown significant cardiovascular benefits in patients with heart failure with reduced ejection fraction (HFrEF), both in those with and without diabetes. In the DAPA-HF trial, dapagliflozin reduced the composite endpoint of cardiovascular death or worsening heart failure by 26%, lowered hospitalization for heart failure, and reduced death from cardiovascular causes. Similarly, empagliflozin in the EMPEROR-Reduced trial reduced the risk of hospitalization for heart failure or cardiovascular death by 25%, with consistent benefits observed regardless of diabetes status.
Aspirin therapy at a dose of 75–160 mg/day is recommended as secondary prevention in persons with diabetes, based on findings from the ASCEND trial which showed a 12% reduction in cardiovascular outcomes with a 4% bleeding risk in individuals with diabetes but without cardiovascular disease. For individuals with diabetes and acute coronary syndrome, treatment with a P2Y12 receptor blocker (ticagrelor or prasugrel) along with aspirin is recommended for one year, and also in those undergoing percutaneous cardiac intervention or coronary artery bypass grafting.
Increased activity of the hexosamine pathway in insulin target tissues, such as skeletal muscle, contributes to glucose-induced insulin resistance and is observed in patients with type 2 diabetes mellitus (T2DM). This pathway involves the enzyme glutamine:fructose-6-amidotransferase (GFA), which catalyzes the formation of glucosamine-6-phosphate and is influenced by glucose, insulin, and glutamine. The end-product of the pathway, UDP-N-acetyl-glucosamine, leads to O-glycation of proteins, affecting those involved in glucose-responsive and insulin-dependent transcription and signaling events, potentially contributing to the development of insulin resistance.
Ustekinumab is being tested in clinical trials for newly diagnosed type 1 diabetes, with one pilot trial evaluating different subcutaneous doses (45 or 90 mg) at various time points (0, 4, 16, 28, and 40 weeks or 0, 4, and 16 weeks) primarily assessing safety in 20 adults. Another phase II/III randomized trial involves 66 adults aged 18–25 years with newly diagnosed type 1 diabetes, administering an intravenous loading dose of ustekinumab (6 mg/kg) followed by seven subcutaneous injections of 90 mg over 48 weeks, with the primary outcome being the 2-hour C-peptide AUC during a mixed-meal tolerance test at 12-month follow-up.
Standardized islet autoantibody tests such as GAD65Ab, IA-2Ab, and ZnT8Ab are used to screen individuals at risk for type 1 diabetes to include them in clinical trials focused on preserving residual beta-cell function. Cell-mediated immunity analyses require further development and standardization to be applicable in such trials. HLA-DQ on chromosome 6 is the most significant genetic factor influencing type 1 diabetes risk, although the HLA class II heterodimeric proteins are necessary but not sufficient for disease development. Recent genome-wide association studies have identified numerous candidate factors for type 1 diabetes risk, but the environmental triggers of islet autoimmunity remain unknown, necessitating studies like The Environmental Determinants of Diabetes in the Young (TEDDY) to investigate potential triggers.
Antipsychotic trials are often underpowered to detect changes in incident diabetes, leading to reports of no differences in diabetes risk among various antipsychotics. Assessing blood glucose changes is a more sensitive method for evaluating metabolic effects, with studies showing a small but greater increase in glucose levels with olanzapine compared to other antipsychotics like amisulpride, aripiprazole, quetiapine, risperidone, and ziprasidone. Similar glucose increases have been observed with newer antipsychotics such as asenapine, iloperidone, and paliperidone. In treatment-naive individuals with first-episode psychosis, mean glucose changes over a year ranged between 0.2 and 0.5 mmol/L across different antipsychotics, with no significant differences between drugs. Despite the small magnitude of these glucose increases, they may lead to meaningful differences in diabetes incidence over the long treatment durations required for severe mental illness.
Sulfonylureas such as glibenclamide (glyburide) are more often associated with hypoglycaemia compared to shorter-acting alternatives like glimepiride. The use of long-acting insulin analogues, including glargine and detemir, as basal insulin in multiple daily injection regimens reduces the incidence of nocturnal hypoglycaemia in both type 1 and type 2 diabetes. Rapid-acting insulin analogues such as lispro, aspart, or glulisine used as prandial insulin also lower the risk of nocturnal hypoglycaemia, particularly in type 1 diabetes. Second-generation basal analogues like insulin degludec and insulin glargine 300U/ml have more consistent pharmacokinetic profiles and are associated with a lower risk of hypoglycaemia, especially nocturnal episodes, while achieving similar HbA1c levels compared to first-generation insulin glargine 100U/ml. In a randomized crossover trial, insulin degludec showed lower rates of symptomatic hypoglycaemic episodes in individuals with type 1 diabetes compared to insulin glargine 100U/ml.
Oral glucose-lowering drugs are categorized by their modes of action and target tissues, with availability and prescribing guidelines varying by country. Fasting hyperglycaemia is a major component of overall hyperglycaemia in type 2 diabetes and should be addressed with appropriate therapy. Post-prandial hyperglycaemic spikes are linked to cardiovascular risk, emphasizing the need to manage this aspect of blood glucose. Treating obesity can improve glycaemic control, and addressing insulin resistance is important due to its association with cardiovascular risk. At diagnosis, insulin resistance is typically well established and shows only modest progression over time. The progressive decline in beta-cell function after diagnosis contributes to worsening glycaemic control, making beta-cell preservation a key therapeutic goal. When beta-cell function deteriorates beyond the effectiveness of oral and non-insulin injectable agents like GLP-1 receptor agonists, insulin therapy should be initiated without delay.
Studies indicate that past psychopathology is the best predictor of future psychopathology in both children and adults with diabetes. Research by Lustman et al. found that 67% of adults with diabetes who had previously experienced depression remained depressed after 5 years, compared to only 15% of those initially nondepressed. Repeated depressive episodes were common among those initially depressed, with an average of 4.2 episodes over the follow-up period. Recurrence of depression was not linked to the duration of diabetes, type of diabetes, or development of complications, but was associated with a family history of psychiatric disorders. Another study noted that the severity of recurrent depressive episodes correlated with the presence of neuropathy at baseline, suggesting that the discomfort from neuropathy may act as a stressor triggering depression in susceptible individuals. The weak connection between diabetes-related factors and mood disorder recurrence implies that depression in people with diabetes is not solely a psychological response to the disease or its complications, but may be significantly influenced by genetic or constitutional factors.
The regulation of insulin secretion involves phospholipase C (PLC), which is activated by receptor agonists such as acetylcholine and cholecystokinin through the GTP-binding protein Gq. PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2) to produce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes calcium from the endoplasmic reticulum, while DAG activates protein kinase C (PKC), both of which enhance insulin secretion. Nutrients can also activate PLC in a calcium-dependent manner, although the role of IP3 and DAG in nutrient-induced insulin secretion remains uncertain.
GLP-1 strongly inhibits glucagon secretion, which is particularly relevant in patients with T2DM who exhibit fasting hyperglucagonemia and exaggerated glucagon responses after meals. Hyperglucagonemia contributes to hyperglycemia in these patients, making this inhibitory effect of GLP-1 potentially as important as its insulinotropic effects. The mechanism by which GLP-1 inhibits glucagon secretion is not fully understood, but evidence suggests that somatostatin-producing D-cells in the islets mediate this effect through paracrine inhibition of α-cells.
CTLA4 immunoglobulin (CTLA4-Ig), also known as abatacept, is proposed to regulate T-lymphocytes by inhibiting their stimulatory activation pathway, and was recently used in a randomized placebo-controlled trial to assess its effects on the progression of new-onset type 1 diabetes mellitus (T1DM) in patients aged 6–45 years.
IKB is a serine kinase that contributes to insulin resistance by inducing IRS serine phosphorylation, a mechanism also involved in the desensitizing effect of TNF-α on insulin signaling. Studies show that heterozygous ablation of the IKB gene in mice on a high-fat diet or in obese leptin-deficient ob/ob mice prevents insulin resistance. Mice with constitutively active IKB specifically in hepatocytes (LIKK mice) develop a type 2 diabetes mellitus (T2DM) phenotype characterized by hyperglycemia, significant hepatic insulin resistance, and moderate systemic insulin resistance affecting muscle. These LIKK mice also show elevated hepatic production of proinflammatory cytokines such as IL-6, IL-1β, and TNF-α, similar to levels seen in high-fat-fed wild-type mice. However, muscle-specific IKB knockout mice do not show differences in obesity-induced insulin resistance compared to wild-type mice, suggesting that IKB plays a more direct role in hepatic insulin resistance than in skeletal muscle.
Metformin is a commonly used medication for diabetes, and its pharmacokinetic and pharmacodynamic responses are influenced by genetic variants. The SLC22A1 gene encodes the organic cation transporter-1 (OCT-1), which plays a key role in metformin absorption, hepatic uptake, and renal excretion. Variants in this gene, such as rs622342 (AA), are associated with greater reductions in HbA1c levels in response to metformin compared to individuals with the minor C allele, likely due to reduced OCT-1 activity and decreased metformin transport. Other OCT-1 variants, including R61C, G410S, 420del, and G465R, have been linked to a lesser response to metformin. Additionally, the SLC47A1 gene encodes the MATE-1 transporter, which mediates metformin efflux in the kidneys and liver. A SNP in rs2289669 of MATE-1 has been associated with larger HbA1c reductions, potentially due to reduced MATE-1 function and decreased metformin efflux.
MIDD (Maternally Inherited Diabetes and Deafness) is associated with the m.3243A > G mutation, which is transmitted maternally. Individuals at risk include maternal relatives of affected patients and children of female patients, warranting periodic screening for diabetes and its complications. Paternal relatives and children of an affected male are not at risk of carrying the mutation.
BP goal in diabetes and chronic kidney disease is less than 130/80 mmHg.
It has been estimated from the 2002 US NHANES that one-third of the 13.3 million US adults with diabetes remained undiagnosed, and a similar estimate has been made for the UK, where in 2015, 940,000 people aged 16 years and over had undiagnosed diabetes according to the Diabetes Prevalence Model by Public Health England. NICE (2012, updated September 2017) recommends a two-stage strategy to identify people at high risk of type 2 diabetes and those with undiagnosed type 2 diabetes, involving a risk assessment followed by a blood test to confirm whether type 2 diabetes or pre-diabetes is present. Risk assessment can be carried out using validated computer-based risk-assessment tools from primary care electronic health records or validated self-assessment questionnaires for individuals over the age of 40 years, people of South Asian and Chinese descent aged 25–39 years, and any adults with conditions that increase the risk of type 2 diabetes, excluding pregnant women. Individuals with high-risk scores should undergo fasting plasma glucose or HbA₁c testing, which determines risk of progression to type 2 diabetes or identifies possible type 2 diabetes. Fasting plasma glucose ≥7.0 mmol/l or HbA₁c ≥48 mmol/mol (6.5%) indicates the need for a second test to diagnose type 2 diabetes, while fasting plasma glucose of 5.5–6.9 mmol/l or HbA₁c 42–47 mmol/mol (6.0–6.4%) indicates high risk, warranting management as pre-diabetes with an intensive lifestyle-change programme.
In type 1 diabetes, lower than normal bone mineral density (BMD) is observed at the hip and spine at the time of diagnosis, and this deficit occurs early in the disease course, possibly before clinical presentation. Longitudinal and cross-sectional studies suggest that BMD does not progressively decline in type 1 diabetes and that bone turnover markers are normal in middle-aged individuals with the condition. Deficiencies in insulin and other pancreatic β-cell hormones such as amylin and preptin, which play roles in skeletal homeostasis, may contribute to decreased BMD. Low IGF-I levels are linked to cortical bone loss in type 1 diabetes, and insulin deficiency alone does not fully account for the reduced BMD since insulin therapy does not normalize it. Lower body weight is also a potential factor, given the positive relationship between weight and BMD.
As children with diabetes grow into adolescence, parental involvement in diabetes management decreases with increasing autonomy, often leading to a deterioration in glycaemic control. Parents continue to play a key role in providing regular meals and managing hypoglycaemia, especially at night. Moving away from the parental home can create challenges for individuals with type 1 diabetes, particularly when living alone or relocating, due to potential social isolation, increased access to alcohol and recreational drugs, and the associated risks. Sexual activity may introduce concerns related to sexual health and pregnancy, and new forms of exercise may become more accessible. Additionally, individuals often lose contact with familiar healthcare professionals from their local diabetes center when they move, reducing immediate access to medical advice during a period of heightened need. Notably, "living alone" has been linked to a more than fourfold increased risk of mortality from acute metabolic complications of diabetes, as observed in the Diabetes UK Cohort Study.
Diagnostic criteria for diabetes in elderly subjects are similar to those in younger individuals, but mortality may be higher when diabetes is diagnosed based on a 2-hour glucose value compared to using fasting criteria alone. Additionally, isolated post-load hyperglycemia, where fasting glucose is normal (<7.0 mmol/L), is linked to increased risk of fatal cardiovascular disease and heart disease in elderly women.
Autonomic nervous system activity influences glucose homeostasis, with parasympathetic nervous system (PNS) outflow increasing insulin secretion during meals and enhancing glucagon secretion during hypoglycaemia. Simultaneously, sympathetic nervous system (SNS) outflow to the pancreatic islets inhibits insulin secretion while promoting glucagon release, contributing to the regulation of blood glucose levels. Additionally, SNS activation stimulates hepatic glucose production, which plays a role in restoring normoglycaemia during low blood sugar states.
SGLT-2 inhibitors are used in diabetes management, particularly when renal function is adequate, as indicated by an eGFR greater than 60 ml/min/1.73 m², to achieve glucosuric efficacy. These inhibitors have shown renoprotective effects in clinical trials, but their dosage should be reduced if eGFR persistently falls below 45 ml/min/1.73 m². Patients with diabetes using SGLT-2 inhibitors should be informed about the importance of hydration and potential side effects such as nocturia and genital infections. For individuals with type 2 diabetes treated with insulin, maintaining an adequate insulin dose is essential for various physiological functions beyond glucose regulation. Some SGLT-2 inhibitors are approved as adjunctive therapy with insulin in type 1 diabetes, emphasizing the need for sufficient insulin to prevent diabetic ketoacidosis. However, SGLT-2 inhibitors should be discontinued during pregnancy.
Addison disease is more prevalent in individuals with type 1 diabetes mellitus (T1DM), affecting approximately 1% of this population compared to 1 in 10,000 in the general population. The condition is associated with autoantibodies targeting 21-hydroxylase (21-OH), which are rare in the general population but found in 1–2% of those with T1DM. About 15% of individuals with these antibodies but no clinical symptoms of Addison disease will develop adrenal insufficiency within a few years. Progression begins with elevated plasma renin activity, followed by increased adrenocorticotropic hormone levels, decreased stimulated cortisol, and eventually abnormalities in basal cortisol. Screening for 21-OH autoantibodies in children with T1DM is recommended, with subsequent monitoring of adrenal function in those who test positive.
Glycated hemoglobin (HbA₁c) levels are now expressed using the International Federation of Clinical Chemistry standard in mmol/mol, with 6.5% and 7.5% corresponding to 48 mmol/mol and 59 mmol/mol respectively. For type 1 diabetes (T1DM), HbA₁c should be measured every 2-6 months depending on glycemic control and therapy changes, and patients are encouraged to self-monitor blood glucose frequently, especially with intensive glycemic control regimens. In type 2 diabetes (T2DM), HbA₁c monitoring is also recommended every 2-6 months, but self-monitoring of blood glucose is generally not cost-effective for well-controlled, non-insulin-treated patients unless there is adequate training, support, and a clear purpose for its use.
Poor perception of hypoglycemia in individuals with diabetes can be dangerous, particularly when drivers with diabetes overestimate their blood glucose levels and drive while hypoglycemic. Impaired awareness of hypoglycemia increases the risk of severe episodes and is a common cause for losing a driving license, though it is not an absolute contraindication to driving if frequent self-monitoring demonstrates sustained freedom from hypoglycemia.
Various agents have been studied for their potential to interfere with advanced glycation end-product (AGE) formation or the cross-linking of proteins by AGEs, including aminoguanidine, pyridoxamine, 2,3-diaminophenazine, OPB-9195, and tenilsetam, which act by scavenging reactive carbonyl intermediates. ALT-711 functions as an AGE cross-link breaker. Additionally, methods to block signal transduction through the receptor for AGEs (RAGE) include the use of RAGE antibodies, antisense oligodeoxynucleotides (AS-ODNs), or soluble RAGE. Clinical trials have investigated the effects of pyridoxamine in both type 1 and type 2 diabetes. In one trial involving patients with mild to moderate renal impairment, pyridoxamine reduced the rate of creatinine increase but did not affect urinary albumin excretion. In another trial with patients having more severe renal impairment, the treatment showed no benefit, suggesting that intervention should occur before significant organ damage develops.
Thiazolidinediones (TZDs) are insulin-sensitizing agents that act as ligands for the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ), improving glycemia and potentially ameliorating dyslipidemia, inflammation, and hypercoagulability associated with insulin resistance. They are of particular interest for their potential cardiovascular benefits in type 2 diabetes mellitus (T2DM). PPAR-γ, the target of TZDs, plays a role in lipid metabolism and inflammatory pathways, influencing adipocyte differentiation, fatty acid uptake and storage, and glucose uptake. PPARs, a nuclear receptor superfamily regulating gene expression, include three types: alpha, delta (or beta), and gamma, with PPAR-γ being most abundant in adipose tissue and also present in pancreatic beta-cells, vascular endothelium, and macrophages.
Hyperglycemia during diabetic pregnancies exposes fetal mitochondria to high levels of glucose-generated pyruvate, which can overwhelm the immature mitochondrial electron transport chain and lead to an overproduction of reactive oxygen species, primarily superoxide. This increased oxidative stress is considered a key mechanism by which elevated metabolic substrates like glucose, pyruvate, and hydroxybutyrate may act as teratogens, contributing to developmental abnormalities in the fetus. Animal studies, particularly in rodents, support the role of glucose as a major teratogen in this context.
Metformin reduces glucose levels by 10% and decreases diabetes risk by 47–48%, while also lowering cardiovascular disease (CVD) risk by 35%. Sulfonylureas (SU) show minimal impact on glucose and diabetes risk, reducing CVD risk by 20%. Thiazolidinediones (TZD) lower glucose by 8% and significantly reduce diabetes risk by 51–58%, though their effect on CVD risk is variable (10–(+43)). GLP-1 agonists reduce glucose by 10% and CVD risk by 11%, but their effect on diabetes risk is unclear. SGLT-2 inhibitors decrease glucose by 10–15% and reduce CVD risk by 12%, though their impact on diabetes risk is unknown. Orlistat lowers glucose by 4% and reduces diabetes risk by 43%, but its effect on CVD risk is uncertain. Other lipid-lowering agents such as statins, fibrates, niacin, ezetimibe, and PCSK-9 inhibitors have varying effects on cardio-metabolic syndrome components, with some showing potential benefits in diabetes and CVD risk reduction.
Small-molecule pharmacological agents targeting proteins in the insulin receptor or IGF-IR and related signaling pathways, such as tyrosine kinase inhibitors including EGFR inhibitors, can cause hyperglycaemia through off-target inhibitory effects on the insulin receptor, while other multikinase receptor inhibitors may lead to hypoglycaemia by potentially inhibiting insulin clearance. Inhibitors of intermediaries in the insulin signaling pathway, such as PI3K, Akt, and mTOR inhibitors, can induce severe insulin resistance and hyperglycaemia by blocking insulin-mediated glucose uptake. Immune checkpoint inhibitors, particularly anti-PD-1 monoclonal antibodies, can cause type 1 diabetes through destruction of pancreatic islet β cells and may contribute to a range of diabetes phenotypes including insulin deficiency, severe insulin resistance with lipodystrophy, or transient hyperglycaemia. Understanding these cancer treatment-related mechanisms is important for preventing diabetes-related complications and selecting appropriate diabetes management strategies.
In type 1 diabetes mellitus (T1DM), the relative risk of cardiovascular disease (CVD) is 1.2-fold higher in microalbuminuric patients and 10-fold higher in proteinuric patients compared to normoalbuminuric patients. The cumulative incidence of CVD by the age of 40 years is 43% in T1DM patients with diabetic nephropathy, compared to 7% in those without diabetic nephropathy, with a 10-fold increased risk of coronary heart disease and stroke. The risk of CVD is even higher in patients with end-stage renal disease (ESRD).
Diabetes services that are most adaptable to the needs of people with diabetes are often paediatric services with significant experience in diabetes health technologies and ecosystem development. Due to a growing shortage of endocrinologists, especially in rural areas, traditional clinical care models struggle to provide timely insulin adjustments necessary for managing type 1 diabetes effectively. Digital decision support systems can help overcome this limitation by enabling more frequent and prompt insulin dose adjustments either in person or remotely. Research has shown that frequent insulin dose adjustments guided by an automated, artificial intelligence-based decision support system are as effective and safe as those made by physicians in controlling glucose levels. This was demonstrated in a six-month, multicentre, multinational, parallel, randomized controlled non-inferiority trial involving 108 participants aged 10–21 years with type 1 diabetes who were using insulin pump therapy, where an automated decision support tool was used to optimize insulin pump settings.
RAGE, a receptor found on endothelial cells and monocytes-macrophages, is involved in diabetic macrovascular complications through its role in promoting inflammation and leukocyte recruitment.
The prevalence of diabetes is increasing due to ageing populations, lifestyle changes, and urbanization, with older individuals, especially those over 75 years, being particularly affected. Ageing contributes to body composition changes that increase insulin resistance and glucose intolerance, raising diabetes risk. The lifetime risk of developing diabetes from age 60 is 22.4% for women and 18.9% for men. Older adults with diabetes face a combination of metabolic dysfunction, vascular disease, and age-related disorders, with geriatric syndromes and frailty emerging as additional complications alongside traditional micro- and macrovascular issues. Diabetes in old age can lead to significant disability, and self-management of the condition may be hindered by comorbidities and geriatric syndromes. Given the diversity in comorbidity, life expectancy, and functional status among elderly patients, treatment and metabolic goals should be individualized, prioritizing quality of life and personal preferences in care planning.
Increased insulin resistance alone does not explain why some individuals develop diabetic ketoacidosis, which results from significantly impaired insulin secretion. Antipsychotics can influence insulin secretion through their interactions with multiple receptors, as blocking α₂ receptors may enhance basal insulin secretion, whereas blocking 5-HT₁a and 5-HT₂a/c receptors may reduce pancreatic β-cell responsiveness to blood glucose. Additionally, antipsychotics may interfere with central glucose homeostasis regulation and directly impair insulin action by inhibiting insulin-mediated glucose uptake and glycogen synthesis.
Recreational drug use among young adults with type 1 diabetes has been studied through uncontrolled questionnaire surveys, showing varying prevalence rates across different regions. In the UK, around 30% of respondents with type 1 diabetes reported using recreational drugs, with cannabis being the most common (28.2%), followed by amphetamine-type stimulants (13%) and cocaine (12%), and 15% using more than one drug. In the USA, a study of individuals aged 12–20 years with type 1 diabetes found a lower overall rate of recreational drug use at 23.4%, with cannabis again being the most prevalent. A separate study from Chile indicated that school-aged adolescents with type 1 diabetes had lower rates of drug use compared to the general population (9.6% vs. 22.2%), though this difference diminished in later school years. Under-reporting of drug use was noted as a significant factor in these studies, largely due to concerns about potential consequences.
In individuals with diabetes, glucose utilization for energy production is significantly reduced to about 10%, leading to a greater reliance on β-oxidation of free fatty acids (FFA), which increases oxygen consumption in the heart. This reduced glucose use stems from a slow rate of glucose transport across the sarcolemmal membrane and decreased glucose phosphorylation, both of which limit glucose entry into the cell and are exacerbated by increased FFA metabolism. Insulin deficiency further contributes to elevated FFA levels through enhanced lipolysis. People with diabetes also face additional cardiac challenges, including reduced myocardial blood flow, a blunted response to ischemia, and diminished myocardial function, which aligns with findings that congestive heart failure is an insulin-resistant state involving increased non-esterified fatty acid release that suppresses glucose uptake and utilization in muscle tissue.
Medical therapy for diabetes focuses on achieving normoglycaemia, particularly through intensive insulin regimens such as subcutaneous injections and external insulin pumps, as demonstrated in the Diabetes Control and Complications Trial (DCCT) for type 1 diabetes. The treatment goal was to maintain HbA1c levels below 60% (42 mmol/mol), which led to a 57% reduction in combined endpoints including non-fatal myocardial infarction, stroke, cardiac death, or revascularization procedures, primarily due to reductions in HbA1c levels.
The ventromedial nucleus of the hypothalamus contains neurons marked by expression of the cholecystokinin B (CCKB) receptor subtype that play a role in glucose homeostasis and diabetes pathogenesis. These neurons are involved in mounting counter-regulatory responses to neuroglycopaenia and contribute to setting the baseline blood glucose level (BDL_G) in mice. Silencing these neurons not only blunts the counter-regulatory response to low glucose but also reduces circulating glucose levels by 25% in normal mice. In diabetic mice with destroyed pancreatic β cells, silencing these neurons ameliorates hyperglycaemia, suggesting that activation of this neuronal subset is required for hyperglycaemia in severe insulin deficiency. The model proposes that impaired brain sensing of blood glucose levels leads to activation of these neurons, triggering neurocircuits that increase BDL_G, similar to the response during neuroglycopaenia. This mechanism does not exclude the roles of insulin resistance or β-cell dysfunction in type 2 diabetes, as declining brain responsiveness to glucose may occur alongside peripheral metabolic impairments, potentially sharing common mechanisms such as systemic and hypothalamic inflammation.
Islet amyloid polypeptide (IAPP), also known as amylin, is a 37 amino acid peptide that is a major component of amyloid deposits found in the islets of Langerhans in patients with type 2 diabetes mellitus (T2DM). Amylin is structurally related to calcitonin and calcitonin gene-related peptide (CGRP), and belongs to the same peptide family as adrenomedullin. It is co-localized with insulin in the secretory granules of pancreatic β-cells and is processed and released alongside insulin in a pulsatile manner. Amylin circulates in both glycosylated and non-glycosylated forms and is primarily cleared by renal metabolism. In healthy individuals, plasma amylin concentrations range from 4 to 25 pmol/L and are distributed similarly to insulin in plasma and interstitial fluids. Amylin is also present in the central nervous system and gastrointestinal tract. The gene for the amylin precursor is located on chromosome 12 and contains three exons and two introns. Functional amylin receptors are formed by the interaction of the calcitonin receptor and receptor activity modifying proteins.
Rates of severe hypoglycaemia, including convulsions and coma, have decreased by more than 50% in children and young people with diabetes over the last two decades according to population-based studies from Western Australia, Denmark, and Germany/Austria. Historically, lower HbA1c levels were associated with severe hypoglycaemia, but this link has weakened in recent years, as shown in a large longitudinal cohort study from Europe and Australia, which also found an annual reduction in severe hypoglycaemic coma rates by 2% in the European DPV cohort and 6% in the Western Australian cohort. Younger age, once a risk factor for severe hypoglycaemia, no longer appears to increase the risk despite improved glycaemic control. Additionally, a combined analysis from the US T1D Exchange and the DPV registry showed no increase in severe hypoglycaemic coma in children under 6 years old with HbA1c levels below 7.5% compared to those with higher HbA1c. Potential reasons for the decline in severe hypoglycaemia include better diabetes education, increased use of insulin analogues, and more frequent use of insulin pump therapy. Despite these improvements, hypoglycaemia remains a major concern for young people with diabetes and their families.
Thiazolidinediones, a class of anti-diabetes medications, are associated with an increased risk of heart failure, leading to recommendations against their use in individuals with heart failure. Clinical studies, including the PROactive trial, have shown that pioglitazone, a thiazolidinedione, can increase the risk of heart failure, with 11% of treated individuals experiencing events compared to 8% on placebo. Concerns over cardiovascular safety were further supported by analyses of muraglitazar and rosiglitazone, which also showed increased risks of heart failure and other cardiovascular events. These findings prompted the US Food and Drug Administration (FDA) to issue guidance in 2008 requiring new anti-diabetes medications to demonstrate cardiovascular safety through dedicated outcome trials.
Hyperglycaemic conditions may provide more fuel to cancer cells, although most cancer cells are capable of meeting their glucose demands even under normoglycaemic conditions. In vitro studies have shown that high-glucose conditions (25 mmol/l) can increase the proliferation of breast and pancreatic cancer cells compared to low-glucose conditions (5.5 mmol/l). High-glucose environments can also induce molecular changes in cancer cells and the tumour microenvironment, including alterations in signalling pathways, increased production of reactive oxygen species, promotion of angiogenesis, and epithelial-to-mesenchymal transition, which may contribute to cancer progression and treatment resistance.
Hyperglycaemia, whether measured by glucose or glycated haemoglobin (HbA1c), in the perioperative period is linked to poor outcomes, particularly in individuals not previously diagnosed with diabetes. These adverse outcomes include extended hospital stays, longer time in the intensive care unit (ICU), increased risk of urinary tract and surgical site infections, and higher mortality. Contributing factors to these outcomes include failure to identify individuals with diabetes or hyperglycaemia, presence of microvascular and macrovascular complications, complex medication regimens leading to insulin prescribing errors, increased susceptibility to infections, episodes of hypoglycaemia and hyperglycaemia, lack of or inadequate institutional guidelines for managing diabetes and hyperglycaemia during hospitalization, and insufficient knowledge of diabetes management among healthcare staff.
Diabetics should avoid refined carbohydrates like glucose, sugar, and sweets, while fat and proteins can be consumed normally unless otherwise restricted. Caloric needs vary based on activity level, with sedentary individuals requiring 30 kcal/kg body weight and hard workers needing 35 kcal/kg per day. Underweight individuals with diabetes may need higher calories, while obese individuals should consume fewer calories, typically 800–1200 kcal/day. A diet rich in vegetables and fiber is recommended, with a suggested calorie distribution of 12–20% from protein, 50–60% from carbohydrates, and 20–30% from fat, of which less than 10% should come from saturated fat. Diabetics should understand the importance of diet, and dietary adjustments should be made if blood sugar remains uncontrolled or if there is unintended weight loss or gain.
Poor control of blood glucose in individuals treated with insulin can result from several factors including poorly defined management plans, lack of coordination of care, inappropriate glycemic targets, insufficient therapeutic adjustments, overuse of sliding scales that are not optimized for control, and underutilization of insulin infusions, with fear of hypoglycemia being another significant contributing factor.
Monogenic diabetes, which results from single-gene variants, can be differentiated from type 1 and type 2 diabetes by specific clinical and biochemical features outlined in Table 20.1. These forms of diabetes may arise from genetic defects affecting β-cell dysfunction or insulin resistance, such as in inherited lipodystrophies and insulin receptor variants. Additionally, certain monogenic multisystem diseases like haemochromatosis and cystic fibrosis can also lead to diabetes, though they are discussed in other chapters. The classification and key features of monogenic diabetes are further detailed in Figure 20.1, while Figure 20.2 illustrates the role of these genes in β-cell physiology.
Sulfonylurea therapy is initiated with a low dose and often requires self-monitoring of blood glucose at least once daily during the first few weeks, particularly in individuals at higher risk of hypoglycaemia such as older adults, those living alone, or people operating machinery or driving. Those who have partially responded to lifestyle measures but still have mild fasting hyperglycaemia are more prone to hypoglycaemia when using sulfonylureas. The dosage is increased every 2 to 4 weeks as needed, though hypoglycaemia or early hypoglycaemic symptoms typically limit further dose escalation. If hypoglycaemia occurs before reaching the glycaemic target or if increasing the dose provides no additional benefit, it is recommended to revert to the previous dose or consider modifying the administration regimen or switching to another type of insulin secretagogue. When sulfonylureas as monotherapy fail to meet glycaemic targets, adding an agent that reduces insulin resistance, an SGLT-2 inhibitor, or an α-glucosidase inhibitor is typically considered. Notably, the maximum blood glucose-lowering effect of sulfonylureas is usually achieved at doses below the recommended maximum, suggesting that insulin secretion has already been maximally stimulated.
Hyperglycaemia-induced increases in polyol pathway flux are thought to contribute to tissue damage in diabetes through several mechanisms, including sorbitol-induced osmotic stress, decreased cytosolic Na/K+-ATPase activity, increased cytosolic NADH/NAD+, and decreased cytosolic NADPH. Initially, it was believed that the accumulation of sorbitol, which does not easily cross cell membranes, could cause osmotic damage, but current evidence shows that sorbitol levels in diabetic nerves and vessels are too low to induce such damage. Another early hypothesis proposed that increased polyol pathway activity reduced phosphatidylinositol synthesis, thereby inhibiting Na/K+-ATPase activity. While decreased Na/K+-ATPase activity is observed in diabetes, further research has shown that this is primarily due to hyperglycaemia-induced activation of protein kinase C (PKC), which promotes the production of two inhibitors of Na/K+-ATPase: arachidonate and prostaglandin E2.
Microbial metabolites can influence glycaemic levels by acting locally at the intestinal mucosa to regulate enteroendocrine cell function and incretin signalling, while the intestinal microbiome can also modulate bile acid composition and downstream pathways such as FXR and TGR5 to affect glycaemic control; additionally, the intestinal microbiota may contribute to the risk of type 1 diabetes by potentially triggering inappropriate immune responses that lead to autoimmune destruction of pancreatic beta cells in genetically susceptible individuals.
Acute complications of diabetes, such as recurrent diabetic ketoacidosis (DKA), can be predicted in children based on indicators of poor psychological functioning within the first year after diagnosis, particularly in girls who exhibit more behavior problems and lower social competence. Higher rates of DKA are also associated with family dysfunction, including greater family conflict and lower family cohesion, especially in girls, and this relationship is independent of HbA1c levels. Boys, in contrast, show lower rates of recurrent DKA but higher rates of recurrent hypoglycemia, which is not linked to psychosocial factors shortly after diagnosis. Family functioning continues to influence DKA risk even after several years of diabetes, with adolescents reporting parental negativity toward their diabetes regimen having a higher likelihood of experiencing DKA. The connection between early behavior problems and DKA in girls may be mediated by psychosocial factors like poor adherence, though conclusive evidence is still lacking.
Real-time continuous glucose monitoring (RT-CGM) in pregnant women with type 1 diabetes leads to improvements in glycaemic control, including a reduction in HbA1c levels, increased time in range, and reduced time spent in hyperglycaemia compared to standard care. Additionally, RT-CGM use is associated with lower incidence of large-for-gestational-age (LGA) infants, fewer neonatal intensive care unit (NICU) admissions lasting more than 24 hours, reduced neonatal hypoglycaemia, and shorter hospital stays. However, no significant benefit of CGM was observed in women planning pregnancy. There was no difference in severe hypoglycaemic episodes between the groups.
One percent of individuals with Type 1 diabetes die within the first year of diagnosis, and 33% die after 30 years. The risk of death is comparable to non-diabetics before the age of 20 but increases twentyfold after 20 years of diagnosis. Maintaining good glycemic control and managing other environmental factors may lead to optimal life expectancy.
Hypoglycemia is a significant adverse effect of sulfonylurea therapy in patients with type 2 diabetes mellitus (T2DM), potentially causing mild to severe impairment of neural or motor function, which can endanger both the patient and others, and may lead to a poor prognosis after a myocardial infarction. Patients on sulfonylureas should be educated on the prevention, recognition, and management of hypoglycemia. In the UK Prospective Diabetes Study (UKPDS), approximately 20% of patients treated with sulfonylureas experienced at least one episode of hypoglycemic symptoms per year, with severe hypoglycemia requiring assistance occurring in about 1% annually. Other studies report lower rates of severe hypoglycemia, ranging from 0.2 to 2.5 episodes per 1000 patient-years, and mortality risk from sulfonylurea-induced hypoglycemia has been estimated at 0.014 to 0.033 per 1000 patient-years. Risk factors for hypoglycemia include the use of longer-acting sulfonylureas, irregular meal patterns, concomitant antidiabetic medications especially insulin, excessive alcohol consumption, near-normal fasting glycemia, advanced age, and drug interactions.
The risk of type 1 diabetes is significantly increased by the concomitant inheritance of both HLA and non-HLA high-risk alleles and haplotypes through a synergistic effect. In individuals with type 1 diabetes, the HLA haplotype $\mathrm{DQ8}(DQA1^{*}0301 - B1^{*}0302)$ is commonly inherited with certain variants of $DRB1^{*}04$, particularly $DRB1^{*}04:01$, $DRB1^{*}04:04$, $DRB1^{*}04:05$, or $DRB1^{*}04:02$, but not with $DRB1^{*}04:03$ or $DRB1^{*}04:07$. Among these, $DRB1^{*}04:01$ confers a higher risk compared to $DRB1^{*}04:04$, while $DRB1^{*}04:03$ or $DRB1^{*}04:07$ shows a negative association with type 1 diabetes. The limited genetic differences between these alleles influence the structure of the heterodimeric proteins formed by the DRA-coded A-chain and the DRB1-coded B-chain, leading to variations in the physicochemical characteristics of the peptide-binding groove despite few amino acid substitutions. These amino acid substitutions appear to largely account for the contribution of $DRB1^{*}04$ variants to type 1 diabetes risk, and further research is needed to clarify how HLA region polymorphisms influence peptide binding and antigen presentation linked to the development of the first autoantibody, which serves as a biomarker for the initiation of islet autoimmunity.
For individuals with diabetes, proper preparation for travel includes ensuring access to necessary medical supplies and documentation. A diabetes annual review should be completed before prolonged travel, and travelers should carry a diabetes identity card or bracelet, a document stating their diagnosis and treatment, a letter from the insulin pump company regarding X-ray machines and scanners, and a copy of their repeat prescription. It is important to have medical insurance and an EHIC, as well as contact information for the insulin pump company care-line and current insulin pump settings. Essential equipment includes insulin vials or cartridges, syringes or pens with spare needles, a cool bag for insulin storage, a blood glucose meter with a spare meter and batteries, a ketone meter if used, a finger pricking device with spare lancets and a container for used needles, spare glucose sensors for continuous or flash glucose monitoring, and a spare insulin pump with extra batteries and consumables. For managing hypoglycaemia, quick-acting carbohydrates such as glucose drinks in screw-top containers, glucose tablets, or confectionery should be available, along with slow-acting carbohydrates like biscuits or cereal bars.
Treatment of hyperglycaemia is essential in managing type 2 diabetes to address acute symptoms and prevent chronic microvascular and macrovascular complications, though treatment is complicated by the disease's multivariable and progressive nature, including insulin resistance, declining β-cell function, and defects in other gluco-regulatory hormones and nutrient metabolism. People with type 2 diabetes often have overweight or obesity, significant comorbidities, and elevated cardiovascular and renal risks, requiring individualized care plans that emphasize lifestyle management from diagnosis, with prompt initiation of drug therapy if lifestyle changes are insufficient. Drug selection should ideally target underlying pathophysiology, often requiring combinations of agents for additive efficacy, including fixed-dose combinations for ease of use, while respecting contraindications and precautions. Metformin, a biguanide, is typically used as initial oral therapy, reducing hepatic glucose production, increasing intestinal glucose-lactate turnover, and enhancing skeletal muscle glucose uptake without causing hypoglycaemia or weight gain, and offering potential cardiovascular benefits; however, gastrointestinal side effects and the risk of lactic acidosis in certain conditions like severe renal insufficiency limit its use. Sulfonylureas stimulate insulin secretion via β-cell mechanisms but carry a hypoglycaemia risk, especially in older individuals, and require caution in hepatic or renal insufficiency. Meglitinides, taken before meals, reduce prandial hyperglycaemia with a lower risk of interprandial hypoglycaemia and are often combined with agents improving insulin resistance. DPP-4 inhibitors enhance the incretin effect by increasing GLP-1 levels, promoting insulin secretion and reducing glucagon release, are weight neutral, and have a low hypoglycaemia risk, commonly used with metformin or thiazolidinediones. SGLT-2 inhibitors promote glucosuria by reducing glucose reabsorption.
Self-monitoring of blood glucose helps individuals with diabetes achieve recommended glycaemic targets, often guided by $\mathrm{HbA_{1c}}$ levels, and also enhances their understanding of their condition and blood glucose management.
Thiazolidinediones, a class of medications used in the management of diabetes, have properties that lead to fluid retention, which can increase plasma volume by up to 500 ml, reduce haematocrit, and decrease haemoglobin concentration by up to 1 g/dl. These effects make thiazolidinediones contraindicated in individuals with evidence of heart failure. The criteria for exclusion based on cardiac status differ by region, with Europe excluding patients in New York Heart Association classes I through IV, while the USA excludes only those in classes III and IV. Clinical monitoring is essential, particularly for those at higher risk for cardiac failure and for patients experiencing significant initial weight gain. Despite the increase in fluid volume, these agents typically do not raise blood pressure and may result in a slight decrease.
Persistent hyperglycaemia in diabetes leads to sustained upregulation of pro-inflammatory genes such as p65 and MCP-1, contributing to macrovascular disease through mechanisms involving novel Set7 networks and immune-inflammatory pathways. Epigenetic regulation by Set7 in vascular cells is associated with increased oxidative stress, as indicated by elevated levels of 8-isoPGF2α, and vascular dysfunction in individuals with diabetes. Histone modifications linked to prior hyperglycaemia, including changes in H3K9 methylation at the p65 promoter and alterations in histone methyltransferases and demethylases like LSD-1, further influence inflammatory gene expression. Additionally, H3K9 hyperacetylation of genes such as HMOX1, IL-8, Cox2, TNFα, and MMP10 has been observed in vascular and immune cells in people with diabetes, highlighting the role of epigenetic changes in diabetes-related inflammation and vascular complications.
GLP-1 suppresses glucagon secretion in a glucose-dependent manner, slows gastric emptying, and promotes satiety, which can aid in weight loss for individuals with T2DM. GLP-1 levels are typically reduced in T2DM, although its ability to enhance insulin release remains intact. Subcutaneous administration of GLP-1 before meals can significantly lower postprandial blood glucose spikes in T2DM. However, GLP-1 is rapidly degraded by DPP-4 and cleared by the kidneys, resulting in a very short plasma half-life of less than two minutes, which limits its practicality as a therapeutic agent.
Stimulation of pancreatic β-cell receptors, including GIP (glucose-dependent insulinotropic peptide) and GLP-1 (glucagon-like peptide-1), enhances insulin secretion, as do activated β₂-adrenoceptors and antagonists of inhibitory Ω₂-adrenoceptors, suggesting potential therapeutic targets for improving nutrient-induced insulin release in diabetes.
Poor glycemic control, visceral obesity, diabetes duration, height, hypertension, age, smoking, hypoinsulinemia, and dyslipidemia are important etiologic factors associated with diabetic peripheral neuropathy (DPN), which is linked to lower extremity impairments like diminished position sense and functional limitations such as reduced walking ability. Surrogate markers of microangiopathy, including albuminuria, as well as DPN-specific markers like nerve conduction velocity and vibration perception threshold (VPT), may predict mortality in people with diabetes. Elevated VPT is also a predictor for the development of neuropathic foot ulceration, a leading cause of hospital admission and lower limb amputations in diabetic patients.
GLP-1(7-36) amide and glycine-extended GLP-1(7-37) are forms of the hormone glucagon-like peptide 1 (GLP-1) that circulate in the body, and they play a role in diabetes management; the enzyme dipeptidyl peptidase 4 (DPP-4) inactivates GLP-1 by removing the two N-terminal amino acids, His and Ala, which has implications for therapies targeting GLP-1 in diabetes.
In diabetic painful neuropathy that was unresponsive to drug treatment, electrical spinal cord stimulation (ESCS) with electrodes implanted between T9 and T11 resulted in more than 50% pain relief in 8 out of 10 patients, and exercise tolerance was significantly improved; complications of ESCS included superficial wound infection in two patients, lead migration requiring reinsertion in two patients, and "late failure" after 4 months in one patient who initially experienced pain relief.
In individuals with diabetes, hyperglycaemia selectively damages certain cell types despite widespread exposure to high glucose levels, due to differences in glucose uptake regulation. Cells such as vascular smooth muscle can reduce glucose transport when extracellular glucose is elevated, making them less susceptible to damage. In contrast, vascular endothelial cells do not adjust their glucose transport rate in response to high glucose, leading to intracellular hyperglycaemia and increased vulnerability to damage. These variations in susceptibility are partly attributed to tissue-specific differences in the expression and function of glucose transporter (GLUT) proteins.
Tight control of blood pressure delays the progression of retinopathy and nephropathy in diabetes, while elevated blood pressure accelerates the onset and progression of nephropathy. Blockade of the renin-angiotensin system, which counteracts the vasoconstrictor effects of angiotensin II, is a gold-standard treatment and a key component in managing microvascular complications such as retinopathy and nephropathy. Beyond its systemic and local hemodynamic effects, the renin-angiotensin system may also have non-hemodynamic effects through autocrine and paracrine actions, and the endothelin system is implicated in the development of microvascular complications in diabetes.
Erectile dysfunction in diabetes can be treated with intracavernosal injection therapy, transurethral alprostadil, vacuum therapy, or surgical insertion of penile prostheses, and sexual dysfunction in women with diabetes is twice as common as in those without diabetes, often linked to high or low blood glucose levels, depression, and body image issues. Although no licensed pharmacological treatments exist for sexual dysfunction in women with diabetes, PDE5 inhibitors may offer some benefit, and psychological interventions have not been studied. Contraception is important in diabetes due to the risks of unplanned pregnancies, and while most methods are safe, the oral contraceptive pill is recommended for its reliability and tolerance. Hormone replacement therapy can be considered short-term in women with diabetes without adverse effects on glycaemic or lipid levels.
Technology-based clinical support has been applied in diabetes care, particularly for retinal screening through mobile digital photography using fundal cameras, with images and reports transmitted via satellite or internet between peripheral and central sites. This approach has been successfully implemented in low-resource settings such as Africa and India. Additionally, primary care providers can receive clinical support from referral centers through information technology, as seen in South Korea where nurses send patients' glucose readings to endocrinologists for review and management advice. Such systems are expected to be extended to health workers in low-resource areas, aiding the development of universal IT-based diabetes management systems.
Hypoglycaemia is the most common acute complication in the treatment of type 1 diabetes, with severe hypoglycaemia contributing to a significant proportion of deaths in people with diabetes under 40 years of age. According to ISPAD guidelines, hypoglycaemic events are categorized into three tiers, with the least severe defined by a clinical hypoglycaemia alert threshold of 70 mg/dl (3.9 mmol/l), at which treatment should be initiated due to the risk of further glucose decline. A level below 54 mg/dl (3.0 mmol/l) is classified as clinically important or serious hypoglycaemia, where children may experience impaired hormonal counter-regulation and reduced awareness. Severe hypoglycaemia, defined by significant cognitive impairment requiring external assistance for treatment, occurs in approximately 6% of individuals with diabetes, though less severe episodes are more frequent. Risk factors for severe hypoglycaemia include lower socioeconomic status, race, younger age, longer diabetes duration, lack of private health insurance, and multiple daily insulin injections.
Studies of type 2 diabetes medical care have included short-term diabetes education covering pathophysiology, medication function, lifestyle guidelines, and self-care improvement through goal setting. The TODAY study monitored medication dosages, both injected and oral, and emphasized transitioning paediatric diabetes care to adult care while promoting consistent self-care practices. Before randomization, participants had to complete a 2–6-month run-in period with 6 to 12 clinic visits, demonstrating ≥80% medication adherence for at least six weeks, missing no more than two visits, and maintaining an HbA1c of <8% (<64 mmol/mol) for at least two months. Despite support such as appointment reminders and follow-up calls or texts, 24% of screened young adults failed to meet these run-in requirements and were excluded from the main trial.
ACE inhibitors are widely used to treat hypertension and heart failure in people with and without diabetes, and they reduce proteinuria as well as the risk of doubling serum creatinine or requiring dialysis or transplantation. Their protective effect on the kidneys supports their use in normotensive patients with early nephropathy.
Amylin, co-secreted with insulin by pancreatic β cells in response to glucose and fatty acid ingestion, acts on the gastric fundus, throughout the central nervous system, and on bone to suppress appetite, potentially influencing diabetes management through its role in regulating food intake and glucose homeostasis.
Erysipelas-like erythema in people with diabetes presents as well-demarcated patches of cutaneous reddening on the legs and feet and can be mistaken for erysipelas, though it lacks associated fever, leucocytosis, or elevated erythrocyte sedimentation rate. Cutaneous signs of ischemia in the lower limbs include cold or cyanosed feet, erythema, hair loss, and atrophy, with dependent rubor and delayed return of color after skin pressure indicating large-vessel disease. Individuals with diabetes who also have venous insufficiency and arterial disease are at high risk for non-healing ulcers, which often become superinfected and difficult to manage. Neuropathy contributes to lower-limb injury and ulceration due to impaired pain sensation, allowing repeated trauma and shear forces to cause skin breakdown without triggering protective responses. Diabetic foot syndrome, which includes vascular and neuropathic changes, affects 4% to 10% of individuals with diabetes and increases the risk of gangrene and amputation compared to those without diabetes.
Several clinical trials are investigating interventions aimed at preserving or improving insulin secretion in individuals with type 1 diabetes mellitus (T1DM), primarily measured through C-peptide levels. Interventions include the use of Rituximab, an anti-CD20 monoclonal antibody administered intravenously over four weeks, being tested in phases II and III for its effects on insulin production in patients aged 8–45 years over a two-year period. Abatacept (CTLA-4), a cytotoxic T-lymphocyte antigen-4 fusion protein given intravenously, is being evaluated for its impact on insulin secretion over two years. Oral human recombinant interferon α (hrlFN-α) is under investigation in a phase II trial for its effect on counter-regulatory anti-inflammatory cytokines. Additionally, Anakinra (Kineret®), an IL-1 receptor antagonist, is being studied in multiple trials: one assessing its potential to protect β-cells by blocking the IL-1β receptor in children with T1DM and another examining its effect on insulin secretion in young adults with T1DM.
Diabetes can present with weight loss, which is common in type 1 but not typically seen in type 2, monogenic, or pancreatic types unless there is marked weight loss that may suggest pancreatic carcinoma. Ketonuria is usually present in type 1 diabetes, though not always in slow-onset cases, and may occur in other types only under specific conditions such as recent fasting, while in pancreatic diabetes it can be present but not required for diagnosis. The time course of symptom onset varies, with type 1 typically developing over days or weeks, type 2 and monogenic developing over months, and pancreatic diabetes occurring over weeks or months. Symptom severity can be marked in type 1, variable in type 2 (often influenced by consumption of sugary drinks), less severe in monogenic, and variable in pancreatic diabetes depending on the clinical context. Family history is relevant in type 1 with possible early insulin dependence, present in 30% of adult-onset type 2, almost always present in monogenic cases regardless of age, and only coincidental in pancreatic diabetes except when associated with hemochromatosis. Age of onset differs across types: type 1 peaks in preschool and teenage years but can occur at any age, type 2 typically presents after age 20, monogenic can appear in childhood, adolescence, or adulthood, and pancreatic diabetes is more common in middle-aged and older individuals.
The UK Prospective Diabetes Study (UKPDS) found that intensive glycemic control in patients with type 2 diabetes mellitus (T2DM) did not reduce macrovascular complications, despite achieving an 11% reduction in HbA1c levels. However, microvascular complications such as retinopathy and neuropathy were significantly reduced in the intensive treatment group. A 10-year follow-up of the same cohort, after treatment differences were no longer maintained, showed sustained reductions in microvascular complications, myocardial infarctions, and all-cause mortality, but not in cerebrovascular accidents. These findings indicate that glycemic control in T2DM is associated with a reduced risk of certain complications, particularly microvascular ones, but has not been linked to a decreased risk of stroke.
Fasting glucose-raising alleles of several loci including MADD, GIPR, GCK, FADS, DGKB, PROX1, TCF7L2, SLC30A8, and C2CD4B are linked to abnormal insulin processing or secretion, while GCKR and IGF1 are associated with oral glucose tolerance test-based disposition indices and beta-cell function. Three loci—TCF7L2, ARAPI, and CDKAL1—are associated with reduced fasting insulin, suggesting beta-cell dysfunction, and type 2 diabetes risk alleles at PPARG, FTO, IRS1, and KLF14 are linked to higher fasting insulin, indicating a primary effect on insulin action.
Interventions initially designed for obesity treatment, such as bariatric surgery, are increasingly considered primary treatments for type 2 diabetes, while anti-obesity medications developed for type 2 diabetes are also effective at higher doses. Many individuals with type 2 diabetes are not receiving guideline-directed weight loss therapy, and a survey found only 2.2% of eligible adults were using anti-obesity medications shortly before being surveyed. Weight loss goals may be undermined by the use of weight-inducing anti-diabetes therapies in up to 66% of individuals. Evidence shows that weight loss, achieved through dietary and lifestyle changes, anti-obesity medications, or bariatric surgery, significantly impacts type 2 diabetes and related complications, warranting its prioritization in diabetes management. However, barriers such as limited healthcare reimbursement for obesity treatment and restricted access to bariatric surgery or continued medication use remain. Guidelines from the UK’s NICE recommend expedited bariatric surgery assessment for people with a BMI ≥35 kg/m² and type 2 diabetes diagnosed within the past decade, as well as for those with a BMI of 30.0–34.9 kg/m² or for people of Asian origin diagnosed at lower BMIs, yet surgery rates meet less than 1% of this need. Despite evolving guidelines recognizing weight management as essential in diabetes care, bias and misconceptions about obesity treatment persist among healthcare providers, including endocrinologists, affecting the quality and time devoted to caring for individuals with diabetes and obesity.
Gene therapies that have shown therapeutic potential in small diabetic animals require further study to demonstrate their efficacy and safety in large animal models before they can be used clinically to treat diabetes in humans.
Mortality rates related to diabetes are often estimated using vital statistics systems based on death certificate data, though the accuracy can be influenced by coding practices and regional awareness of diabetes. This method relies on the certifying doctor's judgment of whether diabetes contributed to the death, introducing subjectivity. More reliable estimates come from studies of defined cohorts with diagnosed diabetes, which capture all deaths among these individuals and allow for comparison with those without diabetes to assess overall and cause-specific excess mortality risk. Current understanding of all-cause mortality trends among people with diabetes is derived mainly from high-income countries in North America, Europe, Australasia, and Asia. A systematic review of 35 studies across 17 regions showed that since 2000, nearly 80% observed declines in all-cause mortality among people with diabetes, with reductions occurring at rates similar to or greater than those without diabetes, primarily in populations of European descent.
Several possible plausible mechanisms have been proposed to link dietary factors to type 1 diabetes mellitus (T1DM), including "molecular mimicry" and a detrimental effect of bovine insulin in cow's milk. A reduced risk associated with prolonged breastfeeding and/or delayed introduction of cow's milk has been suggested in many case-control studies, although most of these studies were susceptible to recall bias and the issue remains controversial. In the largest prospective study to date involving multiple islet autoantibodies or T1DM as the endpoint, no significant association was found between the duration of exclusive or total breastfeeding and T1DM. Additionally, duration of breastfeeding was not linked to self-reported T1DM up to age 30 years in a recent prospective study involving 61 cases. An ongoing randomized controlled trial called TRIGR aims to determine whether delayed introduction of cow's milk protein can reduce the risk of islet autoimmunity and T1DM. Two prospective studies of islet autoimmunity have also provided some evidence for a role of the age at introduction of cereals or gluten, although the relationship is complex and difficult to interpret.
Global increases in diabetes prevalence, predominantly type 2 diabetes, lead to a rise in both chronic and acute diabetes complications, affecting quality of life and increasing demand on health services and economic costs. Macrovascular complications include coronary heart disease, stroke, and peripheral artery disease, while microvascular complications involve end-stage renal disease, retinopathy, and neuropathy. Lower-extremity amputations, often resulting from peripheral artery disease and neuropathy, contribute significantly to diabetes-related burden. Additionally, diabetes is linked to other conditions such as cancers, aging-related outcomes like dementia, infections, and liver disease. As rates of all-cause and cardiovascular disease mortality decrease in people with diabetes, other complications may become more prominent in the future.
Short sleep duration is associated with an increased risk of type 2 diabetes, with studies showing a U-shaped relationship between sleep and diabetes risk. Research indicates that sleep deprivation negatively affects glucose tolerance and insulin sensitivity, and cross-sectional studies link short sleep to both diabetes and obesity. Prospective data from the Nurses Health Study found that women with short sleep duration had approximately a 57% higher risk of developing diabetes over 10 years, while NHANES I reported a 47% increased risk for those sleeping five or fewer hours. Potential mechanisms include activation of the sympathetic nervous system, reduced cerebral glucose utilization, and disruptions in the hypothalamic-pituitary-adrenal axis and other neuroendocrine functions. Additionally, other sleep disturbances and altered circadian rhythms, such as those experienced during shift work, are also linked to a greater risk of diabetes.
Hormone replacement therapy (HRT) has been shown to have favorable effects on lipid profiles in women with diabetes. In a small randomized crossover study involving overweight women with type 2 diabetes mellitus (T2DM), conjugated estrogen therapy led to reductions in central obesity, HbA1c levels, and total cholesterol, along with improvements in physical functioning. Another study involving 61 postmenopausal women with diabetes found that combined HRT reduced total and low-density lipoprotein (LDL) cholesterol levels, though it did not affect serum high-density lipoprotein (HDL) cholesterol or triglyceride levels.
Autoantibodies to insulin (IAA) were discovered in 1983 in patients with diabetes prior to insulin treatment, indicating their involvement in the autoimmune process of the disease. These autoantibodies are not detected using the immunofluorescence test for islet cell antibodies (ICA) and are found in approximately 35-40% of children at the onset of type 1 diabetes mellitus (T1DM).
Insulin pump therapy (CSII) can reduce glycemic variability and may lower the risk of hypoglycemia compared to multiple daily injections (MDI), particularly in individuals with type 1 diabetes mellitus (T1DM) who have high rates of severe hypoglycemia or long-standing diabetes. Clinical guidelines recommend considering pump therapy for T1DM patients with poor glycemic control and problematic hypoglycemia. Meta-analyses have shown conflicting results on the impact of CSII on hypoglycemia, with some showing a significant reduction in severe hypoglycemia with CSII, especially in those with higher baseline hypoglycemia rates and longer diabetes duration. Other analyses found no significant difference, but these were limited by short study durations, low hypoglycemia incidence, use of intermittent glucose monitoring, and older pump technology without bolus calculator features. Education on catheter site care and ketoacidosis prevention remains important for pump users, as complications can still occur with modern pump technology.
Men with diabetes usually require the maximum recommended dose of certain oral agents taken before sexual activity, and they should be advised that the drug only works in conjunction with sexual stimulation.
Sulfonylureas are a class of drugs used in the management of diabetes, and they act by binding to sulfonylurea receptors (SURs), which are present in different tissues. Two isoforms, SUR2A and SUR2B, are found in cardiac muscle and vascular smooth muscle, respectively, and these isoforms lack the sulfonylurea binding site but retain the benzamido binding site. Sulfonylureas containing a benzamido group, such as glibenclamide, glipizide, and glimepiride, can bind to these cardiac and vascular receptors, while those without a benzamido group, like tolbutamide, chlorpropamide, and gliclazide, show minimal interaction. The presence of the benzamido group allows these drugs to block the effects of nicorandil, an anti-anginal medication with cardioprotective properties. Although there is a theoretical concern that benzamido-containing sulfonylureas might interfere with ischemic preconditioning and increase vascular contractility during critical conditions like severe myocardial ischemia, there is no clear evidence that therapeutic concentrations of sulfonylureas cause such effects. Additionally, hyperglycemia itself appears to negate ischemic preconditioning, yet some experts recommend minimizing sulfonylurea use in patients with established coronary artery disease.
Gestational diabetes mellitus (GDM) presentation is influenced by physiological insulin resistance that develops during pregnancy, which can be observed through changes in exogenous insulin requirements in women with type 1 diabetes. Insulin needs typically remain stable until around 18 weeks' gestation, after which they increase linearly until approximately 28–30 weeks. This increase varies between pregnancies, ranging from no change to over a threefold rise, with an average increase of 40% in daily insulin dose. The variation is thought to be due to differences in placental function, as the same woman may experience different levels of insulin resistance in successive pregnancies. Women who are predisposed to GDM are unable to adequately compensate for excessive insulin resistance through β-cell response.
Patients with the m.3243A > G mutation have a high prevalence of renal failure, with focal segmental glomerular sclerosis (FSGS) being more common than diabetic nephropathy based on renal biopsy findings. Diabetic retinopathy may be less prevalent in this context compared to other forms of diabetes, while macular retinal dystrophy is frequently observed but rarely leads to significant visual symptoms. Additionally, cardiac complications such as left ventricular hypertrophy, heart failure, cardiac autonomic neuropathy, and arrhythmias are associated with this mutation.
Sulfonylureas such as glibenclamide (glyburide) are more likely to cause hypoglycemia compared to shorter-acting alternatives like glimepiride. In both type 1 and type 2 diabetes mellitus (T1DM and T2DM), the use of long-acting insulin analogs such as glargine or detemir as basal insulin in a multiple daily injection (MDI) regimen reduces the incidence of nocturnal hypoglycemia, and possibly total and symptomatic hypoglycemia, compared to neutral protamine Hagedorn (NPH) insulin. Additionally, using rapid-acting insulin analogs like lispro, aspart, or glulisine as prandial insulin in MDI regimens reduces nocturnal hypoglycemia, particularly in T1DM. Continuous subcutaneous insulin infusion (CSII) has not yet been conclusively shown to be superior to MDI with insulin analogs in reducing the frequency or severity of hypoglycemia at similar levels of glycemic control. Other approaches to preventing nocturnal hypoglycemia include strategies aimed at achieving sustained delivery of exogenous carbohydrates or sustained endogenous glucose production throughout the night.
Increased activity of protein phosphotyrosine phosphatases (PTPases), particularly PTP-1B and LAR, in skeletal muscle of patients with type 2 diabetes mellitus (T2DM) contributes to reduced insulin signaling through dephosphorylation of tyrosine residues on the insulin receptor and insulin receptor substrate molecules. Elevated levels of PTPase-1B in particular are associated with insulin resistance, as demonstrated by studies showing that mice lacking PTPase-1B exhibit enhanced insulin sensitivity and do not develop insulin resistance when fed a high-fat diet, while muscle-specific overexpression of PTP-1B induces insulin resistance by decreasing insulin receptor autophosphorylation.
The conventional risk factors for hypoglycaemia in diabetes are based on the premise that absolute or relative therapeutic insulin excess is the sole determinant of risk. Absolute therapeutic insulin excess can occur when insulin secretagogue or insulin doses are excessive, ill-timed, or of the wrong type, or when insulin clearance or metabolism is reduced, as seen in renal or hepatic failure. Relative therapeutic insulin excess can occur when exogenous glucose delivery is decreased, such as after missed or low-carbohydrate meals or during overnight fasting; when glucose utilization is increased, such as during and shortly after exercise; when endogenous glucose production is decreased, such as after alcohol ingestion; and when sensitivity to insulin is increased, such as after weight loss, improved glycaemic levels, or during the night. Addressing these risk factors requires collaboration between people with diabetes, their caregivers, and physicians once the issue of iatrogenic hypoglycaemia is identified, although these factors likely explain only a minority of hypoglycaemic episodes.
Macrovascular complications occur in individuals with both type 1 and type 2 diabetes mellitus, posing a growing concern due to the increasing prevalence of diabetes among adolescents and younger adults, which accelerates the onset of long-term cardiovascular issues. Even when accounting for other risk factors like hypertension and hyperlipidemia, people with diabetes still face a higher risk of cardiovascular disease, with diabetes alone contributing to 75–90% of the excess risk for coronary artery disease and amplifying the impact of other cardiovascular risk factors. Stroke and myocardial infarction are the primary causes of death in those with type 1 and type 2 diabetes.
The primary sequence of insulin was reported in 1955 and its three-dimensional structure in 1969, while proinsulin was discovered in 1967 and the human insulin gene sequence in 1980. Radioimmunoassay for insulin was invented in 1956, insulin receptors were deduced in 1971, and the receptor protein isolated in 1972. Diabetic retinopathy and neuropathy symptoms were described in the 19th century, albuminuria noted as a common abnormality, and a unique type of diabetic kidney disease described in 1936. The concept of diabetic angiopathy was developed in the early 1950s. Insulin pharmacology milestones include delayed-action preparations in the 1930s–1940s, synthetic human insulin in 1979, and insulin analogs in the 1990s. Sulfonylureas began with carbutamide in 1955, followed by tolbutamide and chlorpropamide, while biguanides included phenformin and metformin introduced in 1959 and 1960. Improved glucose control benefits in type 1 and type 2 diabetes were proven by studies in 1993 and 1998. Landmark treatments for complications included photocoagulation for retinopathy, blood pressure management for nephropathy, low-dose insulin for diabetic ketoacidosis in the 1970s, and improved care for pregnant women with diabetes.
Increased hepatic gluconeogenesis, hepatic insulin resistance, and fasting hyperglycaemia in suboptimally managed diabetes are promoted by macrophage-induced adipose tissue lipolysis, which raises hepatic acetyl-coenzyme A levels, activates pyruvate carboxylase activity, and enhances the conversion of glycerol to glucose.
The age-adjusted prevalence of type 2 diabetes mellitus (T2DM) in Fergana, Uzbekistan, is estimated to be 8% for both urban men and women, with impaired glucose tolerance (IGT) affecting 5% of men and 6% of women. In the rural area of Sirdaria province, the age-adjusted prevalence of diabetes is 10% in men and 7.5% in women, while IGT prevalence is higher at 11% in men and 14% in women. In Russia, diabetes prevalence is estimated at 6% in males and 7% in females, with IGT at 6% and 13%, respectively, and diabetes in this population is associated with clustering of hyperlipidemia, obesity, hypertension, and low 10-year survival. A survey in Moscow found a low reported diabetes diagnosis rate of 2%, supported by a study based on self-reported doctor diagnosis, and underdiagnosis, undertreatment, and infrequent insulin use are likely contributing to diabetes-related morbidity. Prevalence data from other Eastern European countries have often been extrapolated from Poland, where T2DM prevalence increased from 3.7% to 10.8% between 1986 and 2000, accompanied by a rise in IGT prevalence from 2.9% to 14.5% during the same period.
GDM refers to gestational diabetes mellitus, a condition characterized by high blood glucose levels during pregnancy, and is associated with the HAPO study, which examines hyperglycemia and adverse pregnancy outcomes. Diagnostic and risk assessment tools such as HbA1c, which measures long-term blood glucose control, and the Indian Diabetes Risk Score (IDRS), which evaluates the likelihood of developing diabetes, are commonly used in diabetes management. Therapeutic agents such as GLP-1 receptor agonists (GLP-1RA) help regulate blood glucose levels, while insulin-related terms such as InsR (insulin receptor), IDDM (insulin-dependent diabetes mellitus), and Insulin Degludec (IDeg) reflect both the biological mechanisms and pharmacological treatments for diabetes. Autoimmune aspects of diabetes are indicated by terms like ICA (islet cell antibody) and LADA (latent autoimmune diabetes in adults), which describe immune-mediated destruction of pancreatic beta cells. Complications and associated conditions include impaired glucose regulation (IGR), impaired glucose tolerance (IGT), and the risk of developing type 2 diabetes, with HbA1c being a key biomarker in diagnosis and monitoring. Other diabetes-related complications involve the cardiovascular system, with terms such as HDL, LDL, and hsCRP indicating lipid profiles and inflammation markers relevant to diabetic patients.
Baseline and incident metabolic syndrome can identify individuals at risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), warranting evaluation in all patients starting highly active antiretroviral therapy (HAART). Fasting plasma glucose should be assessed before therapy initiation and monitored every 3–6 months, especially when treatment changes occur or significant risk factors for insulin resistance are present. An oral glucose tolerance test may be necessary in cases of risk factors or unclear glucose levels. General dietary guidelines apply to managing glucose disorders in HIV infection, and weight loss through increased physical activity and calorie restriction is recommended for overweight HIV-infected patients.
Genome-wide association (GWA) studies suggest that type 2 diabetes mellitus (T2DM) is more heterogeneous and polygenic than previously thought, indicating it may encompass many different disorders with potential clinical differences. Many risk variants for T2DM are common in the population, with frequencies ranging from 0.26 for TCF7L2 to 0.90 for THADA, but each variant confers only a small risk of disease, resulting in a large number of individuals carrying multiple variants without developing T2DM. The low penetrance of these risk variants aligns with their mild effects, requiring additional environmental factors to cause hyperglycemia, and may be due to their location in noncoding gene regions, leading to subtle regulatory changes. This contrasts with Mendelian forms of diabetes, such as MODY, which result from rare mutations in coding sequences that cause major amino acid changes or truncated proteins, leading to hyperglycemia independently of other diabetogenic factors.
Limited joint mobility is an early complication of diabetes and is linked to microvascular complications such as retinopathy and nephropathy in type 1 diabetes, and macrovascular complications in type 2 diabetes. It is also associated with fibroproliferative disorders of the upper limb, including frozen shoulder, Dupuytren contracture, and carpal tunnel syndrome. While limited joint mobility itself typically does not cause severe functional impairment, the combination of these upper limb disorders may lead to disability. Risk factors for developing limited joint mobility in diabetes include older age, puberty in type 1 diabetes, longer disease duration, and cigarette smoking.
Patients with diabetes may experience severe complications such as reduced walking ability due to peripheral artery disease or neuropathy, leading to difficulty performing daily tasks like work, and are also at increased risk of amputation, particularly when presenting with rest pain and non-healing ulcers.
For elective surgical procedures, satisfactory preoperative glycaemic control should be achieved, with a target blood glucose level of less than 199 mg% two hours after breakfast. This can be managed using either short-acting sulphonylureas or soluble insulin, depending on the patient and the type of surgery. Biguanides are not recommended due to the risk of lactic acidosis, and long-acting sulphonylureas are also discouraged because they can cause delayed hypoglycemia.
Postnatal screening for diabetes can be conducted using either fasting plasma glucose or HbA1c testing, as recommended by NICE 2015 guidelines, rather than oral glucose tolerance testing (OGTT). Women with gestational diabetes mellitus (GDM) have an increased lifetime risk of developing diabetes and should receive lifestyle interventions similar to those with impaired glucose tolerance. High-risk groups, including certain ethnic minorities, individuals with overweight or obesity, and women diagnosed with GDM early in pregnancy, should be prioritized for intervention strategies. Women with normal or impaired postnatal glucose tolerance should undergo ongoing surveillance through annual fasting glucose or HbA1c testing every 1–3 years, in addition to continuous lifestyle education and monitoring for cardiovascular risk factors.
Thiazolidinediones lower glucose levels primarily by stimulating PPAR-γ, which enhances insulin sensitivity. PPAR-γ is predominantly expressed in adipose tissue and, upon activation, forms a complex with the retinoid X receptor to bind to specific DNA sequences called PPREs, influencing the transcription of insulin-sensitive genes. This process, supported by co-activators like PGC-1, affects genes involved in lipid and carbohydrate metabolism. Activation of PPAR-γ promotes the differentiation of pre-adipocytes into insulin-sensitive mature adipocytes, mainly in subcutaneous areas, which increases fatty acid uptake and lipogenesis, thereby reducing circulating glucose.
RT-CGM technology has been shown to reduce both hyperglycemic and hypoglycemic excursions, increasing the time spent in the target glucose range. In the GuardControl trial using the Medtronic Guardian device, 156 adults and children with T1DM experienced a significant reduction in HbA1c levels after 3 months of RT-CGM use, with a mean decrease of 1.0 ± 1.1% (11 ± 12 mmol/mol) from a baseline of 9.5 ± 1.1% (80 ± 12 mmol/mol), compared to 0.4 ± 1.0% in the control group.
Age-associated reductions in mitochondrial function contribute to muscle insulin resistance, a key feature in the development of type 2 diabetes. Studies in transgenic mice overexpressing human catalase in mitochondria (MCAT mice) show protection from age-related mitochondrial dysfunction and insulin resistance, with preserved ATP synthesis and reduced oxidative damage. In humans, older individuals exhibit a blunted increase in insulin-stimulated pyruvate dehydrogenase flux relative to citrate synthase flux (V_PDH / V_CS), along with lower muscle glucose uptake and higher intramyocellular triglyceride (TAG) accumulation. These findings indicate a mitochondrial inability to switch from lipid to glucose oxidation during insulin stimulation, suggesting that metabolic inflexibility may play a role in the pathogenesis of insulin resistance in type 2 diabetes. However, recent assessments suggest that mitochondrial substrate preference may not be essential for insulin resistance development, indicating that combined age-related and acquired mitochondrial dysfunction may promote intramyocellular lipid accumulation and insulin resistance seen in type 2 diabetes.
Hyperglycaemia in children with diabetes, especially when ketones are present, may indicate a pump malfunction, requiring immediate troubleshooting and alternative insulin administration. If insulin delivery is interrupted, ketonaemia can develop within four hours, posing a significant risk during nighttime when there is no long-acting insulin active. To manage such situations, syringes or insulin pens should always be accessible for injection if pump failure occurs.
Lorcaserin, a selective $5\mathrm{-HT}_{2c}$ agonist, produces appetite suppression through activation of POMC neurons and was studied in the BLOOM-DM trial, a 52-week placebo-controlled trial in people with type 2 diabetes, in which 44.7% achieved more than 5% weight reduction from baseline. A reduction in $\mathrm{HbA_{1c}}$ was also observed, with 52% of participants achieving a level below 7% (53 mmol/mol) at one year. Lorcaserin use is not associated with valvular defects linked to fenfluramine, which are believed to result from activation of $5\mathrm{-HT}_{2p}$ receptors. However, market approval for lorcaserin was withdrawn due to an increased occurrence of cancer observed in a safety clinical trial.
Thiazolidinediones exert their antidiabetic effects primarily by activating PPAR-γ, a receptor highly expressed in adipose tissue and to a lesser extent in muscle and liver, which enhances insulin sensitivity. Activation of PPAR-γ leads to the formation of a complex with the retinoid X receptor that binds to specific DNA sequences called PPREs, altering the transcription of genes involved in lipid and carbohydrate metabolism. These drugs promote the differentiation of pre-adipocytes into insulin-sensitive mature adipocytes, increasing fatty acid uptake and lipogenesis while reducing circulating free fatty acids. This reduction in free fatty acids rebalances the glucose-fatty acid (Randle) cycle, improving glucose utilization and limiting fatty acid availability for hepatic gluconeogenesis, thereby enhancing glucose metabolism. Additionally, decreased circulating fatty acids reduce ectopic lipid deposition in muscle and liver, further contributing to improved glucose metabolism.
Rosiglitazone and pioglitazone are rapidly and almost completely absorbed, reaching peak concentrations within 1–2 hours, though absorption is slightly delayed when taken with food. Both drugs undergo extensive liver metabolism, with pioglitazone primarily metabolized by CYP2C8 and CYP3A4 into active metabolites that are excreted in the bile. Pioglitazone does not significantly lower plasma concentrations of other CYP3A4-metabolized drugs like oral contraceptives. These thiazolidinediones are highly plasma protein-bound but not to an extent that affects other protein-bound medications.
Diabetes has been recognized since ancient times, with early descriptions of a polyuric state noted in the Ebers papyrus (Egypt, 1500 BC) and later named “diabetes” by Aretaeus (Cappadocia, 2nd century AD). Historical accounts from India (Sushrut and Charak, 5th century BC) and China (Chen Chuan, 7th century) identified sugary urine as a key feature, with Indian physicians distinguishing between thin and obese patients. Avicenna (Arabia, 10th century AD) documented complications such as gangrene and impotence. Diabetic ketoacidosis was recognized in the 19th century, with William Prout describing diabetic coma and Adolf Kussmaul noting acidotic breathing. Hyperlipidemia was linked to diabetes through observations like lipemia retinalis by Albert Heyl (Philadelphia, 1880). Retinopathy was described in stages by several physicians: Eduard von Jaeger (Germany, 1855) outlined general features, Stephen Mackenzie and Edward Nettleship (England, 1879) identified microaneurysms, and later classifications specified retinal lesions unique to diabetes. Neuropathy and foot complications were increasingly recognized, beginning with John Rollo (England, 1797) identifying neuropathic symptoms and Marchal de Calvi (France, 1864) establishing neuropathy as a complication. Ocular nerve palsies were noted by William Ogle (England, 1866), Frederick Pavy (England, 1885) described peripheral neuropathy, Julius Althaus (Germany, 1890) reported mononeuropathy, and Thomas Davies Pryce (England, 1887) identified perforating foot ulcers. Nephropathy was first linked to diabetes by Wilhelm Griesinger (Germany, 1859), and Paul Kimmelstiel and Clifford Wilson (USA, 1936) described glomerulosclerosis with heavy proteinuria as a hallmark of diabetic kidney disease.
Diazoxide, a thiazide-like drug, has been used for over 40 years in the management of hypertensive emergencies and hyperinsulinaemic hypoglycaemia. It is currently available as an oral suspension for treating secondary hypoglycaemia such as insulinoma and islet cell hyperplasias. The drug is known to cause drug-induced hyperglycaemia and even diabetic ketoacidosis due to impaired insulin secretion, increased glucose production, and decreased peripheral glucose utilization. Diazoxide inhibits insulin secretion by opening ATP-sensitive potassium (KATP) channels in the pancreatic β cells, a mechanism that may help preserve β-cell function in type 1 and type 2 diabetes. Additionally, it may improve hypoglycaemic unawareness by activating SUR1-selective KATP channels in the central nervous system.
GLP-1 exerts glucagon-suppressive effects in pancreatic cells, which, like its insulinotropic effect, is glucose-dependent and only active when plasma glucose levels exceed 4–5 mmol/l. The exact mechanisms by which GLP-1 reduces α-cell secretion of glucagon are not fully understood, leading to debate over whether the suppression occurs directly through GLP-1 receptors on α-cells—whose presence in pancreatic α-cells is inconsistently reported—or indirectly via β-cell secretory products and/or somatostatin from pancreatic δ cells, or possibly a combination of these mechanisms.
The prevalence of diabetes is increasing, particularly among young adults, and is associated with significant morbidity and mortality due to microvascular and macrovascular complications. These complications contribute to rising healthcare costs and economic losses globally. Major components of medical expenditures for diabetes include hospital inpatient care, which accounts for 50% of total costs, and medications and supplies, contributing 12%. In the USA, the total costs of diabetes, including direct and indirect expenses, rose from$23 billion in 1969 to $174 billion in 2007, with $116 billion attributed to excess medical expenditures and $58 billion to reduced national productivity. Globally, the annual health expenditure for diabetes in 2007 was estimated between $232.0 and $421.7 billion, with half spent in the USA and one-quarter in Europe. Countries such as China, the Russian Federation, India, Brazil, and Tanzania are projected to experience substantial economic losses due to diabetes and cardiovascular disease between 2005 and 2015.
Insulin pump and multiple daily injection (MDI) therapy involve carbohydrate counting, where the grams of carbohydrate to be consumed are measured and a corresponding insulin dose is given, offering flexibility in food choices but requiring expert education and commitment. Exchange planning simplifies this process by using standardized carbohydrate servings of 10 or 15 grams, promoting consistency in daily carbohydrate intake. Another approach, the constant carbohydrate meal plan, was commonly used with older insulin regimens like NPH and regular insulin, maintaining a steady carbohydrate and insulin amount each day, though it is now considered overly restrictive and potentially conflict-inducing.
GLP-1 receptor agonists, which are modified to resist rapid breakdown by DPP-4, have a low incidence of anti-drug antibody production and show little evidence of reduced efficacy. Small-molecule (non-peptide) GLP-1 receptor agonists offer the potential for oral delivery and reduced antibody interference, with several entering clinical trials. Beyond GLP-1, various gastrointestinal and pancreatic hormones, analogues, or small-molecule receptor agonists and antagonists are being explored as therapeutic options for managing type 2 diabetes.
Insulin injection recommendations include using the abdomen, upper buttocks, upper arms, and upper thighs, with site rotation to prevent lipohypertrophy, and injecting at a right angle, leaving the needle in place for 10 seconds; shorter needles are preferred to reduce trauma and avoid intramuscular delivery, with 4 mm needles available for insulin pens and 8 mm needles used for syringes. Continuous subcutaneous insulin infusion is an alternative delivery method that can be highly effective. Multiple-dose insulin therapy, suitable for individuals with type 1 diabetes, involves a daily long-acting insulin for basal needs and short-acting insulin with meals. Insulin pumps offer greater flexibility for type 1 diabetes management, and sensor-augmented pump therapy can lower the risk of hypoglycaemia. Various insulin regimens are available for people with differing levels of insulin resistance and endogenous insulin production, including those with type 2 diabetes who may be on non-insulin therapies, such as once-daily long-acting insulin, twice-daily mixed insulin injections, or combinations of mealtime short-acting and once-daily long-acting insulin; insulin can also be co-formulated with other injectables like glucagon-like peptide 1 receptor agonists.
Lipohypertrophy occurs due to the lipogenic action of insulin, with repeated local stimulation of adipocytes being causative, and it presents as soft subcutaneous nodules or thickening at sites of repeated injections. As lipohypertrophic areas are relatively painless, young people with diabetes tend to inject the same site repeatedly, worsening the hypertrophy. Insulin absorption may be delayed at such sites, potentially resulting in disruption of glycaemic levels. Lipohypertrophy resolves spontaneously, usually over a few months, by changing the site of insulin injections. Hyperkeratotic verrucous variants of lipohypertrophy have also been described.
Stem-cell therapies for type 1 diabetes utilize human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) to generate functional human islets in vitro by recapitulating islet differentiation processes. These therapies offer a potentially unlimited islet supply and allow for modifications to enhance potency and reduce immunogenicity. hiPSCs enable individualized regenerative therapies, and islet-like structures derived from hESCs have demonstrated similar potency to mature islets in reversing diabetes in mouse models. Since the generation of hiPSCs in 2006, diabetes reversal using hiPSC-derived islet-like structures has been increasingly reported in animal studies. While hESCs currently have more evidence supporting their differentiation efficiency and safety, clinical trials in type 1 diabetes have used hESC-derived islet-like cells. Ethical considerations favor hiPSCs, but challenges related to genome integrity, developmental potential, cost, and scalability remain. The potential for personalized medicine makes hiPSCs a key focus of ongoing research despite the current predominance of hESC-based approaches in clinical trials.
In a study involving adults with type 2 diabetes mellitus (T2DM), liraglutide at doses of 1.2 or 1.8 mg/day reduced HbA1c levels more effectively compared to placebo or rosiglitazone, with decreases of 1.1% (12 mmol/mol) from a baseline of 8.5% (69 mmol/mol). Lower doses of liraglutide were less effective, reducing HbA1c by only 0.6% (7 mmol/mol). Fasting plasma glucose levels decreased by week 2 and reached a reduction of 1.6 mmol/L at 26 weeks with liraglutide (1.2 or 1.8 mg/day), while placebo resulted in an increase of 0.9 mmol/L. Post-prandial plasma glucose also decreased more significantly with liraglutide (-2.5 to -2.7 mmol/L) compared to placebo (-0.4 mmol/L) or rosiglitazone (-1.8 mmol/L). Body weight remained relatively stable with liraglutide treatment, whereas rosiglitazone was associated with weight gain. Adverse events across all treatments included minor hypoglycemia, nausea, vomiting, and diarrhea, each occurring in less than 11% of participants.
Cibinetide, a non-hematopoietic peptide of erythropoietin, has shown therapeutic potential in diabetic painful neuropathy by acting as an antagonist of the TRPV1 receptor, leading to disease-modifying and analgesic effects, and resulting in a significant reduction in neuropathy scores along with small nerve fiber regeneration in the cornea and skin.
Amylin and GLP-1 are peptide hormones that slow gastric emptying, suppress postprandial glucagon secretion, and reduce appetite, which are relevant to glucose homeostasis. Amylin has been shown to be the most potent inhibitor of gastric emptying among several gastrointestinal hormones tested in rats, and its effect is counteracted by hypoglycemia. Although the extent to which amylin's impact on gastric emptying contributes to its appetite-suppressing effects is unclear, exogenous amylin decreases meal size, and amylin receptor antagonists increase food intake, indicating that amylin plays a physiological role in regulating food consumption, which may have implications for diabetes management.
A 26-week phase 2 double-blind placebo-controlled study evaluated 316 individuals with type 2 diabetes treated with lifestyle changes and metformin, comparing once-weekly subcutaneous injections of tirzepatide (1, 5, 10, and 15 mg), dulaglutide (1.5 mg), and placebo. Tirzepatide led to dose-related reductions in HbA1c levels by 1.00%, 1.67%, 1.83%, and 1.89% for the 1, 5, 10, and 15 mg doses, respectively, compared to a 1.21% reduction with dulaglutide, indicating greater glucose-lowering efficacy with higher tirzepatide doses. Tirzepatide also caused dose-dependent weight loss ranging from 0.9 kg to 11.3 kg, surpassing the 2.7 kg loss with dulaglutide and 0.4 kg with placebo. Additionally, tirzepatide slightly reduced triglyceride levels and blood pressure without causing hypoglycemia, though higher doses were linked to initial gastrointestinal disturbances and low-titre anti-drug antibodies that did not affect efficacy.
Genetic risk scores for type 1 diabetes, composed of multiple SNPs, serve as a valuable tool to differentiate between type 1 diabetes, type 2 diabetes, and controls, particularly in Europeans. These scores initially included 9 SNPs that tagged high-risk HLA alleles such as DR3 and DR4, as well as the protective DR15 allele, which had the greatest impact on distinguishing type 1 diabetes. These genetic risk scores have also been applied to non-European populations, including those in India, and have been adapted for individuals of African ancestry to enhance the prediction of type 1 diabetes in these groups.
Oral insulin formulations have been explored as alternatives to parenteral administration, with some showing improved glycaemic control comparable to subcutaneous insulin glargine. One such formulation, oral insulin 338, a long-acting basal insulin analogue combined with the absorption enhancer sodium caprate, demonstrated efficacy in insulin-naive individuals but was discontinued due to high required doses and lack of commercial viability. Advances in oral delivery of peptide hormones, such as the use of salcaprozate sodium (SNAC) technology in oral semaglutide for GLP-1 receptor agonists, have renewed interest and research efforts in developing viable oral insulin options.
Gliptins increase circulating levels of incretins by inhibiting dipeptidyl peptidase 4 (DPP-4), which helps in glycemic control and are administered orally. Exenatide and gliptins are alternatives to thiazolidinediones or acarbose for managing type 2 diabetes mellitus (T2DM) in patients on metformin therapy who cannot tolerate or are not suitable candidates for sulfonylureas.
Loss of early prandial insulin release is considered an early event in the development of type 2 diabetes mellitus (T2DM), and postprandial hyperglycemia or impaired glucose tolerance independently predicts cardiovascular disease risk in patients with diabetes and normal fasting glycemia. Several antidiabetic agents target postprandial hyperglycemia, including rapid-acting insulin analogs (aspart, lispro, glulisine), α-glucosidase inhibitors, rapid-acting insulin secretagogues, and incretins, each with distinct preprandial and postprandial effects and side effects.
HbA₁c standardization is managed through an international reference network that has been established for nearly two decades, ensuring all HbA₁c test device manufacturers calibrate their products to this system, and it maintains a stable master equation for converting HbA₁c values between SI units and percentages, allowing for compatibility with historical data from studies like DCCT and UKPDS.
Mobile applications have been developed to support adolescents with type 1 diabetes in managing their condition, with features such as reminders for insulin, meals, and physical exercise. Studies have shown that using these apps can lead to a reduction in HbA1c levels and an increase in daily self-monitoring of blood glucose, resulting in improved glycaemic outcomes. However, the long-term effectiveness of these applications remains uncertain as the observed benefits may not persist beyond 12 months, highlighting the need for engaging and regularly updated apps to ensure continued usage by adolescents.
In patients with type 2 diabetes mellitus (T2DM), insulin resistance in the liver is marked by a reduced ability of insulin to inhibit hepatic glucose production, resulting in mild hyperglycemia and increased insulin secretion. Hepatic insulin resistance also leads to elevated very low density lipoprotein production, contributing to hypertriglyceridemia. This condition is associated with decreased high density lipoprotein levels due to increased cholesterol ester transfer protein-mediated exchange of cholesterol esters for triglycerides. Additionally, small, dense low density lipoprotein particles, which are highly atherogenic, become more prevalent in insulin-resistant states. The degree of hepatic insulin resistance correlates with liver fat content, although the precise molecular mechanisms in humans are not well understood. While liver fat increases in obesity, the link is not strong, suggesting that genetic and dietary factors, among others, play important roles in regulating liver fat accumulation.
Some sulfonylureas may differ in their effects on pancreatic β-cells, with certain agents like glibenclamide promoting β-cell apoptosis and others, such as gliclazide, showing no such effect and potentially offering antioxidant protection in human pancreatic islets. Additionally, glimepiride, glibenclamide, and chlorpropamide have been associated with reduced insulin content in pancreatic islets, though glimepiride does not appear to affect glucose-stimulated insulin release.
In the ACCORD trial, mortality was higher in participants receiving more intense glucose lowering, suggesting that overly aggressive glucose lowering can cause harm in people with diabetes, possibly through weight gain and increased risk for hypoglycaemia. Hypoglycaemia acts as a severe stressor, triggering an adrenergic and inflammatory response and has been associated with an increased risk of cardiovascular events. Additionally, hypoglycaemia can lead to repolarization abnormalities in the heart, potentially causing malignant arrhythmias. While this provides a possible explanation for the increased mortality observed in the ACCORD trial, a direct causal relationship has not been established. Other studies involving hypoglycaemia-prone medications like insulin or sulfonylureas have not consistently shown increased cardiovascular risk despite more frequent hypoglycaemic episodes, which challenges the idea of a direct causal link. Nonetheless, hypoglycaemia negatively affects quality of life and should be avoided whenever possible.
Statins have been shown to significantly reduce major coronary heart disease (CHD) events in people with type 2 diabetes, with a reported 55% reduction in major CHD compared to a 32% reduction in those without diabetes. The absolute benefit of cholesterol-lowering therapy in type 2 diabetes is greater due to the higher baseline risk of atherosclerotic events and CHD in this population. Early statin trials like the Scandinavian Simvastatin Survival Study (4S) included few individuals with diabetes, but subsequent studies confirmed these cardiovascular benefits in diabetic subgroups.
Hyperglycemia in diabetes is associated with depressed neutrophil chemotaxis, adherence to vascular endothelium, phagocytosis, intracellular bactericidal activity, and opsonization, leading to reduced host defense against extracellular bacterial infections. Impaired chemotaxis and phagocytosis are also observed in monocytes of individuals with diabetes. Defects in innate immunity contribute to increased susceptibility to infections such as S. aureus in db/db mice, which exhibit a heightened inflammatory response alongside impaired neutrophil respiratory burst and failure to resolve infections. Advanced glycosylation end-products (AGEs) are thought to play a role in the pathogenesis of impaired neutrophil function in diabetes.
Fasting glucose, two-hour glucose, and $\mathrm{HbA_{1c}}$ identify somewhat different groups of people as having diabetes, meaning an individual may test positive with one test but not another. The OGTT, which includes both fasting and two-hour glucose measurements, identifies more cases than fasting glucose alone, as studies have shown that relying solely on fasting blood glucose may miss nearly one-third of diabetes cases at diagnosis, particularly in Asian populations and according to the DECODE study. Concerns also exist regarding the sensitivity of $\mathrm{HbA_{1c}}$, although over time the groups identified by the three tests tend to align, resulting in all three tests eventually being positive.
Low glycaemic index carbohydrate foods, such as wholegrain breads, pasta, temperate fruits, and dairy products, may help reduce postprandial hyperglycaemia. The glycaemic load approach, which considers both the glycaemic index of food and portion size, has not been fully studied in children. Dietary changes aimed at managing obesity and insulin resistance are gaining interest, particularly due to rising obesity rates, but there is limited data on their effects on glycaemic control and weight management in young people with type 1 diabetes. Low-carbohydrate diets, while effective for weight management in adults with diabetes, raise concerns about potential impacts on growth and development in younger individuals.
Recent data indicate that individuals diagnosed with type 1 diabetes mellitus (T1DM) in childhood have a significantly higher short-term mortality compared to the general population, with standardized mortality ratios (SMRs) ranging from approximately 1.1 to 4.7 across different countries. In Norway, a nationwide cohort followed for up to 30 years after childhood onset of T1DM showed an SMR of 4.0, while a UK cohort with a mean age of 33 years at baseline and up to 7 years of follow-up had an SMR of 3.7. Studies suggest that SMR may vary with age and diabetes duration, although findings are inconsistent.
Some medications have contraindications or precautions for use in patients with diabetes or diabetic complications, such as oxymetazoline hydrochloride nasal spray and verruca gels containing salicylic acid. Additionally, certain drugs like oral rehydration solutions and ribavirin come with warnings advising cautious use in individuals with diabetes.
In fasting healthy individuals, glucose levels are maintained between 3.9 and 5.6 mmol/l through a balance of endogenous glucose production from the liver and kidneys and glucose utilization by peripheral tissues. This regulation is controlled by insulin and counter-regulatory hormones such as glucagon, catecholamines, growth hormone, and cortisol. Insulin, at low concentrations, inhibits lipolysis, free fatty acid oxidation, and ketogenesis, while at higher concentrations, it lowers glucose levels by suppressing hepatic gluconeogenesis and glycogenolysis, increasing peripheral glucose uptake, and promoting glycogen synthesis. Insulin also prevents protein breakdown and, at the highest concentrations, promotes skeletal muscle formation.
Diabetic diarrhea is managed symptomatically with loperamide, typically given in a dose range of 2–16 mg/day, preferably 30 minutes before meals. Reduction in the consumption of sorbitol-containing artificial sweeteners is advised. For refractory cases, clonidine (0.1 mg orally or via patch) may be used, provided there is no significant postural hypotension. Amitriptyline, with its anticholinergic properties, can help alleviate intestinal cramping and transit. Octreotide (25–50 µg subcutaneously 5–10 minutes before meals) delays small intestinal transit and may reduce secretory diarrhea associated with rapid transit, although it may also predispose to bacterial overgrowth by slowing transit. Improving stool consistency can aid fecal continence. Pelvic floor retraining with biofeedback therapy may enhance rectal sensation and coordination of the external anal sphincter contraction, though it is less effective in those with severely reduced rectal sensation. In severe cases of diarrhea with fecal incontinence, a descending colostomy may be considered to improve quality of life.
Autoantibodies to the juxtamembrane region of IA-2 (IA-2-JM-Ab) are associated with a higher risk of progression to type 1 diabetes mellitus (T1DM), while IgE-IA-2Ab may confer protection even in the presence of IA-2-JM-Ab. The presence of IA-2Ab is more frequently associated with the HLA-DRB1*0401 allele compared to DQ8, and patients with DQ2 show a lower association with IA-2Ab, suggesting that HLA genetics play a role in the development of these autoantibodies and the underlying disease mechanisms.
Smart insulin pens, such as the FDA-approved InPen system, assist in diabetes management by recording insulin dose amounts and timing, transmitting data via Bluetooth to a smartphone app, and offering a bolus calculator that adjusts insulin dose recommendations based on insulin on board (IOB). These devices can be used with rapid-acting insulins like insulin aspart or insulin lispro, and the app can generate reports to help healthcare professionals identify trends and guide treatment decisions. Other smart insulin pens also exist that track insulin delivery and transmit data wirelessly, though they may lack a bolus calculator.
Young-onset diabetes is predominantly characterized by classic type 1 diabetes in individuals of white European descent, involving autoimmune islet destruction, acute ketosis, and absolute insulin deficiency. However, in non-Europid populations such as those from Mexico, India, China, and other parts of Asia, classic ketosis-prone type 1 diabetes is less common among young adults diagnosed with diabetes; for example, only 10% of Chinese individuals with young-onset diabetes (diagnosed before age 40) exhibit this classic type. Despite a non-ketotic presentation, some individuals with young-onset diabetes still require earlier insulin treatment compared to those with late-onset disease, while others respond effectively to oral anti-diabetes drugs. This variability in disease presentation emphasizes the need for more precise diagnosis and classification to guide treatment and reduce the risk of complications. In cases of monogenic diabetes with high penetrance, genetic counseling and cascade screening are important for early detection and intervention among carriers of risk-conferring genetic variants.
HONK (Hyperosmolar Hyperglycemic Nonketotic Syndrome) and DKA (Diabetic Ketoacidosis) are acute complications of diabetes that share hyperglycemia as a common feature but differ in their clinical presentation and pathophysiology. HONK typically occurs in individuals with type 2 diabetes and is characterized by severe hyperglycemia, hyperosmolarity, and little to no ketosis, often triggered by illness or medication. DKA, more common in type 1 diabetes, involves hyperglycemia, ketosis, and metabolic acidosis, usually resulting from insulin deficiency or increased insulin demand due to stress or infection. Both conditions require prompt medical intervention to correct fluid and electrolyte imbalances and to restore normal glucose metabolism.
In diabetes, glucagon signaling contributes to hepatic glucose production through activation of the gluconeogenic pathway, involving PKA-mediated activation of CREB and FOXO1, which upregulates gene transcription of key enzymes such as phosphoenolpyruvate carboxykinase (Pepck), peroxisome proliferator-activated receptor-γ coactivator 1 (PGC-1), and glucose-6-phosphatase (G6P), particularly under fasting conditions. Gluconeogenesis, an energy-intensive process requiring six moles of high-energy phosphate bonds per mole of glucose, is closely linked to TCA cycle activity and lipid oxidation for ATP supply, and glucagon also promotes fatty acid oxidation and ketogenesis in the liver.
In type 2 diabetes, intensive glycaemic management has not been found to reduce fracture risk, despite expectations that improved glycaemia would ameliorate such risks. Treatment with thiazolidinediones, including rosiglitazone and pioglitazone, increases fracture risk, particularly in the appendicular skeleton in women. Randomized controlled trials have shown a twofold increase in distal limb fractures in women using these medications, though no such increase was observed in men. Observational data from older cohorts with type 2 diabetes suggest that men also experience elevated fracture risks with thiazolidinedione use, and the incidence of classic osteoporotic fractures, such as those of the hip, forearm, and humerus, is higher in individuals taking these drugs.
Common variants in the TCF2/HNF1β gene may contribute to type 2 diabetes mellitus (T2DM) risk with modest effects, with the strongest intronic variant showing an allelic odds ratio of 1.13 and corrected P values < 0.01. Additionally, two intronic variants in the TCF2 gene have been found to confer protection against T2DM with an odds ratio of 0.91 and a P value of approximately 10^-7 across individuals of European, African, and Asian descent. Several epidemiologic studies have reported an inverse relationship between T2DM and prostate cancer risk, with a meta-analysis estimating the relative risk of prostate cancer at 0.84 (95% CI 0.71–0.92) among individuals with diabetes. While the protective effect of TCF2 SNPs against T2DM is modest, the primary functional impact of TCF2 variants may lie within metabolic or hormonal pathways that could also influence the risk of prostate cancer.
Despite advancements in diabetes management technologies over the past two decades, consistent and effective use of devices like insulin pumps and continuous glucose monitors (CGMs) remains challenging across all age groups. Insulin pumps facilitate insulin delivery throughout the day and night, while closed-loop or hybrid closed-loop systems, such as Control IQ and MiniMed™ 770G, adjust insulin delivery to help users achieve target blood glucose levels. A 2019 multicentre randomized controlled trial found that closed-loop systems increased the time spent in the target glucose range and reduced hypoglycaemia in adolescents and young adults compared to sensor-augmented insulin pumps.
Insulin secretion in response to glucose occurs in two phases, with the first phase being a short-lived increase involving pre-docked granules from a readily releasable pool that accounts for no more than 5% of total granules, and the second phase being a sustained increase involving recruitment from a larger reserve pool and de novo insulin synthesis. The rise in ATP concentration in beta cells upon glucose exposure supports granule movement and exocytosis priming. This biphasic insulin response can be clearly observed using the hyperglycaemic clamp technique, where a rapid elevation in glucose levels elicits an early insulin response followed by a sustained one, a pattern also seen after carbohydrate or meal ingestion, though less distinctly.
In type 1 diabetes, risk factors for hypertensive disorders of pregnancy include longer diabetes duration, elevated HbA1c levels, and presence of diabetic nephropathy or early-pregnancy proteinuria. Pregnant women with type 2 diabetes generally have a lower risk of pre-eclampsia, though fewer studies exist on this population. Compared to those with type 1 diabetes, women with type 2 diabetes tend to be older, have more obesity leading to chronic or essential hypertension, shorter diabetes duration, and greater multiparity. While proteinuria is more common in type 2 diabetes, it is less predictive of pre-eclampsia. Obesity itself is a major risk factor for pre-eclampsia, including severe cases, and may contribute to rising blood pressure levels observed in pregnancies in recent years.
Exenatide, although not approved for use with insulin therapy, is reportedly used in patients with type 2 diabetes mellitus (T2DM), offering potential insulin-sparing effects through multiple mechanisms including enhancing insulin and reducing glucagon secretion at meals, delaying gastric emptying, suppressing appetite, and promoting weight loss. In a study by Sheffield et al., 134 patients with T2DM initiating exenatide alongside insulin therapy showed a 0.87% (9 mmol/mol) reduction in HbA1c over one year, despite a 45% discontinuation of premeal insulin, fewer insulin injections, and discontinuation of sulfonylureas. Exenatide use led to an average weight loss of slightly over 5 kg, with 72% of patients experiencing weight loss. However, 36% of patients discontinued exenatide, mainly due to gastrointestinal side effects, and 10% experienced hypoglycemia. It may be considered as an alternative with basal insulin for selected patients struggling with accurate dosing of mealtime insulin.
Insomnia is more prevalent in individuals with type 2 diabetes compared to those without, and it may serve as a significant risk factor for the condition, especially when accompanied by short sleep duration. Research indicates that symptoms like difficulty initiating sleep and maintaining sleep are linked to increased risks of developing type 2 diabetes, with relative risks of 1.57 and 1.84 respectively. Studies show that individuals with type 2 diabetes are twice as likely to report insomnia, and this association is strongest among middle-aged individuals, followed by older adults, even after adjusting for variables such as age, sex, smoking, BMI, alcohol consumption, other health conditions, and depression.
Diabetes mellitus is categorized into type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), with additional classifications such as transient neonatal diabetes mellitus (TNDM). The UK Prospective Diabetes Study (UKPDS) and the Veterans Affairs Diabetes Trial (VADT) are clinical trials that have contributed to understanding diabetes management. Diagnostic and monitoring indicators include urinary albumin excretion (UA4), which assesses kidney involvement, and maximal oxygen consumption ($\dot{\mathrm{V}}\mathrm{O}_{2\mathrm{max}}$), which may evaluate cardiovascular health in diabetic patients. Treatments include thiazolidinediones (TZDs), which improve insulin sensitivity, and very low calorie diets (VLCD), which may be used for weight management in T2DM. Complications involve vascular issues such as venous beading (VB), vitreous hemorrhage (VH), and vascular endothelial growth factor (VEGF)–related angiogenesis. Inflammatory factors like tumor necrosis factor (TNF) and transforming growth factor (TGF) are implicated in diabetes-related pathology, and transcription factors (TCF) and tyrosine kinase activity (TKA) play roles in cellular signaling. Adhesion molecules such as vascular cell adhesion molecule (VCAM) and toll-like receptors (TLR) are associated with diabetes-induced vascular damage. Additional markers like uncoupling proteins (UCP) and urotensin (UT) have been linked to metabolic and vascular dysfunction in diabetes.
Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, caused by mutations in a single gene and typically presenting before the age of 25 with a strong family history indicative of autosomal dominant inheritance. It is distinguished by the absence of β-cell autoimmunity and preserved pancreatic β-cell function. MODY was first identified in Asian family-based cohorts of young-onset diabetes due to the low prevalence of autoimmune type 1 diabetes in these groups, and further research in Europe has expanded understanding of the condition. Genetic studies using family-based linkage analysis and sequencing have revealed that MODY is linked to biological pathways involved in pancreatic β-cell neogenesis, differentiation, and maturation, as well as intracellular signaling mechanisms related to insulin sensing, synthesis, secretion, and processing.
Aluminium salts, which induce a humoral (Th2) immune response rather than a cellular (Th1) immune response, are used in attempts to modulate the autoimmune process leading to type 1 diabetes mellitus (T1DM), as this process is primarily cell-mediated. By steering the immune response toward a Th2 profile, the likelihood of exacerbating β-cell destruction may be reduced. This approach is applied in trials involving vaccination with Alhydrogel-formulated GAD65 (Diamyd®).
Observational studies have shown that hormone replacement therapy (HRT) use in postmenopausal women with type 2 diabetes mellitus (T2DM) is associated with reduced cardiovascular risk, in contrast to the general postmenopausal population where no such benefit is observed. Different HRT preparations, varying in estrogen type and dose, progestogen combination, and administration route, may influence cardiovascular risk and benefit in patients with diabetes. Placebo-controlled randomized studies in postmenopausal women with T2DM demonstrated that conjugated equine estrogen therapy improved blood glucose and lipid profiles, with similar benefits observed in another study using continuous oral 17β-estradiol and norethisterone. The Women's Health Initiative study found that women randomized to HRT had a lower incidence of self-reported diabetes compared to placebo, both for those taking conjugated equine estrogen alone and those on combination therapy with medroxyprogesterone acetate. A meta-analysis further supported these findings by showing positive effects of HRT on components of the metabolic syndrome in postmenopausal women, suggesting that estrogen replacement therapy can be considered for patients with diabetes.
The text describes clinical trials involving diabetic patients, focusing on changes in glycemic control and weight loss with different treatments. In one study, obese middle-aged subjects with baseline HbA1c levels of 8.6±1.2% (70 mmol/mol) experienced reductions in HbA1c of -0.86±0.11% with a 10μg dose and -0.46±0.12% with a 5μg dose, compared to a placebo group which had an increase of 0.12±0.09%, showing statistically significant differences. Weight loss was less with the 10μg dose (-1.6kg) compared to metformin alone. In another trial involving patients poorly controlled on a combination of sulfonylurea and metformin, similar obese, middle-aged subjects had a baseline HbA1c of 8.5±1.0% (69 mmol/mol), with HbA1c reductions of -0.8±0.1% (10μg), -0.6±0.1% (5μg), and 0.2±0.1% in the placebo group, again showing significant differences. Weight loss averaged 1.6kg for the 10μg dose group, similar to the sulfonylurea alone study.
Increased flux through the polyol pathway leads to accumulation of sorbitol and fructose, myo-inositol depletion, and reduced Na⁺-K⁺-ATPase activity. Disturbances in n-6 essential fatty acid and prostaglandin metabolism result in alterations of nerve membrane structure and microvascular and hemorrheologic abnormalities. Endoneural microvascular deficits cause ischemia and hypoxia, leading to oxidative stress through the generation of reactive oxygen species, activation of the redox-sensitive transcription factor nuclear factor κB (NFκB), and increased activity of protein kinase C (PKC). Deficits in neurotrophism result in reduced expression and depletion of neurotrophic factors such as nerve growth factor (NGF), neurotrophin-3, and insulin-like growth factor I (IGF-I), along with alterations in axonal transport. Accumulation of non-enzymatic advanced glycation end-products occurs on nerve and/or vessel proteins. Immunologic processes involve autoantibodies to vagal nerve, sympathetic ganglia, and adrenal medulla, as well as inflammatory changes.
Older individuals with diabetes can develop severe complications such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state, the latter occurring more frequently in those over 50 years of age. Studies show that 22% of DKA admissions involved individuals aged 60 or older in Birmingham, UK, and 13% of hyperglycemic coma cases across all ages in Melbourne, Australia, were attributed to hyperosmolar hyperglycemic state. People with type 2 diabetes mellitus (T2DM) often retain sufficient insulin to prevent lipolysis and ketogenesis, leading instead to hyperosmolar hyperglycemic state rather than DKA. Hyperosmolarity can exacerbate insulin resistance and may inhibit lipolysis. Elderly patients are particularly vulnerable to hyperosmolarity due to reduced perception of thirst, inadequate fluid intake to compensate for osmotic diuresis, and frequent use of diuretics.
During recovery from hypoglycemia, interstitial glucose levels may lag behind blood glucose levels, leading to situations where blood glucose has normalized but interstitial glucose is still low. This delay can cause patients using real-time continuous glucose monitoring (RT-CGM) to inaccurately assess their glucose response to carbohydrate intake, potentially leading them to consume more carbohydrates than necessary. To avoid this, patients should use fingerstick glucose measurements to accurately evaluate their response to hypoglycemia treatment.
Repaglinide and nateglinide are agents used in the management of diabetes, with repaglinide administered in doses ranging from 0.5 to 4.0 mg per meal up to a maximum daily dose of 16 mg, and nateglinide given in doses from 60 to 180 mg per meal with a maximum daily dose of 540 mg. Both medications have a relatively short duration of action, lasting between 3 to 6 hours. Repaglinide is primarily eliminated through bile (~90%) as inactive metabolites, while nateglinide is mainly excreted in urine (~80%) with one of its metabolites being slightly active.
Several environmental chemicals may influence the immune system and potentially the risk of type 1 diabetes, with the rodenticide Vacor being associated with type 1 diabetes in humans after ingestion of large doses due to structural and mechanistic similarities with streptozotocin and alloxan. Studies on nitrates, nitrites, and N-nitroso compounds have been limited by methodological challenges, while persistent organochlorine pollutants in maternal sera have shown no positive association with type 1 diabetes risk in offspring, and even a possible inverse relationship. More recent research on air pollution and other environmental chemicals remains inconclusive, and overall, there is little direct evidence supporting a significant role for environmental chemicals in human type 1 diabetes incidence.
Rosiglitazone, a medication used in the management of diabetes, has been associated with a 43% relative increased risk of cardiac events based on findings from a meta-analysis, raising concerns about its cardiac safety profile.
Mortality from acute hyperglycaemic episodes such as diabetic ketoacidosis (DKA) is very low in high-income countries like Taiwan, the USA, and Denmark, with death rates ranging from 0.67% to 4.0%. DKA-related complications have generally decreased since the early 1990s, although recent increases in DKA and hyperglycaemic hyperosmolar state have been reported in the USA without clear causes. In low- and middle-income countries (LMIC), particularly in parts of Africa, mortality from DKA can be as high as 25–33%, largely due to barriers such as limited access to healthcare, insufficient medical resources, and lack of trained personnel, which lead to poor metabolic management. These challenges contribute to early-life deaths among people with type 1 diabetes in low-resource settings, where post-diagnosis life expectancy can be as short as one year in some regions.
Gene transfer technologies have enabled the development of potential therapeutic strategies for treating both type 1 and type 2 diabetes, and have also facilitated proof-of-concept studies in small and large animal models to improve understanding of the pathophysiology of these diseases.
Fenofibrate therapy in combination with statins showed a nonsignificant 9% reduction in cardiovascular events over five years among individuals with type 2 diabetes, with a more pronounced but still non-significant 29% reduction in a pre-specified dyslipidaemic subgroup compared to no change in the non-dyslipidaemic group, leading to limited use of fibrates in combination therapy in the USA. However, fibrates demonstrated benefits in reducing microvascular complications such as retinopathy and nephropathy in both the FIELD and ACCORD studies. A new trial, PROMINENT, is investigating the use of pemafibrate, a selective PPAR modulator with fibrate-like lipid effects, to clarify the role of fibrates in dyslipidaemic individuals with type 2 diabetes.
Administration of the adrenal androgen dehydroepiandrosterone (DHEA) and its metabolite etiocholanolone can decrease adiposity, improve glycemic control, and reduce insulin resistance in obese diabetic animal models. These effects may occur through mechanisms that involve increasing tyrosine phosphorylation of IRS proteins and enhancing the translocation of glucose transporters GLUT-1 and GLUT-4 to the cell membrane.
Maturity-onset diabetes of the young (MODY) can be caused by mutations in either glucokinase or transcription factor genes, leading to distinct clinical characteristics. Glucokinase MODY is characterized by mild fasting hyperglycemia that is often detected in childhood or early adulthood and typically does not progress significantly over time. In contrast, transcription factor MODY, such as MODY caused by mutations in HNF1A or HNF4A, is associated with a progressive decline in beta-cell function, leading to worsening hyperglycemia and a higher likelihood of microvascular complications if not properly managed. Patients with transcription factor MODY may also exhibit extrapancreatic features, such as liver dysfunction or cardiac abnormalities, depending on the specific gene involved. Diagnosis of MODY relies on clinical features, family history, and genetic testing to differentiate it from other forms of diabetes like type 1 or type 2 diabetes. Treatment approaches vary, with glucokinase MODY often requiring no pharmacological intervention, while transcription factor MODY may necessitate sulfonylureas or insulin therapy.
People with diabetes have an increased risk of infections, with 46% experiencing at least one hospitalization or outpatient visit for infections compared to 38% of those without diabetes, resulting in a relative risk ratio of 1.21. The risk ratios for infectious disease-related hospitalization or death are higher at 2.17 and 1.92, respectively, which may be due to increased severity and presence of complications. Diabetes is also a significant risk factor for acquiring severe bloodstream infections requiring intensive care admission, with a relative risk ratio of 5.9. Common organisms causing such infections include Staphylococcus aureus, Escherichia coli, and Streptococcus pneumoniae.
Monogenic diabetes, specifically $\beta$ cell monogenic diabetes, differs from type 1 and type 2 diabetes in that it is caused by a single gene mutation affecting insulin production, often leading to diabetes in childhood or early adulthood. Unlike type 1 diabetes, which involves autoimmune destruction of $\beta$ cells, and type 2 diabetes, which is characterized by insulin resistance and relative insulin deficiency, monogenic diabetes may present with mild fasting hyperglycemia and can sometimes be managed with specific treatments such as sulfonylureas rather than insulin. Diagnosis typically involves genetic testing, especially in cases where there is a strong family history of diabetes without typical features of type 1 or type 2 diabetes.
Metformin is used to treat diabetes and should be taken with meals or immediately before meals to reduce gastrointestinal side effects. Initial dosing typically starts at 500 or 850 mg once daily, or 500 mg twice daily, with gradual increases every 1 to 2 weeks until the target blood glucose level is achieved. If further dose increases do not improve blood glucose control, the previous effective dose should be continued. When monotherapy with metformin is insufficient, combination therapy with other agents such as insulin-releasing drugs, SGLT-2 inhibitors, or thiazolidinediones may be considered. The maximal effective dose of metformin is around 2000 mg per day, though some countries allow up to 2550 or 3000 mg daily when divided into multiple doses with meals.
The regulation of insulin secretion involves adenylate cyclase, which is activated by glucose and certain receptor agonists such as glucagon, glucagon-like peptide-1, and pituitary adenylate cyclase-activating polypeptide. These agonists bind to receptors coupled to the Gs protein, leading to the production of cyclic AMP (cAMP) from ATP, which in turn activates protein kinase A (PKA) and EPACs, both of which enhance glucose-stimulated insulin secretion. In contrast, inhibitory agonists like norepinephrine and somatostatin act through receptors linked to the inhibitory G protein Gi, reducing adenylate cyclase activity and lowering intracellular cAMP levels, thereby decreasing insulin secretion.
Hyperglycemia induces the production of mitochondrial superoxide, which leads to the modification of GAPDH by ADP-ribose polymers, reducing its activity. This process is mediated by PARP, an enzyme activated by DNA damage caused by reactive oxygen species (ROS) generated from elevated glucose levels. Increased ROS in mitochondria leads to DNA strand breaks that activate PARP, resulting in the cleavage of NAD+ and the subsequent formation of ADP-ribose polymers that accumulate on GAPDH and other nuclear proteins. This modification of GAPDH impairs its function and contributes to the pathophysiology of diabetes. The inhibition of mitochondrial superoxide production, either by UCP-1 or MnSOD, or the use of a specific PARP inhibitor, can prevent both the ADP-ribosylation of GAPDH and the reduction of its activity under hyperglycemic conditions.
Diabetes-related data from various health care settings reveal trends in lipid management among diabetic patients. In a diabetes clinic, general medical clinic, and university clinic setting, 28.6% of patients with type 2 diabetes mellitus (T2DM) had low-density lipoprotein (LDL) levels below 2.6 mmol/l. From 1996 to 2005. In a Swedish study involving primary care and hospital outpatient clinics, 28% of T2DM patients in 2003 had total cholesterol (TC) levels below 4.5 mmol/l. Another Swedish national diabetes registry study found that among type 1 diabetes mellitus (T1DM) patients on LDL-lowering therapy, 48% had LDL levels below 2.5 mmol/l in 2004. A multinational study across Asia, Eastern Europe, and Latin America showed that 39.5% of T1DM and 33.2% of T2DM patients had LDL levels below 100 mg/dL, while 15.1% of T1DM and 49.0% of T2DM patients had triglyceride (TG) levels below 150 mg/dL between 2005 and 2010.
SGLT-2 inhibitors are a class of glucose-lowering agents used in the management of type 2 diabetes, particularly when lifestyle changes alone are insufficient. They can be used as monotherapy or in combination with other oral agents or insulin due to their unique mechanism of action. These inhibitors are beneficial for individuals with overweight or obesity as they promote body weight reduction, and they carry a low risk of hypoglycaemia, making them suitable for patients with blood glucose levels near target. Additionally, they may offer modest blood pressure reduction in individuals with hypertension.
Inhibition of glucagon secretion reduces both fasting and postprandial glucose levels, and while failure to suppress glucagon has little impact on glucose production and tolerance when insulin is functioning normally, it leads to significant hyperglycemia when insulin secretion is impaired and delayed, as seen in type 2 diabetes mellitus (T2DM). Agents that enhance insulin secretion, improve insulin action, increase glucose effectiveness, and regulate glucagon secretion are expected to have a major positive impact on glucose metabolism in individuals with T2DM.
Bladder dysfunction affects up to 50% of individuals with diabetes and can present with symptoms ranging from bladder overactivity to impaired bladder contractility and urinary retention. The condition, known as diabetic cystopathy, begins with an increased threshold for the micturition reflex, followed by decreased detrusor activity and incomplete bladder emptying. In the early stages, people with mild autonomic neuropathy may experience reduced urinary frequency, but as autonomic efferent fibres are damaged, urination frequency declines, leading to dribbling and overflow incontinence. This dysfunction is linked to hyperglycaemia-induced polyuria, which causes compensatory bladder hypertrophy and subsequent myogenic and neurogenic changes. Important differential diagnoses such as urinary tract infection should be excluded through urinalysis and culture, and in older men, evaluation for benign prostatic hypertrophy is essential. In women, a full urogynaecological examination is necessary to rule out pelvic organ prolapse and to assess pelvic floor muscle integrity.
Certain compounds stimulate insulin secretion by closing ATP-sensitive potassium ($\mathrm{K}_{\mathrm{ATP}}$) channels, a mechanism relevant to diabetes treatment. Mitiglinide, a meglitinide derivative, binds at the benzamide site on SUR1 and is an example of such an insulin secretagogue that has advanced in clinical development. Other compounds like the morpholinoguanidine BTS67582 and certain imidazolines, including S22068, also interact with $\mathrm{K}_{\mathrm{ATP}}$ channels, though they have not progressed beyond early clinical studies. Some imidazoline compounds enhance insulin secretion through combined effects, including $\mathrm{K}_{\mathrm{ATP}}$ channel closure and interaction with $\mathrm{I}_1$, $\mathrm{I}_2$, and other receptors. However, not all imidazolines act through $\mathrm{K}_{\mathrm{ATP}}$ channels; for instance, EL11282 enhances glucose-induced insulin secretion via effects on protein kinases without closing these channels. Additionally, $\alpha_{2}$-adrenergic receptor antagonists such as phentolamine can promote insulin secretion by reducing tonic suppression mediated through $\alpha_{2}$-adrenergic activation, and some of these agents may also close $\mathrm{K}_{\mathrm{ATP}}$ channels.
Following a healthy dietary pattern reduces the risk of developing diabetes. In women with obesity and previous gestational diabetes mellitus (GDM), a weight loss regimen consisting of 40% carbohydrate resulted in similar weight loss compared to 55% carbohydrate, though the former had lower triglyceride levels. Asian women who followed a low glycaemic index eating plan experienced significant reductions in body weight, BMI, and waist-to-hip ratio at six months postpartum. Among those with a history of GDM in the Nurses’ Health Study II cohort, women consuming diets high in Mediterranean, DASH, or alternate Healthy Eating Index diets had a 40–57% lower risk of developing postpartum diabetes over 14 years compared to those with the lowest diet quality. Dietary changes during pregnancy for women with GDM have shown benefits during the pregnancy, but these changes were not maintained postpartum, indicating a need for strategies to support long-term adherence. Losing 10–15% of body weight through dietary modification can lead to remission of type 2 diabetes.
The Edmonton Protocol initially showed promise for achieving insulin independence in diabetes treatment, but long-term sustainability was limited, with only about 10% of individuals remaining insulin-independent after five years. Later reports noted a one-year insulin independence rate of 44%, emphasizing the role of center experience in islet isolation and transplant care. Over two decades, outcomes have improved, with recent data showing five-year insulin independence rates of approximately 30% and 10-year rates between 18–28% in single-center studies. Insulin use consistently decreases following islet cell transplantation, with reductions of about 70% at five years and 50% at ten years.
When blood glucose exceeds 200 mg/dL (11.1 mmol/L), recommended actions include administering rapid-acting insulin based on ketone levels: 1 unit for each 50 mg/dL above 100 mg/dL if blood ketones are less than 0.6 mmol/L or urine ketones are negative/small; 10% of the total daily insulin dose if blood ketones are between 0.6–1.5 mmol/L or urine ketones are moderate or large; and 10–20% of the total daily dose if blood ketones exceed 1.5 mmol/L or urine ketones are moderate or large. Acidosis is common in patients with hyperglycemia and blood ketones above 3.0 mmol/L, necessitating emergency department referral.
Persistent hyperglycemia is associated with increased mortality at 90 days and parenchymal hemorrhage in the context of acute stroke, while the absence of hyperglycemia at baseline but its presence at 24 hours after admission is linked to higher mortality and poor outcomes. Baseline hyperglycemia alone, without persistence at 24 hours, does not correlate with adverse outcomes, suggesting that stress-related hyperglycemia may not be the primary cause of damage in acute stroke.
People of Black and South Asian ethnicity are at a higher risk of developing type 2 diabetes compared to white Europeans, with data showing that individuals with type 2 diabetes are twice as likely to be of Black or South Asian origin. The NHS Health Check Programme in the UK found a higher prevalence of diabetes among South Asian men (9.0% vs 3.9%) and women (7.4% vs 3.3%) compared to white European individuals. A recent large-cohort study further confirmed the increased risk of type 2 diabetes in the South Asian community, with the highest risk observed among those of Bangladeshi origin.
SGLT-2 inhibitors act on SGLT-2 transporters in the renal proximal tubules, reducing glucose reabsorption and lowering the renal threshold for glucosuria, which leads to the excretion of approximately 20–30% of filtered glucose in the urine of individuals with type 2 diabetes. This mechanism lowers blood glucose levels without relying on insulin, making it effective even in the presence of insulin resistance or β-cell failure, although it requires adequate kidney function. The resulting glucosuria can also promote weight loss and cause mild osmotic diuresis, potentially contributing to a modest reduction in blood pressure. As blood glucose levels decrease, the extent of glucosuria diminishes, helping to prevent hypoglycemia.
Nausea and vomiting can be symptoms associated with diabetes, particularly when blood glucose levels are significantly elevated or as a result of diabetic ketoacidosis.
Higher amounts of habitual physical activity are associated with decreased incidence of diabetes-related complications and reduced mortality in individuals with type 1 diabetes mellitus (T1DM). A prospective study involving 548 patients with T1DM followed over 7 years showed that the risk of microvascular complications varied inversely with self-reported activity levels at baseline. Sedentary male patients were three times more likely to die than active ones after adjusting for age, body mass index, smoking, and diabetic complications. A similar relationship, though statistically non-significant, was observed in females.
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemia by reducing renal glucose reabsorption and lead to significant weight loss due to calorie excretion in urine, with 25% of individuals experiencing more than 5% weight loss in phase three trials with canagliflozin. Weight loss contributes to improvements in HbA1c and systolic blood pressure, accounting for 15% and 42% of the changes respectively. Canagliflozin, dapagliflozin, and empagliflozin also reduce fatal and non-fatal cardiovascular events, with empagliflozin showing a 38% relative risk reduction in fatal cardiovascular events in people with type 2 diabetes as demonstrated by the EMPA-REG OUTCOME trial.
Metformin is often preferred for treating type 2 diabetes in individuals with overweight or obesity due to its weight-neutral effects, and it demonstrates similar anti-hyperglycaemic efficacy in those with normal weight. It should be used cautiously in patients with impaired renal function, particularly when creatinine clearance is less than 60 ml/min or eGFR is below 45 ml/min/1.73 m², though reduced doses may be used down to an eGFR of 30 ml/min/1.73 m². Metformin is contraindicated in cases of significant cardiac or respiratory insufficiency, conditions leading to hypoxia or reduced tissue perfusion, significant liver disease, alcohol abuse, or a history of metabolic acidosis. It can be used in older adults if renal and other organ functions are adequate.
In type 2 diabetes mellitus (T2DM), β-cell mass is reduced by approximately 30–50% compared to weight-matched individuals with normal glucose tolerance, and a similar decrease in β-cell mass has been observed in individuals with impaired fasting glucose. This reduction in β-cell mass is due to a decrease in the number of β-cells rather than a change in the volume of individual cells, and is associated with a several-fold increase in β-cell apoptosis without sufficient compensatory replication or neogenesis. Additionally, a reduction in β-cell secretory granules has also been reported.
β₂-adrenoceptor agonists stimulate insulin secretion, but their overall effect leads to hyperglycemia due to increased hepatic glucose output. High doses of β₂-agonist drugs like salbutamol, ritodrine, and terbutaline, used in treating asthma and premature labor, often result in hyperglycemia and can even induce diabetic ketoacidosis in previously non-diabetic pregnant women. Continuous nebulization of β₂-agonists for status asthmaticus can similarly cause hyperglycemia, with the effects being most significant in patients with type 1 diabetes mellitus (T1DM). Co-administration of dexamethasone with β₂-agonists, as in preterm labor treatment, may lead to severe hyperglycemia even in normoglycemic individuals. Due to these risks, current guidance from NICE recommends avoiding β₂-adrenoceptor agonists for tocolysis in women with diabetes to prevent hyperglycemia and ketoacidosis.
Clinical signs of diabetes can include dehydration, deep sighing respirations known as Kussmaul respiration, and a sweet-smelling breath resembling nail varnish remover due to the presence of ketones. The ability to detect ketone odors varies genetically, with about one-third of people unable to perceive it, making awareness of this limitation important for accurate diagnosis. Clouded consciousness may occur, and if the condition progresses to coma, signs of dehydration should prompt urgent testing of blood glucose, urinary or blood ketones, and blood pH to facilitate timely treatment.
In type 2 diabetes, skeletal fragility is increased despite higher body weight, which typically helps preserve bone mass. Bone mineral density (BMD) in the axial skeleton is higher in people with type 2 diabetes compared to those without diabetes, yet BMD remains a significant risk factor for fractures, as those with lower BMD have higher fracture rates. Additionally, individuals with type 2 diabetes who also have neuropathy and nephropathy tend to have lower BMD than those without these complications.
Motivational interviewing, when used during clinic visits with teenagers aged 14 to 17 years with type 1 diabetes, has been shown to lead to lower mean HbA1c levels compared to control participants, with the improvement maintained for a year after the intervention ended. This approach involves collaborative communication between a member of the paediatric diabetes team and the adolescent to strengthen the teenager’s personal motivation for change and commitment towards achieving specific self-management goals, and may be particularly useful in supporting the transition to greater self-care responsibility.
When capillary blood glucose monitoring is necessary for individuals with diabetes includes circumstances such as experiencing symptoms of hypoglycemia, before and after physical activity, prior to driving, during illness, when adjusting medication or insulin doses, and in the presence of signs suggesting hyperglycemia.
Dietary fibre from fruits and vegetables is associated with a reduced risk of diabetes. Nuts and seeds, along with their insoluble fibres and magnesium content, are linked to a lower risk of diabetes, while increasing the ratio of polyunsaturated and monounsaturated fatty acids to saturated fatty acids helps reduce fasting plasma glucose, HbA1c, and insulin resistance. Pulses with soluble fibres can reduce post-prandial glucose and lower HbA1c levels, and wholegrains and cereal fibre also reduce diabetes risk through their insoluble fibres and magnesium content. A low glycaemic index diet reduces diabetes risk and HbA1c levels. Replacing butter and saturated fat spreads with vegetable oils increases the PUFA/MUFA to SFA ratio, which is beneficial for diabetes management. Low-fat dairy intake is associated with reduced diabetes risk, with milk proteins potentially lowering glucose levels and enhancing insulin secretion, while vitamin D and calcium also contribute to risk reduction. Moderate alcohol consumption is linked to a reduced risk of diabetes, whereas high intake of red and processed meats increases diabetes risk. Sweetened beverages increase BMI, which in turn raises diabetes risk. A decreased PUFA/MUFA to SFA ratio, such as from butter consumption, increases diabetes risk. There is no known effect of omega-3 fatty acids or sodium on diabetes risk or management.
In patients with type 2 diabetes mellitus (T2DM) and high urinary albumin excretion (UAE), the use of renin-angiotensin system (RAS) inhibitors is recommended, and these should be titrated to the maximum tolerated dose. Direct comparisons between angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in microalbuminuric T2DM patients have not shown clinically significant differences in renal outcomes, although some studies may lack the power to detect small differences.
Prevention of $\beta$-cell destruction in diabetes may be achievable through genetic manipulation of $\beta$-cells to produce protective or survival factors, which could help individuals experiencing early autoimmune destruction of these cells. Approaches under investigation include the use of transgenes encoding antioxidant enzymes like glutathione peroxidase, mitochondrial manganese superoxide dismutase (MnSOD), catalase, and cytosolic copper-zinc superoxide dismutase, as well as anti-apoptotic proteins such as members of the heat shock protein and Bcl-2 families. Additionally, modulators of cytokine signaling pathways, particularly those affecting nuclear factor $\kappa$B (NF-$\kappa$B), and immune modulators like interleukin-1 (IL-1) receptor antagonist, hepatocyte growth factor, transforming growth factor $\beta$ (TGF-$\beta$), adenoviral E3, calcitonin gene-related peptide, inhibitors of Fas ligand signaling, and antistress factors such as thioredoxin are being explored for their potential to promote $\beta$-cell survival when expressed in patients with diabetes.
Unexplained hyperglycemia necessitates re-evaluation of insulin therapy, and hyperglycemia or hypoglycemia during intercurrent illness requires specific "sick day" management. Adjustments in insulin dosage are necessary with changes in daily activities, and special guidance is needed for situations such as travel, fasting, and alterations in routine. For individuals on a twice-daily insulin regimen, approximately two-thirds of the daily insulin requirement is administered in the morning and one-third in the evening, with one-third of each dose given as regular insulin and two-thirds as intermediate-acting insulin. In a basal-bolus regimen, nighttime intermediate-acting insulin typically constitutes 30–50% of the total daily dose, while rapid-acting insulin makes up 50–70% of the total, divided into three or four pre-meal boluses.
Good glucose control during surgery, particularly in cardiac surgery, may reduce mortality, with "good control" defined as maintaining blood glucose levels between 80-110 mg/dL (4.4-6.1 mmol/L). However, there is a lack of sufficient clinical trials to determine the optimal level of glucose control in surgical settings outside of cardiac surgery.
HNF4A variants are associated with increased insulin secretion in utero and early infancy, leading to macrosomia and hypoglycaemia in neonates, which later evolves into reduced insulin secretion and diabetes in adulthood.
The table presents data from several clinical trials examining the effects of intensive glucose control in patients with diabetes, showing that intensive treatment reduces microvascular complications and mortality compared to conventional control. In the UK Prospective Diabetes Study (UKPDS), intensive therapy targeting an HbA1c of 7.0% reduced microvascular complications by 25% compared to a conventional HbA1c of 7.9%. Long-term follow-up from UKPDS showed sustained benefits with a 24% reduction in microvascular events. The ADVANCE trial demonstrated a 14% relative risk reduction in microvascular outcomes with intensive control (target HbA1c of 6.5%) versus conventional control (HbA1c of 7.3%), although there was no significant reduction in mortality. The ACCORD trial showed a 33% reduction in microvascular complications and a 10% reduction in mortality with intensive therapy (target HbA1c of 6.4) compared to conventional control (HbA1c of 7.5). In the Veterans Affairs Diabetes Trial (VADT), intensive treatment (HbA1c of 6.9) led to a modest 2.5% reduction in microvascular events and a non-significant 12% mortality reduction versus conventional control (HbA1c of 8.4). These findings suggest that intensive glucose control can significantly reduce microvascular complications in diabetes, particularly when initiated early in the course of the disease.
Insulin regulates glucose transport in cells by modulating the activity of GLUT-4 transporters, which are responsible for increased glucose uptake in response to insulin stimulation. In the absence of insulin, most GLUT-4 transporters are stored intracellularly, and glucose transport is primarily mediated by GLUT-1. When insulin binds to its receptor, it triggers the translocation of GLUT-4 transporters to the plasma membrane, enhancing glucose uptake. After the insulin signal subsides, GLUT-4 transporters are internalized, reducing glucose transport activity. This mechanism is crucial for maintaining glucose homeostasis and is impaired in conditions such as diabetes.
HNF4A variants are associated with an increased risk of macrosomia in pregnancies, and recent advances in non-invasive prenatal testing allow for the detection of cffDNA in maternal blood to identify such pregnancies, enabling personalized management based on fetal genotype. Further guidance on managing pregnancies in individuals with HNF4A variants can be found at www.diabetesgenes.org.
Type 2 diabetes is strongly associated with non-alcoholic fatty liver disease (NAFLD), affecting up to 70% of individuals with the condition, and increases the risk of developing more advanced forms such as NASH, cirrhosis, liver failure, and hepatocellular carcinoma. NAFLD in people with type 2 diabetes is linked to higher glycated haemoglobin (HbA1c) levels and greater hepatic and peripheral insulin resistance. It also contributes to atherogenic dyslipidaemia and the release of pro-inflammatory, procoagulant, and proatherogenic factors, which play a role in the development of chronic vascular complications of diabetes. Management strategies include weight loss through diet and exercise, control of cardiometabolic risk factors, and prevention of disease progression. Bariatric surgery improves NAFLD histology, including fibrosis, and is considered for those with type 2 diabetes and severe obesity. Certain glucose-lowering agents, such as pioglitazone and GLP-1 receptor agonists like semaglutide, may improve NASH without worsening fibrosis, while SGLT-2 inhibitors are potential future treatments. Obeticholic acid, a synthetic bile acid analogue, can improve both NASH and fibrosis but raises low-density lipoprotein cholesterol levels.
A significant reduction in β cell volume, up to 60%, is observed in individuals with pre-diabetes, with further decline in those with overt diabetes, primarily due to increased apoptosis, autophagy, and dedifferentiation. This loss of β cell mass is exacerbated by a lack of compensatory replication, attributed to the limited regenerative capacity of adult human β cells. Various factors associated with the metabolic environment of type 2 diabetes, such as hyperglycaemia, hyperlipidaemia, chronic β cell stimulation, and impaired incretin effect, contribute to the progressive dysfunction and loss of β cells. These factors activate common damaging pathways, including oxidative stress, endoplasmic reticulum stress, inflammation, immune activation, and amyloid deposition, which impair β cell function and survival. While both β cell function and mass are affected, functional abnormalities are more prominent. Preserving β cell function is crucial for long-term glycaemic control in type 2 diabetes.
Proteinuria and microalbuminuria are risk factors for pre-eclampsia and preterm birth, particularly relevant in the context of diabetes. The increasing prevalence of maternal obesity and type 2 diabetes mellitus (T2DM) contributes to higher risks in pregnancy, especially for older women. Women with pre-gestational diabetes or a history of gestational diabetes mellitus (GDM) require pre-pregnancy care to optimize glycemic control, ensure folic acid supplementation, discontinue unsafe medications, and screen for complications such as retinopathy and nephropathy. Antenatal management focuses on maintaining maternal glucose levels as close to normal as possible and monitoring for medical and obstetric complications. National evidence-based guidelines should be followed for the care of women with diabetes during pregnancy, and women at risk of GDM should be screened at 28 weeks' gestation using a 75-g oral glucose tolerance test (OGTT) with World Health Organization criteria. Treatment for GDM includes diet, exercise, and, if necessary, medications such as metformin, glibenclamide, or insulin. Women with either pre-gestational diabetes or GDM are advised to consider induction of labor at 38 weeks to reduce the risk of stillbirth and birth injury. Insulin requirements typically return to pre-pregnancy levels postpartum, necessitating dose adjustments. The use of insulin pumps, continuous glucose monitors, and basal analog insulin is growing but requires further evaluation in pregnancy.
Many built environment features that are tied to type 2 diabetes risk, including inequitable food security, alcohol outlets, tobacco outlets, and gun violence, are echoes of historical, racist practices of land distribution and use like redlining.
Renal failure from diabetes is the most common single cause of entry into renal replacement programs worldwide, with the majority of cases involving individuals with type 2 diabetes and major co-morbidities. To manage this condition, if UAE is raised, an inhibitor of the renin angiotensin system should be commenced and titrated up to the maximum tolerated dose. Maintaining blood pressure below 125/75 mmHg can reduce the rate of decline of glomerular filtration rate (GFR), and reducing dietary protein intake to 0.7-1.0 g/kg body weight per day may slow deterioration in renal function. Aggressive management of other cardiovascular risk factors and prescription of aspirin can reduce the incidence of cardiovascular events and progression to nephropathy by around 60%. For patients with end-stage renal disease (ESRD) and significant co-morbidities, dialysis should be offered, while fitter patients may benefit from kidney or kidney-pancreas transplantation, though a full cardiovascular assessment and treatment are necessary before transplantation if indicated.
Oral antidiabetic agents have limited use in children and adolescents, though metformin has been safely used in controlled pediatric settings starting at age 10, and sulfonylureas have been used in certain pediatric cases of maturity-onset diabetes of the young (MODY). Treating type 2 diabetes mellitus (T2DM) in women of childbearing age requires caution due to the risk of unplanned pregnancy while using these agents. Use of oral antidiabetic medications during conception and the first trimester has not shown adverse effects on mother or fetus, and metformin has demonstrated benefits in reducing miscarriage and gestational diabetes. Despite this, insulin remains the preferred treatment during pregnancy due to strong evidence supporting its safety and flexibility. Evidence is limited regarding the safety of thiazolidinediones and gliptins during pregnancy and lactation, leading to contraindications for their use in these periods.
Thiazolidinediones such as pioglitazone and rosiglitazone act as insulin-sensitizing agents by activating the nuclear receptor PPARγ, which enhances the transcription of insulin-sensitive genes, improves glycemic control, increases adipogenesis, and exerts anti-inflammatory and vascular effects. Newer thiazolidinediones like rivoglitazone are under development, as are non-thiazolidinedione PPARγ agonists, which may offer improved therapeutic profiles by selectively modulating gene transcription through different coactivator recruitment. Partial PPARγ agonists, including halofenate/metaglidasen and FK614, activate a different set of genes compared to full agonists, potentially reducing side effects while maintaining beneficial effects. Targeting coactivators such as PGC-1α may also enhance the therapeutic potential of PPARγ modulation in diabetes.
The text describes various genetic defects related to diabetes, including mutations affecting β-cell function such as those in HNF4α (MODY 1), glucokinase (MODY 2), HNF1α (MODY 3), and IPF-1 (MODY 4), as well as a mitochondrial DNA 3243 mutation. It also notes defects in insulin action, including conditions like Type A insulin resistance, leprechaunism, Rabson-Mendenhall syndrome, and lipoatrophic diabetes. Additionally, diabetes can result from diseases of the endocrine pancreas such as fibrocalculous pancreatopathy, chronic pancreatitis, trauma or pancreatectomy, neoplasia, cystic fibrosis, and hemachromatosis. Endocrinopathies like Cushing syndrome, acromegaly, pheochromocytoma, glucagonoma, and somatostatinoma can also lead to diabetes, as can drug-induced causes including nicotinic acid, glucocorticoids, thyroxine, α-adrenergic agonists, thiazides, pentamidine, and vacor. Infections such as congenital rubella, cytomegalovirus, and mumps are listed as potential causes, along with rare immune-mediated conditions including insulin autoimmune syndrome, anti-insulin receptor antibodies, and "stiff man" syndrome.
Continuous subcutaneous glucose monitoring (CGM) was compared to self-monitoring of blood glucose (SMBG) in a clinical trial, showing only a small change in HbA1c values over 26 weeks, ranging from a 0.5% (6 mmol/mol) improvement to no change. The effectiveness of CGM was more pronounced in individuals aged 25 years or older. The findings indicate that merely monitoring blood glucose without systematically adjusting insulin or oral medications based on the data may have limited impact on long-term metabolic control in diabetes.
Metformin use in diabetes management is supported by evidence from the UKPDS trial, which showed a 39% risk reduction in myocardial infarction and 36% risk reduction in total mortality among 342 obese individuals with newly diagnosed diabetes. However, the subgroup's small sample size and limited number of events restrict the generalizability of these findings. As a result, the ESC recommends SGLT-2 inhibitors or GLP-1 receptor agonists as first-line therapy for patients with diabetes and high or very high cardiovascular risk, while metformin is recommended only for those with moderate cardiovascular risk. In contrast, the ADA/EASD continue to recommend metformin as first-line therapy for most people with type 2 diabetes.
Low adherence to recommended treatment guidelines is common among both individuals with type 2 diabetes and healthcare providers. A multidisciplinary approach is currently advocated for treating type 2 diabetes, involving system support for evidence-based guidelines, reorganization of practice systems and team functions, support for patient self-management, improved access to expertise, and better availability of clinical information to monitor and provide feedback on physician performance. Key elements of quality diabetes care by a multidisciplinary team include periodic risk stratification, protocol-driven care with regular review, patient empowerment, treatment-to-target strategies, and thorough record keeping to track clinical progress and outcomes.
Infants of mothers with diabetes commonly have a raised haematocrit, possibly due to fetal hyperinsulinaemia and chronic tissue hypoxia, and are at increased risk of respiratory distress syndrome, most likely related to prematurity and delivery by caesarean section. Jaundice is more common in large-for-gestational-age (LGA) babies and is likely multifactorial, including birth trauma, erythrocytosis, haemolysis, and immature hepatic bilirubin conjugation. Transient hypertrophic cardiomyopathy, characterized by ventricular septal hypertrophy obstructing the left ventricular outflow tract, occurs in 30–80% of these infants and may present with congestive cardiac failure but typically resolves within one month without sequelae. Transient neonatal hypocalcaemia, possibly related to glycaemia or hypomagnesaemia, can occur but is rarely clinically significant unless other complications like perinatal hypoxia–ischaemia are present, and routine screening is not required.
Metformin is an effective antidiabetic medication that improves insulin sensitivity in patients with HIV lipodystrophy but should be used cautiously in those receiving NRTIs or with impaired renal function due to the risk of lactic acidosis. Thiazolidinediones also enhance insulin sensitivity in this population, though rosiglitazone may exacerbate hyperlipidemia. Insulin therapy should follow standard guidelines, and substituting an NNRTI for a PI may improve insulin resistance, although this must be weighed against potential risks to viral control. Collaboration with an HIV physician is crucial, and in some cases, intensifying antihyperglycemic treatment may be preferred over altering the HAART regimen.
Hyperglycemia impairs immune function by affecting macrophages, monocytes, and neutrophils, leading to reduced adherence to endothelium, chemotaxis, phagocytosis, and bactericidal activity. Additional abnormalities include compromised apoptosis, wound healing, and cytokine responses to infection, with antioxidant systems also being affected. These impairments are worsened by hyperglycemia and acidaemia but may be partially or fully reversed by normalizing pH and blood glucose levels. The severity of these effects does not always correlate predictably with HbA1c levels, possibly due to long-term changes such as the accumulation of advanced glycation end-products (AGEs), which are thought to contribute to impaired neutrophil function. Improved diabetes control generally enhances both innate and adaptive immune function, although the relationship with HbA1c can be variable.
Local complications of insulin therapy include lipoatrophy and lipohypertrophy, both of which can affect insulin absorption and blood glucose control. Lipoatrophy, an allergic response mainly associated with older animal insulins, involves the loss of subcutaneous fat at the injection site and is now rarely seen. Lipohypertrophy, which is common and not allergic, results from a trophic response of adipose tissue to insulin, often due to poor injection technique or failure to rotate injection sites. Injecting into areas of lipohypertrophy can lead to inconsistent insulin absorption and impaired glycemic control. Lipohypertrophy typically resolves within two months if injections are avoided in the affected area. Other injection site issues include mild ulceration, pitting, and bruising, which may be managed by rotating sites and using shorter needles.
Fasting and weight loss can improve carbohydrate metabolism in individuals with diabetes. Protein-sparing modified fasts, similar to modern very low-energy or very low-calorie diets (VLED/VLCD), were studied in the 1970s for managing insulin-treated type 2 diabetes, showing that within 19 days, insulin could be discontinued with improvements in blood pressure, lipids, carbohydrate metabolism, and cardiorespiratory function while maintaining lean body mass. Although a 2004 Cochrane review found insufficient evidence to favor VLCDs over other diets for type 2 diabetes, subsequent research has continued to support their benefits. In individuals with type 2 diabetes undergoing VLED treatment, β-cell function improves, along with reductions in fasting plasma insulin and C-peptide levels, and enhancements in dynamic insulin secretion, overall insulin production, pulsatility modulation, and improved synchrony.
In families with multiple siblings who have type 1 diabetes, if one sibling has advanced diabetic nephropathy, the other sibling has a 72–83% risk of developing nephropathy, compared to a 17–22% risk if the first sibling does not have nephropathy. Genetic factors influence the risk of diabetes complications, with associations found between diabetic nephropathy and polymorphisms in genes such as HLA-DQB1, aldose reductase, sorbitol dehydrogenase, and erythropoietin. Studies have identified links between diabetic nephropathy and variations in 20 genes, including those involved in growth factors, intracellular processes, extracellular matrix components, and kidney function. Additionally, the DCCT/EDIC trial found familial clustering of severe retinopathy and coronary artery calcification in people with diabetes, and variants of the superoxide dismutase 1 gene were linked to the progression of diabetic nephropathy.
Persistent hyperglycemia, defined as blood glucose greater than 7.0 mmol/L, in the 72 hours following an acute stroke is linked to increased infarct size and poorer stroke outcomes. Despite this association, there is currently a lack of conclusive evidence regarding the impact of plasma glucose control on stroke outcomes. The largest study to date, involving 993 patients, did not achieve effective glucose control within 24 hours, and no studies have yet evaluated glucose management in the critical early hours after stroke presentation, which may be the optimal time to address hyperglycemia for better outcomes.
Intensive diabetes therapy in patients with type 1 diabetes mellitus (T1DM) slows but does not fully prevent the development of diabetic peripheral neuropathy (DPN). Long-term benefits of intensive therapy on neuropathy, as observed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, persist for at least 8 years after the end of the Diabetes Control and Complications Trial (DCCT), even when HbA1c levels become similar between treatment groups, a phenomenon known as hyperglycemic memory. In patients with T1DM and advanced peripheral neuropathy, nerve conduction deficits may stabilize after 3–4 years of normoglycemia following pancreatic transplantation, though autonomic neuropathy does not improve. The DCCT data suggest that there is no specific HbA1c threshold for the onset or progression of long-term complications in T1DM, indicating that optimal glycemic control should aim for normal glycemia rather than a particular HbA1c target within the diabetic range. Intensive diabetes therapy is associated with an increased risk of weight gain and hypoglycemia.
Hyperglycemia induces long-lasting changes in chromatin remodeling, leading to persistent atherogenic effects during subsequent normoglycemia. This occurs through the recruitment of the histone methyltransferase Set7, resulting in increased H3K4 monomethylation at the proximal promoter region of the NFkB subunit p65 gene, which enhances the expression of pro-atherogenic pathways such as monocyte chemotactic protein 1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1). Studies in mice that transitioned from diabetes to normoglycemia have shown persistent upregulation of pro-inflammatory genes like p65 and MCP-1 due to prior hyperglycemia. Further epigenetic research has identified additional changes, including H3K9 methylation of the p65 promoter and alterations in various histone methyltransferases and demethylases such as LSD-1.
Adherence to diet, exercise, monitoring, and medication is required for optimal diabetes outcomes. Confidence, also referred to as self-efficacy, plays a key role in a patient's ability to make behavior changes, and can be enhanced through problem-solving and discussion of alternative strategies. Patient empowerment and increased self-efficacy are important for enabling individuals to feel confident in making necessary changes. Motivational interviewing is a promising behavior change approach from the psychological literature that has been applied to diabetes care. Clinician counseling style significantly influences patient readiness to change, either increasing resistance or facilitating behavior change. Social and societal factors also impact adherence in diabetes management.
Lifestyle interventions, particularly in type 2 diabetes mellitus (T2DM), are an established and effective therapeutic strategy for achieving target glycemic control and should be initiated as part of the treatment for new-onset T2DM. Modest weight loss, especially in abdominal fat, improves insulin sensitivity, glucose tolerance, and serum lipid concentrations while reducing blood pressure, with greater benefits for cardiac risk factors observed in individuals with a high waist circumference. Visceral body fat, measured by waist circumference, is used along with body mass index (BMI) to assess the risk of diabetes and cardiovascular disease (CVD).
Diabetes is strongly associated with cardiovascular disease (CVD), with the link first noted over a century ago and later attributed to atherosclerosis in 1906. Landmark studies, including the Framingham Study, established diabetes as a significant CVD risk factor, showing a two- to fourfold increase in risk. Many guidelines consider diabetes a coronary heart disease (CHD) risk equivalent, a concept supported by a Finnish cohort demonstrating that individuals with type 2 diabetes mellitus (T2DM) for over 10 years had CHD outcomes comparable to those with established CHD, even after adjusting for other risk factors. The OASIS study further showed that patients with diabetes and no prior CVD had similar long-term mortality and morbidity after hospitalization for unstable coronary artery disease as those with established CVD but no diabetes. However, this equivalence varies depending on population, diabetes duration, and existing risk factors, and has not been consistently confirmed in all studies, particularly in older individuals. Most evidence pertains to T2DM, although type 1 diabetes mellitus (T1DM) also increases CVD risk, potentially leading to higher rates of premature CVD. A cohort of T1DM patients showed a 35% cumulative CAD mortality rate by age 55, highlighting the elevated CVD risk across all ages in T1DM, though direct comparisons with T2DM remain lacking.
In patients with type 1 diabetes mellitus (T1DM) who have proteinuria and hypertension, adding an ACE inhibitor to other antihypertensive therapy reduces the risk of a doubling of serum creatinine by 48% and decreases the composite endpoint of death, need for dialysis, or renal transplantation by 50%, with both benefits occurring independently of blood pressure. Short-term studies indicate that angiotensin II receptor blockers (ARBs) have similar effects on blood pressure and urinary albumin excretion as ACE inhibitors in proteinuric patients with T1DM.
GH secretory pulses are larger and more frequent in diabetes, particularly during periods of poor control, leading to elevated total GH levels. This contributes to insulin resistance, especially during early morning hours, causing the "dawn phenomenon" of fasting hyperglycemia, a condition more pronounced in individuals with T1DM. GH resistance is observed, as indicated by inappropriately low IGF-I levels despite high GH, attributed to reduced GH receptors and post-receptor defects, along with decreased GH-binding protein. Administration of recombinant human IGF-I (rhIGF-I), with or without IGFBP-3, can reverse GH hypersecretion, improve glycemic control, and reduce insulin requirements. rhIGF-I is also effective in treating severe insulin resistance involving impaired insulin receptors, such as in Donohue and Rabson-Mendenhall syndromes, and can manage ketoacidosis when insulin is ineffective.
Pregnancy can accelerate the progression of diabetic retinopathy, particularly in women with moderate to severe retinopathy who have hyperglycaemia before pregnancy and experience rapid improvements in glucose levels during the first trimester. The exact mechanism behind this progression is unknown, but it may involve hormonal, haemodynamic, metabolic, and immunological changes during pregnancy. In a study of 155 women with diabetes, the development of retinopathy varied based on baseline severity: 10.3% of those with no retinopathy developed it, compared to 21.1% with microaneurysms only, 18.8% with mild non-proliferative retinopathy, and 54.8% with moderate to severe non-proliferative retinopathy. Proliferative retinopathy developed in 6.3% of those with mild baseline retinopathy and 29% of those with moderate to severe baseline retinopathy. The risk of progression to sight-threatening retinopathy is estimated at 20–30% for women with moderate to severe retinopathy prior to pregnancy, but less than or equal to 2% for those with minimal or no retinopathy.
Genome-wide association studies have identified over 400 genetic variants for type 2 diabetes, with genetic susceptibility mediated through effects on insulin release and insulin sensitivity. Epigenetic effects that impair β-cell function, which can be acquired in utero or through lifestyle factors such as inactivity and obesity, are also linked to type 2 diabetes. Observational studies show correlations between obesity (and fat distribution) and type 2 diabetes, and the causal relationship between obesity and type 2 diabetes has been established using Mendelian randomization techniques. A polygenic risk score based on 93 obesity-related single-nucleotide polymorphisms found a nearly twofold increased risk for type 2 diabetes for each 4.83 kg/m² increase in BMI, a finding replicated in large-scale studies.
Thiazolidinediones, such as pioglitazone, exert insulin-sensitizing effects primarily through activation of PPARγ, but their clinical use is limited by side effects like fluid retention, increased adiposity, and bone resorption. Dual PPARγ and PPARα agonists (glitazars) offer lipid-lowering and anti-inflammatory benefits via PPARα but also have notable side effects. Triple PPARγ/α/δ agonists (pan-PPARs) add increased energy expenditure and weight loss through PPARδ activation, though they have not yet been approved for clinical use. Research continues into selective PPAR agonists for potential diabetes-related applications, including the treatment of hepatic steatosis.
Subcutaneous implantation of human pluripotent stem cell–derived insulin-producing cells is a promising approach in diabetes treatment due to its retrievability and ease of delivery, although it faces challenges related to poor spontaneous vascularization. A key objective is achieving tolerance of transplanted human pluripotent stem cell–derived β-like cells. Genetic strategies are being explored to help these cells evade the immune system after transplantation, including the use of gene editing to reduce the expression of human leucocyte antigen proteins and regulate immunomodulatory factors. Additional approaches involve cellular immunotherapy with monoclonal antibodies that target T-cell costimulatory pathways.
Social determinants of health, such as economic and social inequities shaped by political decisions, play a significant role in the risk and management of type 2 diabetes, with systemic and reinforcing structures contributing to long-standing, intergenerational impacts on the condition. Obesity, diabetes, and hypertension are more common and severe among certain racial groups, such as First Nations or African Americans, reflecting systemic factors that drive racial inequities in health.
HbA₁c standardization efforts began in 1995 through the IFCC, leading to the formation of an international network of reference laboratories in 1997 to implement a reference measurement procedure. This allowed for the development of conversion equations between IFCC values and national schemes like NGSP, facilitating global consistency. To avoid confusion due to differences in measurement systems, SI units were adopted for HbA₁c, aligning with blood glucose measurements in mmol/l. However, in countries using mg/dl for blood glucose, confusion persists, which is why the American Diabetes Association has not adopted SI units. Ongoing education remains essential to ensure proper understanding of HbA₁c changes among people with diabetes and healthcare professionals.
Bile acids influence insulin secretion through interactions with receptors expressed in islet cells, specifically the nuclear receptor farnesoid-X receptor (FXR) and the G-protein-coupled receptor TGR5. Activation of TGR5 has been shown to stimulate insulin secretion from mouse and human islets in vitro, while in vivo studies suggest that FXR is primarily responsible for enhancing insulin secretion. Alterations in bile acid composition and plasma concentrations following gastric bypass surgery, potentially due to changes in the gut microbiome, have been associated with improved β-cell function and metabolic regulation. However, recent studies in humans indicate a limited role for bile acids in acute glucose regulation after gastric bypass surgery when both FXR/TGR5-activating bile acids and bile acid sequestrants were administered.
Sulfonyureas, which are the most common oral hypoglycemic agents used in the treatment of diabetes, can cause various skin reactions in 1–5% of patients taking first-generation formulations, typically within 2 months of starting treatment. Common cutaneous reactions include maculopapular, morbilliform, urticarial, or generalized erythematous eruptions, which usually resolve once the medication is discontinued. Photosensitive reactions, particularly of the photoallergic type, and lichenoid eruptions have also been reported. Erythema multiforme, a severe drug reaction characterized by erythematous and hemorrhagic skin lesions including "target" lesions, may occur and can progress to extensive blistering involving mucosal surfaces. Involvement of the conjunctiva in such reactions requires urgent ophthalmologic evaluation. Less commonly, sulfonyureas may trigger erythema nodosum or exacerbate porphyria cutanea tarda.
Gestational diabetes mellitus (GDM) is associated with higher prevalence rates in South Asian and Hispanic populations, reflecting the higher background prevalence of type 2 diabetes. The rate of intrauterine growth in GDM is as rapid as in type 1 and type 2 diabetes. Early diagnosis of GDM provides significant benefits for both mother and child, and the risk of developing subsequent diabetes in women with GDM ranges from 2.6% to 70% over periods from 6 weeks to 28 years. According to NICE guidelines, blood glucose testing should occur prior to discharge to rule out persistent hyperglycaemia, followed by fasting plasma glucose testing at 6–13 weeks postpartum, or HbA1c testing after 13 weeks if necessary, with annual HbA1c tests for those with an initial negative postnatal test. These measures may miss some cases with normal fasting glucose but impaired glucose tolerance, and it is important to emphasize that a history of GDM should prompt recommendations for significant lifestyle changes and weight loss.
Increased gene and protein expression of Nox1 and Nox4 occurs in hyperglycaemic conditions associated with increased atherosclerosis. Nox1-derived superoxide plays a role in AGE-mediated vascular smooth muscle cell activation and diabetes-associated endothelial dysfunction, and has been shown to accelerate atherosclerosis in the aorta of diabetic mice. While Nox4 is constitutively expressed and primarily produces hydrogen peroxide, its role in vascular disease depends on the disease and experimental model; recent evidence suggests a vasculoprotective role for Nox4 in long-term diabetes-associated atherosclerosis.
Thiazolidinediones, a class of medications used in the management of diabetes, have been associated with an increased risk of bone fractures, particularly at distal sites and among postmenopausal women, partly due to a reduction in bone mineral density. Additionally, there has been concern regarding a potential increased risk of bladder cancer with the use of pioglitazone, although long-term safety analyses have not confirmed a significant increase in risk; nevertheless, the drug is not recommended for individuals with active or a history of bladder disease. Theoretical concerns also exist about the effect of PPAR-γ stimulation on tumor risk, leading to a contraindication for thiazolidinediones in familial polyposis coli.
HNF4A mutations are linked to an increased risk of diabetes, with affected individuals showing reduced insulin secretion in later life after a period of increased insulin secretion during fetal development and early infancy, and they also exhibit reduced HDL levels along with elevated LDL levels.
Teplizumab and otelixizumab are anti-CD3 monoclonal antibodies that may help in type 1 diabetes by reducing activated autoreactive T cells, which contribute to the destruction of pancreatic beta cells. These antibodies cause a temporary decrease in CD4+ and CD8+ T cells during treatment, with a preferential depletion of T-effector cells that maintain inflammation in the pancreas, while favoring the preservation of regulatory T cells (Tregs), which promote immune tolerance. Following treatment, Tregs and CD8+ T-effector cells with an exhausted phenotype may expand, potentially contributing to a more tolerogenic immune environment.
DPP-4 (dipeptidyl peptidase 4) is an enzyme involved in the degradation of GLP-1 (glucagon-like peptide 1), a hormone that enhances insulin secretion and is relevant in the management of diabetes. ESRD (end-stage renal disease) is a severe complication that can arise from long-standing diabetes due to progressive kidney damage, often assessed using eGFR (estimated glomerular filtration rate), which measures kidney function.
A diabetes-focused model of care incorporating metabolic surgery emphasizes improved glycaemic control as a primary treatment target, although weight loss is often considered secondary. However, obesity plays a significant role in the pathophysiology of type 2 diabetes, and bariatric surgery can influence multiple pathways involved in obesity development. Following bariatric procedures such as sleeve gastrectomy and Roux-en-Y gastric bypass (RYGB), there are notable changes in gut hormone secretion, particularly GLP-1 and PYY, which are linked to both improved glucose metabolism and appetite regulation. GLP-1, secreted by terminal ileal L cells, contributes to rapid improvements in glucose homeostasis and also reduces appetite. PYY further enhances satiety by decreasing gastric acid secretion and delaying gastric emptying, counteracting hunger signals that arise from reduced leptin levels after surgery. Additionally, the anatomical bypass of the proximal small bowel during RYGB leads to increased bile acid exposure in the terminal ileum, further stimulating GLP-1 release and supporting sustained postprandial satiety and weight loss maintenance.
Transdermal insulin delivery via microneedles can effectively lower glucose levels, and the smart insulin patch utilizes glucose-responsive vesicles made of hypoxia-sensitive hyaluronic acid loaded with insulin and glucose oxidase enzyme. In a hyperglycemic state, glucose oxidation causes hypoxia, which reduces hyaluronic acid and triggers vesicle dissociation to release insulin. This patch has demonstrated effectiveness in regulating glycaemia in vivo, and similar patches with insulin-loaded microneedles and non-degradable glucose-responsive polymers have shown good function in animal models. These glucose-responsive insulin systems are still in early development but hold promise as potential functional replacements for pancreatic β cells.
Candida albicans infection can be a presenting feature or a complication of poorly controlled diabetes, manifesting as erythematous papules with satellite pustules in flexural areas, the vulva and penis, and nail margins causing paronychia. In women, vulvovaginitis is common, presenting with intense pruritus and erythematous, fissured vulva with peripheral pustulation, especially during hyperglycemia and glycosuria. Men may experience candidal balanitis, balanoposthitis, or phimosis, which can be initial signs. Oral manifestations include angular stomatitis and an atrophic tongue resembling median rhomboid glossitis, with oral candidiasis more frequent in diabetic patients who smoke or wear dentures. Candidal intertrigo affects opposing skin surfaces such as under the breasts, in the groins and axillae, or abdominal folds, and scratching can lead to bacterial superinfection.
Type 1 diabetes incidence varies widely across the world, with the highest rates observed in individuals of northern European descent, while most countries have a lifetime risk of less than 1%. Incidence in childhood is similar between sexes, but men are more commonly affected in early adulthood. An annual incidence rate of 20 per 100,000 corresponds to a cumulative incidence of approximately 0.3% by age 15, or 1 in 330 children, with a prevalence of about 0.15% in the 0–15 years age group. Childhood type 1 diabetes incidence is rising rapidly globally, particularly in children under 5 years, with the European incidence doubling over the last two decades. The annual increase of 2–4% equates to doubling times of 18–35 years, though the relative increase is more pronounced in low-incidence regions like Japan. This rising trend suggests a significant environmental influence, although specific pathogenic factors remain unclear. Recent studies in children with genetic predisposition are offering new insights into potential mechanisms, including virus infections, though some regions like Australia and Finland have reported decreases in incidence.
The prognosis for individuals with diabetes, especially type 1 diabetes, has significantly improved over the past 50 years, with median life expectancy increasing by over 15 years in the last 30–40 years, largely due to reduced rates of diabetic nephropathy. Research suggests that life insurance assessments for people with type 1 diabetes should focus on the risk of developing diabetic nephropathy, and a model has been proposed to calculate insurance terms based on factors such as current age, age at diagnosis, sex, presence of nephropathy or proliferative retinopathy, and other pre-existing conditions. The risk of developing new nephropathy decreases after 25 years of diabetes duration, and individuals who reach 50 years of age without nephropathy should receive reduced insurance premiums. Regular updates of mortality and life expectancy data are necessary to avoid penalizing people with diabetes and to inform actuarial advisers and insurance underwriters.
Hyperglycaemia, defined as serum glucose levels exceeding 400 mg/dL (22.2 mmol/L), is a contraindication for inclusion in certain clinical trials due to concerns such as its potential to cause focal neurological deficits that mimic stroke. Current guidelines recommend initiating aggressive glycaemic management when serum glucose exceeds 200 mg/dL (11.1 mmol/L), while also recognizing that levels between 140–185 mg/dL (7.8–10.3 mmol/L) may still pose harm. In some clinical scenarios, it may be reasonable to attempt glucose reduction to assess for improvement in focal neurological symptoms before proceeding with thrombolysis if no improvement occurs, although this approach remains untested.
Allergic reactions to insulin, though less common with modern human and analogue insulins, can occur either to the insulin molecule itself or to components of the preparation such as protamine or metacresol. These reactions typically present as local acute urticarial responses and can be managed by identifying a better-tolerated insulin preparation through intradermal skin testing, often using 1:20 dilutions. Antihistamines are often helpful, and in severe cases, high-dose steroids may be used. Rarely, systemic allergic reactions occur, necessitating referral to clinical immunology services.
For individuals with diabetes, particularly those facing personal, social, and financial barriers, effective self-management support relies on understanding and negotiation rather than direct instruction. Healthcare educators should acknowledge the individual's autonomy in decision-making and engage in dialogue to address informational, motivational, emotional, relational, or practical barriers to behavior change. The AADE7 Self-Care Behaviors framework emphasizes key behaviors including healthy eating, physical activity, glucose monitoring, medication adherence, problem-solving, risk reduction, and healthy coping. Successful implementation of self-management support requires a collaborative relationship where the person with diabetes feels comfortable discussing their challenges without judgment.
Sibutramine has been studied in diabetes management, often in combination with sulfonylureas, metformin, or a hypocaloric diet, leading to an average body weight loss of 5.5 kg compared to approximately 1 kg weight gain in comparator groups. It also resulted in an average HbA1c improvement of 0.28% (3 mmol/mol), with variability across studies. Additional benefits included reductions in triglycerides and increases in high-density lipoprotein (HDL), without adverse effects on blood pressure, though small increases in heart rate were observed. Hypertension, particularly if poorly controlled, is a contraindication for sibutramine use due to the sensitivity of diabetic patients to minor blood pressure fluctuations and the impact of blood pressure on diabetes complications.
Whole pancreas transplants have become feasible, particularly during renal transplantation for end-stage diabetic nephropathy, with advancements in immunosuppression and surgical techniques. Early challenges such as peritonitis from exocrine drainage were addressed by using bladder drainage, leading to over 80% one-year graft survival rates. Newer techniques involving enteric drainage have further reduced complications, including metabolic acidosis from bicarbonate loss associated with bladder drainage. Although more than 25,000 pancreas transplants have been performed worldwide and one-year graft survival has improved due to fewer technical and immunologic failures, the 10-year survival rate remains at 48% for deceased donor transplants between 1995 and 1999. Simultaneous pancreas-kidney transplantation shows better graft survival compared to pancreas transplant alone or staged transplants. The procedure still carries some morbidity and mortality but provides excellent glycemic control, which can reverse diabetic renal lesions, stabilize or improve neuropathy and vascular status, and stabilize retinopathy, though not necessarily improve it.
Metformin counters insulin resistance, while sulfonylureas and prandial insulin releasers stimulate insulin secretion, with the latter being rapid or short-acting. Thiazolidinediones increase insulin sensitivity through PPARγ agonism. GLP-1 analogs and DPP-4 inhibitors both potentiate insulin secretion. α-Glucosidase inhibitors inhibit carbohydrate digestion, and pramlintide promotes satiety, slows gastric emptying, and decreases glucagon. Insulin decreases glucose production and increases glucose disposal, storage, and utilization. Other agents with blood glucose-lowering activity include acipimox and niacin, which decrease lipolysis and reduce NEFAs; alcohol, which inhibits gluconeogenesis; quinine and salicylates, which stimulate insulin secretion; and β-adrenoceptor blockers, which inhibit the adrenergic counter-regulatory response.
In studying type 2 diabetes mellitus (T2DM), robust survey methods are essential for accurate comparison and standardization, with large, random community samples and high response rates being most reliable. Workplace samples may introduce a "healthy worker" effect, and selective samples such as volunteers or those with other diseases are less useful due to recruitment bias. Age distribution is critical in T2DM research as prevalence increases with age, requiring age-stratified populations and age-adjusted comparisons either internally or against a reference population. Accurate ascertainment methods, such as the use of oral glucose tolerance tests (OGTT), with or without initial blood glucose screening, are also vital for reliable diagnosis and data collection.
When managing diabetes with an insulin pump, reviewing priming history helps assess how often the infusion system is changed, which can affect insulin delivery. Examining bolus history is important to identify missed meal boluses, which can contribute to hyperglycemia. The ratio of basal to bolus insulin is also significant; a high basal percentage in someone with frequent high blood sugar may indicate missed boluses, while a high basal percentage in someone with frequent low blood sugar may suggest that the basal rates are too high and need adjustment. Pump suspension or basal rate reductions, even temporarily for activities like bathing, can lead to elevated glucose levels, emphasizing the need for a bolus to compensate for the missed basal insulin. Some individuals may reduce basal rates or suspend the pump when experiencing hypoglycemia, but this can result in a rebound effect, causing significant hyperglycemia afterward.
Adults with type 1 diabetes who experience recurrent hypoglycaemia, or a single episode of severe hypoglycaemia accompanied by seizure or coma, develop greater fear of hypoglycaemia, which can lead to broader diabetes-specific distress and impaired emotional well-being. This fear is influenced by pre-existing personality traits such as neuroticism or trait anxiety, as well as current psychological distress. Research has identified four subgroups based on the relationship between fear of hypoglycaemia and risk of severe hypoglycaemia — low fear/low risk, high fear/high risk, low fear/high risk, and high fear/low risk — highlighting the complexity of this fear and the importance of understanding its nature to determine appropriate clinical interventions.
Low insulin-like growth factor I (IGF-I) levels are associated with impaired glucose metabolism and may contribute to insulin resistance, a key feature in the pathophysiology of type 2 diabetes. IGF-I plays a role in mediating the effects of growth hormone and has insulin-sensitizing properties, and its deficiency may be linked to increased risk of metabolic complications, including diabetes.
People with severe mental illness (SMI) have higher rates of microvascular and macrovascular complications, acute metabolic dysregulation, and three- to fourfold more diabetes-related deaths. A study from Denmark found that among individuals diagnosed with diabetes, 15.0% of those aged ≤50 years, 30.7% of those aged 50–69 years, and 63.8% of those ≥70 years died within seven years. A third of physical cause deaths were attributed to diabetes, with 14% linked to the interaction between diabetes and SMI. Additionally, an observational study in England found that SMI was associated with nearly double the risk of all-cause mortality and over twofold increased cardiovascular-specific mortality in people with diabetes.
In resource-rich countries, mobile phones have been integrated into diabetes care through real-time telemedicine systems, where blood glucose monitors are connected to mobile phones to transmit patients' glucose levels with subsequent feedback, and studies have shown the feasibility and effectiveness of this approach in randomized controlled trials, with further advancements including direct blood glucose measurement via mobile phones and the development of specialized devices like the "diabetes phone."
A single intracerebroventricular injection of human or mouse fibroblast growth factor (FGF)-1 at a dose of 3μg induces sustained diabetes remission in a mouse model of type 2 diabetes (Lepob/ob mice), demonstrating the potential of central FGF-1 treatment for long-term blood glucose lowering in diabetes.
Hyperglycemia contributes to metabolic memory through various molecular mechanisms, including the formation of advanced glycation end products (AGEs), glycation of DNA, and increased glucose metabolism flux, which lead to oxidative damage, overproduction of PKC-β, and mitochondrial stress. Transient hyperglycemia can induce long-lasting epigenetic changes in the promoter region of the NFκB subunit p65 in aortic endothelial cells, both in vitro and in vivo, which can be prevented by reducing mitochondrial superoxide production or the generation of α-oxoaldehydes like methylglyoxal. These epigenetic changes result in persistent atherogenic effects during later normoglycemia by altering chromatin remodeling, with reactive oxygen species (ROS) playing a key role in modulating glucose-responsive pathways. Specifically, hyperglycemia promotes the recruitment of the histone methyltransferase Set7 to the nucleus, increasing H3K4 mono-methylation in the proximal promoter region of relevant genes.
Diabetes prevalence varies across populations and regions, with studies in South Africa showing higher rates in both urban and rural communities. In Cape Town, the age-adjusted prevalence of diabetes is 8%, while impaired glucose tolerance stands at 7%. A rural South African study using a 75g OGTT and 1998 WHO criteria found an overall age-adjusted diabetes prevalence of 3.9%, with 85% of cases previously undiagnosed. Additional risk factors for type 2 diabetes in African populations include family history, ethnic origin, central adiposity, and physical inactivity. Ethnic differences have been observed, with migrant Asians in Tanzania and South Africa showing higher diabetes prevalence than Indigenous Africans, potentially due to lifestyle differences. A systematic review of 11 South African studies from 1997 to 2020 found a pooled prevalence of type 2 diabetes at 15.25% in adults aged 25 or older, with 9.59% for impaired glucose tolerance, 3.55% for impaired fasting glycaemia, and 8.29% for newly diagnosed type 2 diabetes.
Autoantibodies against the GAD65 isoform (GAD65Ab) are present in 70–80% of children with new-onset type 1 diabetes mellitus (T1DM), in 8% of first-degree relatives of T1DM patients, and in about 1% of the general population. Unlike islet cell autoantibodies (ICA), GAD65Ab remain detectable for many years even after significant loss of beta-cell function, and their detection rate increases with age at T1DM onset. A gender difference is observed when the onset occurs before 10 years of age, with a higher prevalence in females. GAD65Ab levels are persistent, more common, and correlate well with plasma C-peptide levels, making them valuable markers for predicting and monitoring beta-cell dysfunction in individuals at risk for T1DM.
SGLT-2 inhibitors reduce the risk of cardiovascular and renal outcomes, including cardiovascular fatal and non-fatal events and end-stage kidney disease, with consistent benefits across individuals regardless of the degree of kidney impairment, presence of heart failure, cardiovascular disease, or diabetes. These drugs are broadly beneficial for many people with diabetes, making precision medicine less relevant in their use. However, a clinical trial with dapagliflozin showed that approximately 20% of treated individuals did not respond to the drug in terms of systolic blood pressure or albuminuria reduction, and the same individuals remained non-responsive upon re-exposure to the same dose after a six-week washout period, highlighting variability in treatment response that should be further studied for other diabetes treatments to develop strategies to address therapy resistance.
The diagnostic criteria for diabetes and intermediate hyperglycaemia differ between the WHO and ADA, with the ADA using a lower threshold for impaired fasting glucose, leading to more diagnoses of intermediate hyperglycaemia compared to WHO guidelines. Increased use of diagnostic tools like the oral glucose tolerance test can raise the ratio of diagnosed to undiagnosed diabetes and influence reported prevalence rates. Studies show that using HbA1c ≥ 6.5% (48 mmol/mol) to diagnose diabetes has a pooled sensitivity of approximately 53%, lower than diagnosing with fasting glucose ≥ 7.0 mmol/L, indicating that HbA1c identifies fewer cases in populations without a known history of diabetes.
Living with diabetes involves managing glucose levels through insulin administration, monitoring food intake and physical activity, and adjusting insulin, food, or exercise in response to fluctuating glucose levels or during illness. For individuals with type 1 diabetes or insulin-treated type 2 diabetes, this includes regular insulin dosing and frequent glucose checks, while those with non-insulin-treated type 2 diabetes may follow a less intensive regimen.
Vitamin D has been shown to have immunomodulatory effects and may have a preventive role in diabetes development in experimental animals when administered in pharmacologic, hypercalcemic doses. The systemic concentration of 1,25-dihydroxyvitamin D, the active form of vitamin D, is tightly regulated through hydroxylation of 25-hydroxyvitamin D, a factor that must be considered in interpreting animal studies. Vitamin D can be synthesized in the skin upon ultraviolet exposure, but no prospective studies have yet established a link between serum 25-hydroxyvitamin D levels and the risk of type 1 diabetes mellitus (T1DM). A multicenter case-control study reported a lower risk of T1DM associated with early-life vitamin D supplementation, although potential biases may have influenced the findings; this result was supported by a prospective Finnish study. However, prospective studies examining maternal dietary vitamin D intake during pregnancy and the risk of islet autoimmunity in children have not provided strong evidence of a relationship.
In the early stages of type 2 diabetes mellitus (T2DM), several defects in islet β-cell function occur, including a reduced and eventually lost acute first-phase insulin secretory response to glucose, impaired processing of proinsulin to insulin, and a disturbed pulsatile rhythm of basal insulin secretion. The second phase of insulin secretion is often extended but diminished in magnitude, coinciding with prolonged postprandial hyperglycemia. In advanced stages of T2DM, β-cell mass and insulin biosynthesis become compromised. An ideal insulin secretagogue would restore β-cell sensitivity to glucose and support adequate biosynthesis, processing, and secretion of insulin in response to other nutrients, hormones, and neural factors. Insulin secretagogues are categorized into initiators, such as sulfonylureas, which stimulate insulin secretion on their own or with low glucose concentrations, and potentiators, such as GLP-1 analogs, which enhance the effect of rising glucose and other secretagogues but do not induce insulin release independently of glucose.
Islet transplantation is offered to patients with type 1 diabetes mellitus (T1DM) who experience severe hypoglycemia, hypoglycemia unawareness, or glycemic lability despite optimal medical therapy, which includes frequent blood glucose monitoring and multiple daily insulin injections or continuous subcutaneous insulin infusion. The decision to proceed with transplantation is primarily based on clinical judgment, though tools like the HYPO score and lability index (LI) provide an objective measure. Some patients continue to develop progressive complications even with optimized medical therapy, although they are now considered exceptions due to concerns that immunosuppression may worsen renal impairment.
Mitochondrial diabetes is primarily caused by the m.3243A > G point variant in mitochondrial DNA, which impairs the mitochondrial respiratory chain and leads to cellular energy deficiency. This variant particularly affects organs with high metabolic activity, such as the endocrine pancreas, resulting in abnormal beta-cell function, loss of beta-cell mass, and insulin deficiency. Mitochondrial DNA is inherited maternally, so only the maternal line is affected, and all children of an affected woman inherit the variant, although the severity of the condition varies widely within families due to heteroplasmy, which leads to variable proportions of variant and wild-type mitochondrial DNA in different tissues.
The diagnosis of diabetes, particularly type 1, can contribute to the development of eating disorders in individuals with pre-existing vulnerability factors such as early life events, major life transitions, past psychiatric history, or personality traits like perfectionism. Drastic weight loss prior to diagnosis followed by weight regain due to rehydration and insulin treatment, along with the necessity of monitoring carbohydrate intake and food management, may trigger disordered eating behaviors. Traits including perfectionism, low self-esteem, poor body image, and difficulties with emotion regulation increase susceptibility when combined with the dietary focus required in diabetes management. These factors can lead to harmful behaviors such as strict dieting, insulin restriction, and binge eating, which in turn cause neuroadaptive changes related to loss of control over eating and fluctuating blood glucose levels. The cycle is perpetuated through dietary restriction causing hypoglycemia, followed by binge eating and hyperglycemia, often accompanied by purging or further insulin restriction.
The CEMACH study found that only 37.1% of pregnancies had an HbA1c measurement within 6 months of conception, with evidence of good glycemic control, defined as HbA1c < 53 mmol/mol (< 7.0%), observed in 24% and 41% of women with type 1 and type 2 diabetes, respectively. Further analysis showed that 88% of women with poor pregnancy outcomes, defined as major congenital anomalies, stillbirths, or early neonatal deaths, had suboptimal pre-pregnancy HbA1c levels, compared to 69% of women with good outcomes.
Improvement in glycaemic levels can occur with alcohol withdrawal, better diet, and weight loss, and structured diabetes care can be effectively provided by a specialist physician. However, facilities for managing diabetes in police custody are often limited, lacking the ability to measure blood glucose, treat emergencies, or provide insulin and appropriate meals. A Scottish initiative between a diabetes department and local police improved custody facilities through the provision of glucose monitoring equipment and training for police staff, supported by forensic nursing services.
Covid-19 contributes to worsening dysglycaemia in individuals with diabetes beyond the effects of stress hyperglycaemia, and case reports suggest that SARS-CoV-2 may potentially trigger new-onset diabetes. Some hospitalized individuals without a prior history of diabetes developed hyperglycaemia during Covid-19, with some having normal HbA1c levels on admission. A meta-analysis reported a pooled proportion of 14.4% for newly diagnosed diabetes among hospitalized Covid-19 patients, while another cohort study found a lower rate of 4.9% newly diagnosed cases in a similar population.
Type 1 diabetes mellitus (T1DM) is associated with several endocrine disorders due to shared autoimmune etiology and pathology, such as autoimmune adrenalitis (Addison disease) and autoimmune thyroid disease. Patients with T1DM require monitoring for new autoimmune conditions, and annual screening for thyroid dysfunction via serum TSH measurement is recommended. Addison disease increases insulin sensitivity in diabetic patients, leading to reduced insulin requirements and unexpected hypoglycemic episodes. Hypoglycemia can also occur in Addison disease even without diabetes, particularly in children. Rare conditions with features similar to T1DM, such as autoimmune polyglandular syndromes or POEMS syndrome, may present with multiple endocrinopathies. Monogenic forms of diabetes can affect other endocrine organs, as seen in hemochromatosis (primary hypogonadism), Wolfram syndrome (diabetes insipidus), and Kearns-Sayre syndrome (hypoparathyroidism, hypogonadism, and hypopituitarism). Polycystic ovarian syndrome (PCOS), characterized by insulin resistance, is another complex endocrine disorder linked to mechanisms involved in glucose homeostasis during pregnancy and obesity.
Secretagogues, which can be rapid or longer-acting, are effective when used with metformin or thiazolidinediones, and are also evidence-based when combined with basal insulin therapy such as evening NPH or glargine. Their use alongside a regimen of evening basal plus mealtime insulin helps reduce insulin requirements and prevents interim hyperglycemia during insulin dose adjustments, though using them with two or more mealtime insulin doses is unnecessary and may increase the risk of hypoglycemia. Insulin secretagogues function by binding to sulfonylurea receptors (SUR1A subtype in the pancreas), which are linked to potassium inward rectifier (Kir 6.2) channels; when these channels close due to secretagogue binding, calcium channels open and insulin is released. The DIGAMI-1 study demonstrated that insulin treatment reduced mortality from acute myocardial infarction in patients with diabetes mellitus compared to usual care, suggesting that secretagogues, especially glyburide, should be avoided in those with active ischemic heart disease. However, the DIGAMI-2 study did not confirm the same mortality benefit observed in DIGAMI-1.
Some recommendations for improving diabetes management in care homes include ensuring proper training for staff in diabetes care, maintaining individualized care plans, regularly monitoring blood glucose levels, promoting appropriate nutrition and hydration, encouraging physical activity as tolerated, and ensuring timely administration of medications including insulin when required.
Coping skills training programmes improve diabetes management skills in adolescents undergoing intensive insulin therapy by using a cognitive behavioural skills-building model. These programmes involve role-playing social scenarios that challenge diabetes management, such as making food choices with friends, with guidance from trained leaders who model and correct coping behaviours. A typical programme consists of six weekly sessions of 60–90 minutes each, followed by monthly visits. Over a 12-month follow-up, adolescents who received this training alongside intensive diabetes management showed significantly lower HbA1c levels (7.5% vs. 8.5% [58 vs. 69 mmol/mol]), greater self-efficacy, and reduced difficulty coping with diabetes and lower rates of depression compared to those receiving intensive management alone.
DPP-4 inhibitors enhance glucose-dependent insulin secretion through an incretin-mediated effect, primarily acting during meals to lower postprandial hyperglycemia, with a carry-over effect on interprandial glycemia. These agents do not initiate insulin secretion independently and only suppress glucagon secretion in hyperglycemic conditions, resulting in a low risk of hypoglycemia during interprandial periods.
Understanding the burden of diabetes-related complications is crucial for comprehending the overall health impact of diabetes, providing context to changes in diabetes prevalence. Despite extensive international assessments of diabetes growth, there is limited data on the global burden and variation in incidence of diabetes-related complications, largely due to the concentration of studies in high-income countries (HIC) such as Europe, North America, and parts of the Asia-Pacific, with minimal data from low- and middle-income countries (LMIC). This data gap is attributed to the lack of population-based systems measuring healthcare use, as surveys and cohort studies are generally insufficient for evaluating diabetes complications. Additional challenges include the absence of uniform diabetes diagnosis criteria and standardized methods for assessing diabetes-related complications, which hinder global comparisons. Notable patterns and regional variations in diabetes-related complications exist, though data remains incomplete.
Insulin resistance in young, lean individuals leads to reduced post-prandial muscle glycogen synthesis and increased hepatic lipid synthesis, contributing to atherogenic dyslipidaemia, which is a feature of the metabolic syndrome independent of visceral obesity or subclinical inflammation. This insulin resistance is associated with higher plasma triglycerides and uric acid, lower HDL cholesterol, and increased liver triglyceride content without non-alcoholic fatty liver disease (NAFLD). Hepatic fat mass, rather than visceral fat, correlates with hepatic insulin resistance and increased triglyceride release. Impaired adaptation of hepatic mitochondria to excessive substrate delivery may accelerate steatosis and promote NAFLD progression, which is a major predictor of cardiovascular risk in type 2 diabetes. A single bout of moderate-intensity exercise can reverse the abnormal energy storage pattern, enhancing muscle glycogen synthesis after carbohydrate intake through increased glucose transport activity.
Education programmes tailored for diabetes management can help individuals better understand and manage their condition, particularly focusing on recognizing and treating hypoglycaemia.
Common polymorphisms of mitochondrial DNA (T16189C) are associated with an increased risk of type 2 diabetes in Asian populations, with studies showing consistent risk associations in Chinese, Indian, Turkish, and Chinese Uyghur populations, while European populations show no such link. Additionally, Asian individuals without diabetes have a higher frequency of the T16189C variant compared to Europeans, and there are significant inter-ethnic differences in mitochondrial haplotypes related to type 2 diabetes risk.
The suitability of cognitive behavioral therapy (CBT) for individuals with diabetes has received limited research attention. Managing diabetes becomes more complex when it coexists with bulimia, as it can hinder patient engagement in treatment, potentially requiring strategies like motivational interviewing. Adapting standard treatment approaches to include monitoring of self-care behaviors is important, and involvement of a therapist familiar with diabetes management is beneficial. A challenge arises from the conflicting dietary recommendations for bulimia, which encourage flexible eating, versus those for diabetes, which emphasize regular controlled eating and avoidance of certain foods. The DAFNE (Diabetes Adjusted for Normal Eating) program has been developed to address this conflict by integrating flexible eating with diabetes care.
Fructosamine reflects average glycaemic exposure over the preceding 1–3 weeks and may be useful in individuals where HbA₁c measurement is not suitable, such as during pregnancy or the preconception period, allowing evaluation of glycaemic changes at shorter intervals. However, fructosamine measurement is not appropriate for routine use due to interference from excessive albumin turnover or excretion, as seen in renal disease. Current data on the correlation between fructosamine and HbA₁c show wide confidence intervals around the diagnostic cut point of 48 mmol/mol, and there are no direct outcome data linking fructosamine to diabetes-related complications. Indirect linkage via comparison with HbA₁c remains of limited value, indicating the need for further research to enhance its clinical utility.
Aerobically trained athletes without diabetes have low fasting plasma insulin levels and reduced insulin responses to a glucose challenge despite normal glucose tolerance, along with increased insulin-mediated glucose uptake under glucose clamp conditions. Physical training enhances muscle and hepatic insulin sensitivity in previously untrained individuals. Regular aerobic exercise leads to less atherogenic lipid and lipoprotein profiles, including potential increases in serum HDL cholesterol and possible decreases or no change in total and LDL cholesterol levels. Serum triglyceride levels may decline with training, and even when LDL cholesterol concentrations remain unchanged, there is an increase in mean LDL particle diameter, indicating more buoyant and less atherogenic LDL particles.
Striving for optimal glycaemic levels is particularly challenging in type 1 diabetes due to the significant risk of iatrogenic hypoglycaemia, a common adverse effect of intensive insulin treatment. Early clinical trials noted a 2–6-fold increase in severe hypoglycaemic episodes, with over half occurring during sleep, and approximately 50% of individuals with type 1 diabetes experiencing such episodes. Although severe hypoglycaemia is often associated with type 1 diabetes, a meta-analysis found a 23% prevalence of severe hypoglycaemic episodes in those with type 2 diabetes receiving insulin. Hypoglycaemia also contributes to diabetes-related mortality, with a reported 4.49 deaths per 1000 total diabetes deaths attributed to it, making it a key barrier to effective glycaemic control.
In chronic kidney disease, managing glucose control is particularly challenging due to factors such as reduced renal clearance of insulin, decreased hepatic glucose production, and impaired counterregulatory hormone responses, which collectively increase the risk of hypoglycemia, especially in patients with advanced kidney dysfunction.
SMBG (self-monitoring of blood glucose) may help patients with type 2 diabetes mellitus (T2DM) who do not require glucose-lowering therapy understand how daily activities affect their blood glucose levels. Evidence supporting this comes from qualitative and observational studies. When HbA1c testing is unavailable, measuring fasting glucose can serve as an alternative indicator of overall glycemic control. Additionally, for patients not meeting HbA1c targets, assessing post-meal hyperglycemia and aiming to reduce postprandial glucose levels below 10 mmol/L may be a potentially beneficial approach worth further evaluation.
Diabetic metabolic dysregulation is believed to trigger processes in the retina that initiate and accelerate the development of diabetic retinopathy, although the exact mechanisms are not fully understood. Vascular changes similar to early diabetic retinopathy have been observed in small rodents, and more advanced retinopathy-like changes have been produced in diabetic dogs, pigs, and monkeys. However, these animal models do not fully replicate the range of lesions seen in human diabetic retinopathy, which hinders the study of its pathophysiology. Research in this field is influenced by varying hypotheses and perspectives due to the lack of definitive knowledge, and since diabetes is a systemic disease affecting all parts of the eye, many proposed changes in ocular parameters can be confirmed. This makes the research environment open and productive but uncertain in terms of which investigative directions will lead to major advancements in understanding and managing diabetic retinopathy.
The diagnosis of diabetes is based on glycaemic levels associated with the onset of microvascular complications, and these diagnostic thresholds have evolved over time. The oral glucose tolerance test (OGTT), introduced in 1889, was not initially standardized, with varying glucose amounts and two-hour thresholds used until the 1980s. A key development came with the 1980 WHO report, which standardized diabetes diagnosis using either a casual plasma glucose level above 11.0 mmol/l (200 mg/dl) or a 75g OGTT with fasting and two-hour thresholds of ≥8.0 mmol/l (145 mg/dl) and >11.0 mmol/l (200 mg/dl), respectively. The two-hour threshold was determined based on the risk of retinopathy, while the fasting glucose threshold was later adjusted to the current standard of 7.0 mmol/l (126 mg/dl) due to limited supporting data for the original value.
The UKPDS study involved individuals with newly diagnosed type 2 diabetes who were assigned to either conventional or intensive therapy based on weight. Conventional therapy focused on avoiding marked hyperglycaemia, primarily through diet and lifestyle advice, aiming to keep fasting plasma glucose below 15 mmol/l or prevent symptoms of hyperglycaemia. Intensive therapy aimed for tighter control with a fasting plasma glucose target below 6.0 mmol/l using insulin or sulfonylureas, though no specific HbA1c target was set. The study found that intensive therapy significantly reduced microvascular complications by 25%, mainly due to a reduction in the progression of retinopathy.
The prevalence of diabetes in the general Canadian population is approximately 6%, but the lifetime risk for First Nations people is significantly higher at 8 in 10, with women being about twice as likely to be affected as men. While type 2 diabetes risk typically increases with age, there has been a rapid rise in its incidence among adolescents in First Nations populations. In Ontario, the prevalence of diabetes has grown much faster in First Nations people compared to non-First Nations people, increasing from 11.1% in 1995 to 16.6% in 2014 for First Nations individuals, versus from just under 4% to approximately 8% for non-First Nations individuals during the same period. The increase was especially pronounced for the on-reserve population, which reached a point prevalence of 18.7% in 2014.
The data presents prevalence rates of type 2 diabetes and impaired glucose tolerance across several Middle Eastern countries between 1992 and 2014, showing varying rates among men and women in urban and rural populations. In Oman, type 2 diabetes prevalence among men remained relatively stable, ranging from 9.7% in 1995 to 11.8% in 2006, while women saw a slight increase from 9.8% in 1995 to 11.3% in 2006. In Saudi Arabia, there was a notable increase in type 2 diabetes prevalence over time, rising from 11.8% in men and 12.8% in women in 1995 to 34.7% in men and 28.6% in women by 2011. Impaired glucose tolerance was also observed, with values reaching up to 14.9% in urban women in Iran in 1992. In Iran, both urban and rural populations showed comparable prevalence rates of type 2 diabetes, around 7.1–7.3%, though urban women had a higher rate of impaired glucose tolerance compared to rural women. In Iraq (2014), men and women had similar rates of type 2 diabetes at 19.6% and 19.8%, respectively, while impaired glucose tolerance was higher in men at 29.1%. Kuwait (2014) showed a prevalence of 20.4% in men and 17.4% in women for type 2 diabetes. Jordan (2004) reported a type 2 diabetes prevalence of 17.1%, with impaired glucose tolerance at 7.8%. Qatar (2009) recorded a type 2 diabetes prevalence of 16.7%, with women showing a slightly higher rate than men at 18.1% versus 15.2%.
Fasting glucose, 2-hour post-challenge glucose, and HbA₁c are equally effective in predicting future microvascular complications of diabetes and can serve as diagnostic and screening tests. Impaired fasting glucose, defined as a fasting glucose level of 5.5 mmol/L or higher, provides a simple method to identify dysglycemia. Urinalysis for glycosuria is highly specific (96–100%) but poorly sensitive (16–43%) for detecting diabetes, and random blood glucose testing is specific but lacks sensitivity.
A significant proportion of Europid patients with type 2 diabetes mellitus (T2DM) and elevated urine albumin excretion (UAE) do not exhibit classic histological signs of diabetic glomerulosclerosis, with arterial hyalinization being the most common abnormality observed instead. Some patients with T2DM experience a progressive decline in glomerular filtration rate (GFR) despite having normal albumin excretion or only mild, non-progressive microalbuminuria. Clinical data from the UK Prospective Diabetes Study (UKPDS) indicate that over half (51%) of patients who developed renal impairment did not have prior albuminuria. Identifying patients with non-diabetic kidney changes is challenging and may involve assessing clinical features such as the absence of diabetic retinopathy. The underlying cause of kidney disease in these cases is likely a combination of factors, including diabetes, hypertension, atherosclerotic vascular disease, or a specific obesity-related glomerulopathy.
Type 2 diabetes risk variants in the KCNJ11 gene, which codes for four subunits of the ATP-sensitive potassium (K-ATP) channel, have been identified, with the other four subunits coded by ABCC8. The E23K polymorphism in KCNJ11 and the P12A polymorphism in PPARG are thought to act together to increase type 2 diabetes risk. In pancreatic β cells, K-ATP channels are essential for regulating glucose-stimulated insulin secretion and are targeted by sulfonylureas, which are oral hypoglycaemic agents used to treat type 2 diabetes, as well as by diazoxide, a potassium channel opener. Activating mutations in KCNJ11 can cause neonatal diabetes, while loss-of-function mutations in both KCNJ11 and ABCC8 lead to hyperinsulinemia in infancy.
Some disturbances in the complement system and cytokine responses have been observed in individuals with diabetes, such as reduced complement factor 4 levels and diminished cytokine responses following stimulation, though the connection of these changes to increased infection susceptibility remains uncertain. No consistent or clear defects in adaptive immunity have been identified in diabetes.
Free sugars should not exceed 10% of total energy and when fixed daily insulin doses are used, carbohydrate intake should be consistent in terms of time and amount.
Thiazolidinediones (TZDs) have adverse skeletal effects that are relevant to diabetes, as these drugs are used in the treatment of type 2 diabetes. TZDs negatively impact bone health by directly inhibiting bone formation through the diversion of mesenchymal stem cells away from the osteoblast lineage toward adipocyte development. They also increase or maintain bone resorption at elevated levels by affecting osteoclast development. Additionally, TZDs exert indirect effects on the skeleton by reducing systemic and skeletal levels of insulin-like growth factor I (IGF-I), modulating adipokine production, and decreasing pancreatic β-cell hormone levels that have known skeletal activity. These actions highlight the complex interplay between diabetes therapy and bone metabolism.
Gestational diabetes mellitus (GDM) is associated with an increased risk of childhood obesity, but this relationship is complicated by the influence of higher maternal body mass index (BMI), shared genetics, and environmental factors. Both maternal and paternal BMI are linked to obesity and high waist circumference in offspring, potentially due to shared genetic and postnatal lifestyle factors. Studies examining the long-term risk of obesity related to intrauterine exposure to diabetes should account for parental obesity and environmental influences to avoid confounding bias. Adjusting for maternal BMI has led to inconsistent results and in some cases weakened the association between GDM and childhood obesity, raising questions about whether the link is independent of maternal weight status.
Being admitted to hospital can be a worrying time for individuals with diabetes, but providing a full explanation of the treatment and allowing an opportunity to discuss concerns can alleviate fears. Patients should be encouraged to continue self-managing their diabetes where possible and bring their own insulin supplies, particularly in planned admissions. Access to their regular diabetes healthcare team should be facilitated, as hospitalization offers an opportunity to review diabetes management techniques and results. It is important to ensure ready access to carbohydrate sources and coordinate mealtimes, snacks, and medication appropriately to prevent hypoglycaemia and reduce the need for more intensive treatment.
Defective insulin signaling at the level of the insulin receptor and IRS1-associated PI3K is associated with reduced insulin-stimulated muscle glucose storage, contributing to metabolic disease. However, deletion of the skeletal muscle insulin receptor in MIRKO mice does not lead to hyperglycaemia or hyperinsulinaemia despite mild obesity and elevated free fatty acids and triglycerides. Further deletion of the type 1 IGF receptor in MIGIRKO mice results in significantly reduced muscle mass but normal glucose and insulin tolerance due to increased basal glucose uptake. In MDKO mice with progressive muscle autophagy, hyperglycaemia and glucose intolerance do not develop, even with complete loss of Akt phosphorylation, indicating that insulin receptor/type 1 IGF receptor signaling is a major driver of Akt activation. Isolated skeletal muscles from MDKO mice show elevated basal glucose uptake but absence of insulin-stimulated uptake, with glucose metabolism shifting to lactate production, increasing the AMP/ATP ratio, and activating AMPK, which can enhance glucose uptake through phosphorylation of AS160/TCB1D4 and TCB1D1, promoting GLUT4 translocation even in the presence of insulin resistance.
Excess fatty acids, diacylglycerol, and products of glucotoxicity can impair insulin action by activating certain isoforms of protein kinase C (PKC), which phosphorylate insulin receptors and IRS proteins at serine or threonine sites, contributing to insulin resistance. Inhibiting these PKC isoforms has shown some promise in improving insulin action and treating complications such as diabetic retinopathy and neuropathy, though it has not yet proven effective for managing hyperglycaemia in type 2 diabetes. Other molecules involved in insulin resistance include IKKβ, JNK, and mTOR, which inhibit insulin receptor or IRS protein activity through serine phosphory; IKKβ and JNK are implicated in cytokine-induced insulin resistance, while mTOR mediates a negative feedback loop from AKT. Enhancing post-receptor insulin signaling through the administration of compounds like methylchiroinositol (pinitol), which facilitates phosphatidylinositol 3-kinase activity, has shown benefits in improving glycaemic control in animal models of insulin resistance and deficiency.
In recent decades, diabetes prevalence has increased globally, primarily due to a rise in type 2 diabetes and its associated risk factors. In 2019, 1 in 11 adults aged 20–79 years had diabetes, totaling 463 million people, with 79% residing in low- and middle-income countries (LMIC). Accurate quantification of diabetes prevalence is essential for healthcare planning and developing prevention strategies, but reliable data from many LMIC remain insufficient. Challenges in estimating the true global burden include inconsistent diagnostic criteria, poor methodological standardization, and limited geographic coverage, particularly underrepresentation of rural populations. To overcome these issues, organizations like the IDF and WHO employ advanced modeling techniques to generate country-specific diabetes prevalence estimates. The discussion highlights patterns in the three main diabetes types: type 1 diabetes, type 2 diabetes, and gestational diabetes mellitus (GDM), with comparisons across different income-group regions.
Glycated haemoglobin ($\mathrm{HbA_{1c}}$) was introduced in 2011 as a diagnostic criterion for diabetes, with a threshold of 6.5% (48 mmol/mol), and should be measured using a method certified by the National Glycohemoglobin Standardization Program or International Federation of Clinical Chemistry. An $\mathrm{HbA_{1c}}$ value below 6.5% does not exclude diabetes when diagnosed using glucose tests, and individuals with an $\mathrm{HbA_{1c}}$ between 5.7% and 6.5% are considered at risk of diabetes and may be diagnosed with pre-diabetes. The risk of diabetes is continuous, extends below the lower limit of this range, and is greater at the higher end.
Hyperglycemia in individuals with diabetes impairs various aspects of innate immunity, including neutrophil chemotaxis, adherence to vascular endothelium, phagocytosis, intracellular bactericidal activity, and opsonization. Specifically, hyperglycemia reduces opsonophagocytosis by redirecting nicotinic acid adenine dinucleotide phosphate (NADPH) from superoxide production into the aldose reductase-dependent polyol pathway, leading to decreased host defense against extracellular bacterial infections. Additionally, both chemotaxis and phagocytosis are impaired in monocytes of people with diabetes.
People with diabetes lose their first and second physiological defenses against hypoglycemia and must rely on the catecholamine response, primarily epinephrine, which serves as the third line of defense. This response becomes especially important when the glucagon response is poor, as catecholamines significantly modulate hepatic glucose production during hypoglycemia and exercise. However, in individuals with type 1 diabetes and advanced type 2 diabetes, the epinephrine response to hypoglycemia is progressively reduced, leading to an attenuated adrenomedullary response, which compromises this final defense mechanism.
Fulminant type 1 diabetes is an uncommon condition that can occur at any age, marked by a rapid onset of diabetic ketoacidosis within days, often following a viral illness, and typically lacks islet autoantibodies despite very low C-peptide levels, necessitating long-term insulin therapy. Immune checkpoint inhibitors, used in cancer treatment, have been linked to the development of autoimmune diseases, including type 1 diabetes, highlighting the role of immune components such as cytotoxic T lymphocytes, natural T-regulatory cells, programmed death 1 receptors, and PD1 ligands in the pathogenesis of diabetes. These immune pathways are involved in a range of diseases from cancer to autoimmunity, where their disruption can lead to conditions like type 1 diabetes.
Reactions to insulin were previously common due to impurities such as animal proteins and preservatives, but the use of recombinant human and analog insulin has reduced the incidence of insulin allergy to less than 1% of insulin-treated patients. Allergic reactions can be classified as immediate-local, systemic, delayed, or biphasic. Immediate-local reactions occur within minutes of injection and may involve erythema and urticaria, potentially mediated by IgE. These reactions can be managed by switching to a more purified insulin product. Systemic reactions include generalized urticaria and, rarely, anaphylaxis, particularly in patients previously sensitized to animal insulins. Delayed hypersensitivity reactions are the most common, presenting as itchy nodules at injection sites 4–24 hours after injection, typically appearing about two weeks after starting therapy. Biphasic reactions involve immediate urticaria followed by a delayed response and are thought to be IgG-mediated immune complex reactions, possibly related to hypersensitivity to insulin or its preservatives.
Hypertriglyceridaemia is the most frequent lipoprotein abnormality found in dysregulated diabetes, driven by mechanisms including increased absorption and production of triglycerides, along with reduced catabolism of triglyceride-rich particles due to decreased lipoprotein lipase (LPL) activity. Insulin resistance or insulin deficiency leads to increased adipose tissue lipolysis, resulting in elevated release of free fatty acids from fat cells, which are transported to the liver. This increase in fatty acid supply, combined with elevated hepatic triglyceride levels, influences the production of apolipoprotein B (apoB), a key component of VLDL and LDL particles, thereby contributing to dyslipidemia in diabetes.
Specific changes to the amino acid sequence of insulin reduce its molecular associations, leading to faster absorption into the bloodstream, which allows insulin to be injected just before or after eating. This has resulted in the development of three rapid-acting insulin analogs (RAIs): insulin lispro, insulin aspart, and insulin glulisine. These analogs act more quickly (within 10–20 minutes) and have a shorter duration of action (3–5 hours) compared to soluble insulin (30–60 minutes and 6–8 hours, respectively). RAIs are used safely in both type 1 diabetes (T1DM) and type 2 diabetes (T2DM) as part of a basal bolus regimen or in continuous subcutaneous insulin infusion (CSII). Their time-action profile makes them well-suited for controlling blood glucose at meal times, resulting in better glycemic control with fewer hypoglycemic episodes compared to soluble insulin, particularly in T1DM patients and those using CSII.
Atypical ketoacidosis has been observed in individuals treated with SGLT-2 inhibitors, particularly those with type 1 diabetes or unclear diabetes diagnoses who were insulin-treated and had their insulin doses overly reduced due to the glucose-lowering effect of SGLT-2 inhibitors. This condition, known as hyperosmolar ketoacidosis, often occurs with only modest hyperglycaemia. Maintaining basal insulin in insulinopenic individuals is important as it suppresses lipolysis, reducing fatty acid availability for ketogenesis, and serves other physiological functions beyond glycaemic control. SGLT-2 inhibition may also decrease renal ketone clearance and trigger increased glucagon release, especially at low glucose levels, promoting ketogenesis. Individuals with a history of ketotic episodes are considered poor candidates for SGLT-2 inhibitor therapy.
Adiponectin is a therapeutic candidate for type 2 diabetes and obesity, with insulin-sensitizing and anti-inflammatory properties. In humans, adiponectin levels are inversely correlated with adiposity, insulin resistance, and type 2 diabetes. Gene transfer of adiponectin using AAV vectors improved insulin sensitivity, reduced obesity, and decreased hepatic gluconeogenesis, de novo lipogenesis, and inflammation in HFD-fed diabetic rats. Nonviral overexpression of adiponectin in obese-diabetic rats yielded similar results. Additionally, adenoviral expression of C1q/TNF-related protein-12, an adipokine partially homologous to adiponectin, improved glucose tolerance and insulin sensitivity and normalized hyperglycemia and hyperinsulinemia in obese diabetic mice.
α-Glucosidase inhibitors such as acarbose reduce glucose absorption by inhibiting intestinal α-glucosidase enzymes, leading to delayed carbohydrate digestion and reduced post-prandial glucose spikes without stimulating insulin secretion. These medications are effective only when taken with meals containing complex carbohydrates and do not cause weight gain or hypoglycemia when used alone, making them suitable for combination therapy. In advanced type 2 diabetes where β-cell function is severely impaired, insulin therapy should be initiated while potentially continuing oral antidiabetic agents as part of the treatment regimen.
Infections, particularly severe ones, can worsen hyperglycemia in individuals with diabetes by increasing insulin resistance through the release of stress hormones and cytokines such as IL-1 and tumor necrosis factor. Infections are also a significant contributing factor in the development of diabetic ketoacidosis and hyperosmolar hyperglycemia. Additionally, infections may lead to hypoglycemia when symptoms like anorexia, nausea, and vomiting result in decreased food intake, and malaria treatment with quinine can also cause hypoglycemia.
Anti-diabetes agents can affect triglyceride concentrations through insulin's peripheral actions on adipose and muscle tissues or via their influence on lipoprotein lipase. In poorly managed type 1 diabetes and diabetic ketoacidosis, hypertriglyceridemia and reduced HDL cholesterol are commonly observed and are typically corrected with insulin therapy. In type 2 diabetes, medications such as metformin, sulfonylureas, and acarbose lead to modest reductions in triglycerides that are correlated with HbA1c levels. Thiazolidinediones generally have more favorable effects on lipid profiles compared to sulfonylureas or insulin, though individual agents within this class differ: pioglitazone reduces triglycerides while rosiglitazone increases them. The PROACTIVE study demonstrated that adding pioglitazone to other anti-diabetes treatments in type 2 diabetes reduced cardiovascular disease events by 11% in the main secondary endpoint.
Islet cell transplantation faces challenges due to early cell death, which necessitates repeated infusions, as at least 25% of islets are lost shortly after infusion into the portal circulation, largely due to the instant blood-mediated inflammatory response—an innate immune reaction that activates coagulation, the complement system, cytokine release, and cell damage. This response can be mitigated with anticoagulants and anti-inflammatory drugs like TNF-α inhibitors and interleukin-1 inhibitors, improving clinical results. Additionally, hypoxia significantly affects islet survival since β cells have limited capacity to manage low oxygen and oxidative stress due to low antioxidant levels. Neovascularization, which takes about 7–14 days post-infusion, is critical for islet survival, and various strategies such as pre-vascularization, extracellular matrix scaffolds, proangiogenic factors, co-culture, and co-transplantation with supportive cells are being explored to enhance vascularization and improve transplant outcomes, particularly in subcutaneous sites.
Gestational diabetes mellitus (GDM) is influenced by physiologic insulin resistance that develops during pregnancy, which can be observed through changes in exogenous insulin requirements in women with type 1 diabetes mellitus (T1DM). Insulin requirements typically remain stable until around 18 weeks' gestation, after which they increase linearly until approximately 28 weeks. The increase varies widely between individuals, ranging from no change to over a threefold increase, with an average rise in daily insulin dose of about 40%. This variability is thought to be related to differences in placental function, as evidenced by variations seen in successive pregnancies in the same woman.
Oral antidiabetic drugs are categorized into different classes based on their modes of action, with their glucose-lowering effects primarily illustrated in specific tissues. Treatment strategies in type 2 diabetes mellitus (T2DM) must address fasting glycemia, which typically accounts for most hyperglycemia, and postprandial hyperglycemic excursions, which are linked to cardiovascular risk. Improving glycemic control can also be achieved through treating obesity. At diagnosis, insulin resistance is usually well established and does not significantly progress over time, but it remains important to ameliorate due to its association with cardiovascular risk. The progressive decline in β-cell function after diagnosis is a major factor in worsening glycemic control, making the preservation of β-cell function and mass crucial for long-term management. When β-cell function deteriorates beyond the effectiveness of oral agents, insulin therapy should be introduced without delay. Combining therapies to adapt to the evolving nature of the disease is now a standard approach in diabetes care.
Management of lipid and blood pressure to individualized targets is recommended, as is lifestyle management, including optimal nutrition, smoking cessation, moderate alcohol intake, and exercise, though it is important to recognize that behavioural change may be difficult to implement in the setting of cognitive impairment, especially executive dysfunction, and that making small changes or enlisting help from caregivers can be useful strategies.
Insulin resistance in patients with type 2 diabetes mellitus (T2DM) increases with the severity of hyperglycemia, and this resistance, particularly via the hexosamine pathway, may serve as a compensatory mechanism to protect muscles from excessive glucose uptake. Studies show that insulin-stimulated glucose transport in skeletal muscles of hyperglycemic T2DM patients is comparable to that in normoglycemic individuals, but this function becomes impaired when the muscles are exposed to normoglycemia short-term and is fully restored after prolonged normoglycemic exposure. Clinically, the hyperglycemia-induced insulin resistance in T2DM explains why treatments that improve glycemic control, such as sulfonylureas, can also enhance insulin sensitivity, even if their primary action is not on insulin-sensitive tissues.
Biguanides, such as metformin, lower glucose by countering insulin resistance, especially by decreasing hepatic glucose output, and enhance various insulin-dependent and independent actions including activation of AMPK. Sulfonylureas, including glimepiride, gliclazide, glyburide/glibenclamide, and glipizide, stimulate insulin secretion for 6–24 hours by binding to SUR1 sulfonylurea receptors on pancreatic β-cells, which closes ATP-sensitive Kir6.2 potassium channels. Meglitinides, such as repaglinide and nateglinide, also stimulate insulin secretion but with a faster onset and shorter duration than sulfonylureas by binding to a benzamido site on SUR1 receptors, closing ATP-sensitive Kir6.2 potassium channels in pancreatic β-cells. Gliptins, or DPP-4 inhibitors, such as sitagliptin, vildagliptin, and saxagliptin, increase prandial insulin secretion by inhibiting the DPP-4 enzyme, thereby prolonging the plasma half-life of insulinotropic incretin hormones. Thiazolidinediones, or PPAR-γ agonists, such as pioglitazone and rosiglitazone, increase insulin sensitivity, especially peripheral glucose utilization, by activating the nuclear receptor PPAR-γ primarily in adipose tissue, influencing insulin action and the glucose–fatty acid cycle. α-Glucosidase inhibitors, including acarbose, miglitol, and voglibose, lower glucose by slowing carbohydrate digestion through competitive inhibition of intestinal α-glucosidase enzymes.
Low circulating levels of adiponectin, a protein abundantly expressed in adipose tissue, are associated with higher BMI and predict the development of type 2 diabetes mellitus (T2DM). Adiponectin exerts antidiabetic effects, including stimulating fatty acid oxidation through an AMP-activated protein kinase-dependent mechanism.
The DECLARE-TIMI 58 trial involved 17,160 individuals with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, and evaluated the effects of dapagliflozin compared to placebo over a median of 4.2 years. The trial uniquely included over 10,000 participants without evident cardiovascular disease but with multiple risk factors. While dapagliflozin did not significantly reduce MACE (HR 0.93; 95% CI 0.84 to 1.03), it significantly lowered the risk of cardiovascular death or hospitalization for heart failure (HR 0.83; 95% CI 0.73 to 0.95), primarily due to fewer hospitalizations for heart failure (HR 0.73; 95% CI 0.61 to 0.88). Additionally, dapagliflozin reduced by 24% the incidence of a composite kidney outcome involving a more than 40% reduction in eGFR, new end-stage renal disease, or death from renal or cardiovascular causes.
High MBL levels are associated with an increased risk of mortality in both type 1 and type 2 diabetes, with studies showing that individuals with higher MBL concentrations have a greater risk of dying compared to those with lower levels. A U-shaped association between MBL and cardiovascular events has been observed in type 2 diabetes, where both the lowest and highest MBL levels are linked to increased risk compared to intermediate levels. High MBL levels also represent an increased risk for diabetic kidney disease in both type 1 and type 2 diabetes, supported by animal studies indicating a causal role of MBL in its development. Inhibition of complement factor C5 has been shown to reduce renal injury in diabetic rats, and clinical studies using the C5 inhibitor pexelizumab initially showed some benefits in reducing mortality after acute myocardial infarction and coronary artery bypass graft surgery, though these findings were not confirmed in a larger subsequent study.
Insulin action begins when insulin binds to high-affinity receptors on the plasma membrane of target cells, a process critical for glucose metabolism and impaired in diabetes. The insulin receptor, a transmembrane glycoprotein composed of two α- and two β-subunits, facilitates this signaling. Upon insulin binding to the extracellular α-subunits, conformational changes enable ATP to bind to the intracellular β-subunit, triggering autophosphorylation of specific tyrosine residues. This autophosphorylation enhances the β-subunit's tyrosine kinase activity, which is essential for propagating the insulin signal. Key phosphorylation sites on the β-subunit, such as Tyr^972, Tyr^1158, Tyr^1162, Tyr^1163, Tyr^1328, and Tyr^1334, play distinct roles in signal transduction, substrate phosphorylation, and activation of pathways like Ras/MAPK involved in mitogenic responses. Dysfunction in insulin receptor signaling contributes to insulin resistance and the pathophysiology of diabetes.
The HbA1c test has limitations in capturing hypoglycaemic episodes or glucose variability and may be unreliable in conditions affecting red blood cell turnover such as anaemia, haemoglobinopathies, or end-stage renal disease with erythropoietin therapy, where capillary glucose measurements may be more useful for treatment decisions. Self-monitoring of blood glucose has limited clinical value for glycaemic management in non-insulin-dependent individuals and is associated with higher costs without clear benefits to quality of life. Continuous glucose monitoring (CGM) is now integral to managing type 1 diabetes, though evidence for its use in type 2 diabetes is limited. Metrics such as time in range (TIR) and glucose management indicator (GMI) from CGM data correlate well with HbA1c and are useful for assessing glucose control. The ambulatory glucose profile (AGP), which includes time above and below target glucose ranges, supports personalized treatment planning, especially for those on insulin therapy, and remote access to CGM data may transform diabetes care. Future trials in type 2 diabetes are expected to assess anti-diabetes agents using TIR as a primary glycaemic endpoint instead of HbA1c.
Autoantibody-positive individuals, whether single or multiple, exhibit a relative β-cell area similar to those without autoantibodies. Combining clinical features, genetic risk scores, plasma C-peptide levels, and islet autoantibodies can model insulitis even without histological confirmation. The transition from stage 1 to stage 2 of diabetes progression and the initiation of insulitis are not yet fully understood. Detecting β-cell autoantigen-specific T lymphocytes remains challenging, and developing standardized assays for T lymphocytes targeting islet autoantigens like insulin, GAD65, and IA-2 is still difficult. Soluble HLA class II tetramer assays may help track progression between disease stages. Potential peripheral blood cellular biomarkers include neutrophils, regulatory T cell counts, NK cell signatures, transcriptomic profiles of peripheral blood mononuclear cells, RNA sequencing of individual sorted cells, and possibly HLA class I restricted pancreatic islet antigen peptide-specific CD8+ T cells. However, these biomarker analyses require standardized T-cell testing methods that have not yet been established. Longitudinal studies in children progressing through stages 1, 2, and 3 are essential to identify specific cellular factors involved in diabetes pathogenesis.
Patients with diabetes have an increased risk of surgical complications and poorer results of revascularization, making a conservative approach to revascularization especially important for them. However, early revascularization may be beneficial for diabetic patients with critical limb ischemia, particularly when performed before widespread infection occurs, as it can be limb-saving. The focus for managing diabetic patients should be on preventive measures to halt the atherosclerotic process due to their higher risk of cardiovascular complications compared to the risk of amputation.
Telemedicine has become an integral part of paediatric type 1 diabetes care, relying on the ability of children, adolescents, and their families to share glucose and insulin data with providers, which is essential for making appropriate insulin adjustments. Effective telemedicine delivery faces challenges including the digital divide—defined as disparities in access to internet, broadband, and devices across socioeconomic and racial or ethnic groups—and the complexity of current methods for downloading and transferring diabetes data. Addressing these technological and health literacy barriers is crucial for equitable and efficacious type 1 diabetes management.
GLP-1 receptor agonists (GLP-1RAs) have become a key component in the treatment of type 2 diabetes due to their cardiovascular benefits and ability to promote weight loss. These effects are notable within a few years of starting therapy and represent an improvement over older anti-diabetes medications. Liraglutide and semaglutide, two GLP-1RAs, are approved at higher doses for obesity treatment. Research is expanding into other type 2 diabetes-related conditions, including chronic kidney disease, eye disease, and heart failure with preserved ejection fraction, as well as their application in type 1 diabetes, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis. Additionally, studies are exploring the potential impact of GLP-1RAs on neurological conditions such as Alzheimer disease, Parkinson disease, and depression.
Insulin resistance and type 2 diabetes are associated with reduced sensitivity of adipose tissue to insulin's effects on lipolysis, leading to elevated plasma concentrations of triglycerides and fatty acids, which can further impair insulin sensitivity in the liver and skeletal muscle. Obesity and metabolic syndrome are linked to subclinical inflammation originating from adipose tissue, causing an imbalance in adipocytokine secretion—such as increased proinflammatory cytokines like leptin, tumor necrosis factor-α, and interleukin-6 and decreased anti-inflammatory, insulin-sensitizing adiponectin. These proinflammatory cytokines can induce insulin resistance through activation of JNK1 and IKKβ/NF-κB pathways, which increase serine phosphorylation of IRS1. Anti-inflammatory treatments such as acetyl salicylate or salsalate can modestly improve glycemic levels and insulin resistance in individuals with type 2 diabetes and obesity, suggesting a role for inflammatory pathways in obesity-associated insulin resistance and hyperglycemia. Endoplasmic reticulum stress is another potential contributor to cellular inflammation and insulin resistance via JNK activation. Weight loss following bariatric surgery may alleviate some of these effects in humans.
Increased production of PI(3,4,5)P3 due to activated PI3 kinase is crucial for metabolic insulin signaling and the downstream activation of PDK1, while PTEN and SHIP can dephosphorylate PI(3,4,5)P3, thereby inhibiting its ability to activate PDK1 and exerting negative regulatory effects on insulin signaling, suggesting that PTEN and SHIP may play a role in impairing insulin action, particularly in pathophysiologic states, though the exact role of PTEN in human insulin resistance remains unclear.
Studies on diets in people with diabetes often focus on short-term changes in lipids, while cardiovascular outcome studies are less common and usually underpowered. However, meta-analyses indicate that Mediterranean diets may offer benefits for populations at risk of cardiovascular disease. The PREDIMED trial, involving 7447 individuals at high cardiovascular risk, with about 50% having type 2 diabetes, demonstrated a 28–31% reduction in cardiovascular events among those following a Mediterranean diet.
MODY is a form of diabetes characterized by a well-defined mode of inheritance with high penetrance and early onset, typically developing in thin young adults before the age of 25, and is associated with primary insulin-secretion defects. It is genetically, metabolically, and clinically heterogeneous, with heterozygous mutations or chromosome rearrangements in at least seven genes identified as responsible for the condition, including GCK (MODY type 2), HNF4A (MODY type 1), and HNF1A. The prevalence of MODY is estimated to be less than 1–2% of patients with type 2 diabetes mellitus (T2DM), though it may account for up to 5% of European diabetes cases.
Metformin is widely used as a first-line therapy for type 2 diabetes due to its efficacy, safety, and low cost, and it does not increase the risk of hypoglycaemia while potentially reducing body weight. In a substudy of the UK Prospective Diabetes Study (UKPDS), intensive treatment with metformin was linked to lower all-cause mortality compared to diet alone in overweight individuals with newly diagnosed type 2 diabetes. However, another UKPDS substudy found increased mortality when metformin was added to sulfonylurea compared to sulfonylurea alone, though this finding was later attributed to chance. A meta-analysis showed a neutral effect of metformin on all-cause mortality, and long-term follow-up from the Diabetes Prevention Program (DPP) and Diabetes Prevention Program Outcomes Study (DPPOS) demonstrated no effect of metformin on major cardiovascular events over 21 years.
Metformin, derived from guanidine found in the herb Galega officinalis, is the only biguanide currently used in most countries for treating diabetes. Historically, guanidine derivatives were used in the 1920s for their glucose-lowering effects but were largely replaced by insulin. In the late 1950s, three biguanides—metformin, phenformin, and butformin—were introduced, but phenformin and butformin were later withdrawn due to causing lactic acidosis. Metformin, introduced in the United States in 1995, has become the most prescribed glucose-lowering medication globally.
Blood glucose measurement has limitations due to high biological variability, poor reproducibility, and influence by acute factors such as stress, food, exercise, and certain medications. Precautions like adding anti-glycolytic agents, such as sodium fluoride, are necessary to prevent a decline in glucose levels in samples, although glucose concentration may continue to decrease for up to four hours. Variations in glucose levels also exist between whole blood, plasma, serum, and between capillary and venous blood. Point-of-care testing using glucometers has partially addressed these limitations by enabling rapid bedside measurements.
The use of $\mathrm{HbA_{1c}}$ is suggested as a new method for diagnosing diabetes and identifying individuals at high risk, with a diagnostic threshold of 6.5% (47.5 mmol/mol) gaining acceptance based on cross-sectional studies linking $\mathrm{HbA_{1c}}$ levels to retinopathy. These studies showed that moderate retinopathy is rarely found at $\mathrm{HbA_{1c}}$ levels below 6.5%, supporting its use as a diagnostic cutoff. However, as modern methods for detecting retinopathy are more sensitive and background retinopathy can occur in normoglycemic individuals, it is advised to use moderate retinopathy as the basis for diagnostic thresholds. Additionally, $\mathrm{HbA_{1c}}$ levels between 6.0–6.4% (42–47 mmol/mol) or 5.7–6.4% (39–47 mmol/mol) have been proposed to identify individuals at high risk of developing diabetes, similar to the use of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG).
Gene therapy for diabetes carries risks such as inducing severe hypoglycemia if insulin production from modified cells is not precisely controlled, and requires advancements in gene transfer techniques to ensure long-term expression, in vivo regulation, and minimal immune response before it can be effectively applied to β-cells. Type 1 diabetes mellitus (T1DM), being generally more severe than type 2 diabetes mellitus (T2DM), is likely to be the initial focus of gene therapy efforts, with insights from T1DM trials guiding future T2DM treatments, provided that the benefits of gene therapy clearly outweigh the risks and surpass those of conventional therapies.
GLP-1 receptor agonists may reduce the risk of myocardial infarction, which is a major risk factor for heart failure, and this effect could contribute to their beneficial impact on cardiovascular outcomes in patients with diabetes. Among these agents, albiglutide and efpeglenatide showed the greatest reductions in myocardial infarction risk in cardiovascular outcome trials.
Monogenic diabetes involves primary disorders affecting the $\beta$-cell and presents clinically in four main forms: familial mild fasting hyperglycemia (glucokinase maturity-onset diabetes of the young [MODY]), familial young-onset diabetes (transcription factor MODY), neonatal diabetes, and diabetes with extrapancreatic features. Clinical and biochemical features help distinguish these forms of monogenic diabetes from type 1 and type 2 diabetes. Additionally, single-gene mutations can lead to diabetes through mechanisms of insulin resistance, as seen in inherited lipodystrophies and insulin receptor mutations. Monogenic multisystem diseases such as hemochromatosis and cystic fibrosis can also cause diabetes.
Programs have been developed to teach individuals using insulin how to recognize and anticipate blood glucose fluctuations in order to prevent extreme highs and lows and reduce fear of hypoglycaemia, with the face-to-face Blood Glucose Awareness Training (BGAT) program showing substantial benefits including a 57–92% reduction in severe hypoglycaemic events, a 65–86% reduction in driving mishaps, a 10–51% improvement in hypoglycaemia awareness, and a 6–21% reduction in fear of hypoglycaemia.
Repeated injections of anti-VEGF compounds may serve as an alternative to photocoagulation for treating proliferative diabetic retinopathy, and vitrectomy may offer benefits in managing diabetic macular oedema, although the clinical significance of these findings remains under debate and has not been integrated into established treatment guidelines.
The World Health Organization (WHO) DIAMOND Study and the EURODIAB ACE Study have collected standardized incidence data for type 1 diabetes mellitus (T1DM) among children under 15 years of age, relying on notifications from diagnosing physicians and defining the date of diagnosis as the date of the first insulin injection, with both studies estimating the degree of undercounting using a secondary information source.
In diabetes, impaired glucose handling and a shift in myocardial substrate utilization toward increased free fatty acid oxidation contribute to maladaptive metabolic changes that elevate myocardial oxygen consumption and increase susceptibility to hypoxia and injury, particularly during ischaemia. The reduced glucose uptake due to decreased transport proteins and excessive fatty acid availability lead to lipotoxicity, lipid deposition in the myocardium, and subsequent myocardial injury, inflammation, and adverse remodeling. These metabolic and structural alterations, combined with the high prevalence of ischaemic heart disease, contribute to the elevated risk of heart failure in individuals with diabetes. Increased myocardial triglyceride content in diabetic individuals is linked to subclinical diastolic dysfunction, further heightening the risk of heart failure development.
Insulin resistance, which refers to the reduced responsiveness of tissues to normal insulin concentrations, is a significant risk factor for the metabolic syndrome and can progress to cardiovascular disease, non-alcoholic fatty liver disease, and type 2 diabetes. The insulin receptor, a transmembrane protein composed of α and β subunits, plays a key role in insulin signaling, with the α subunits containing the ligand binding sites and the β subunits housing the intracellular tyrosine kinase. Insulin receptor substrate (IRS) proteins coordinate insulin and IGF signaling through tyrosine and serine phosphorylation sites, some of which bind signaling proteins like the p85 subunit of PI3K and Grb2-Sos during insulin or IGF-I stimulation.
Infections can contribute to metabolic disturbances that create a bidirectional relationship with hyperglycemic states, meaning that infections may worsen hyperglycemia and hyperglycemia may increase susceptibility to infections. Additionally, certain infections may play a more direct role in the development of diabetes.
SGLT-2 inhibitors, a class of medications used in the management of diabetes, have been evaluated in multiple studies regarding their association with cancer risk. A meta-analysis of 21 randomized controlled trials involving 20,308 patients treated with SGLT-2 inhibitors and a median follow-up of 52 weeks found an increased risk of skin cancers. However, another meta-analysis of 7 studies including 27,744 patients on SGLT-2 inhibitors with follow-up of at least 52 weeks did not show any association with cancer, although long-term follow-up data were limited. The evidence remains inconclusive, with no definitive association established between SGLT-2 inhibitors and cancer risk, but concerns persist due to the limited duration of follow-up in available studies.
Differing screening methods and diagnostic criteria for diabetes make comparative epidemiology challenging. In the UK, the estimated crude prevalence of diabetes is 22.8% of live births, with an age-standardized prevalence of 19.9%, of which 5.1% is attributable to overt diabetes. The National Institute for Health and Care Excellence (NICE) in England and Wales reported a lower overall prevalence of 5.0%, composed of 87.5% gestational diabetes mellitus (GDM), 7.5% type 1 diabetes, and 5% type 2 diabetes. A retrospective study showed a 30% increase in the incidence of GDM when using International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria compared with the 2015 NICE criteria. Obesity, which affects about one in five women who give birth, contributes to the rising incidence of GDM. Despite variations in diagnostic criteria, there has been a progressive rise in the prevalence of both GDM and overt diabetes during pregnancy over recent decades.
Exercise interventions in type 2 diabetes demonstrate a significant effect on glycemic control as measured by HbA₁c levels, with post-intervention values showing a statistically significant overall effect (z score 4.01, P < 0.001) when comparing exercise to non-exercise control groups; similarly, combined exercise and diet interventions also show a significant improvement in glycemic control (z score 2.66, P = 0.008), although baseline values across studies exhibit some heterogeneity. The conversion of HbA₁c results to International Federation of Clinical Chemistry (IFCC) units follows the equation: DCCT result (%) = (0.0915 × IFCC result in mmol/mol) + 2.15.
Autoantibodies to glutamic acid decarboxylase (GAD65) are present in 55–60% of children with type 1 diabetes mellitus (T1DM) at disease onset, and GAD65, which converts glutamic acid to γ-aminobutyric acid (GABA), is found in pancreatic islet β-cells and specific neurons.
Sensor-augmented insulin pumps provide continuous glucose monitoring and insulin delivery, which can help manage blood glucose levels more effectively, particularly in individuals with diabetes who experience frequent hypoglycaemic episodes, and combining their use with regular consultation from a specialized hypoglycaemia service may improve diabetes management and reduce complications.
Perioperative and postoperative hyperglycaemia is linked to increased short- and long-term risks such as surgical site infections, longer hospital stays, acute kidney injury, myocardial infarction, extended ICU or ventilator use, and higher mortality rates, with perioperative mortality up to 50% higher in people with diabetes compared to those without. Individuals with diabetes are also less likely to undergo day-case surgery, more likely to require emergency surgery, and experience longer hospital stays and higher 28-day readmission rates. Optimizing glycaemic control before and during surgery is crucial to mitigate these risks, though achieving this for elective procedures requires significant coordination among healthcare teams.
SGLT-2 inhibitors, such as empagliflozin, have been associated with a non-significant increased risk of both fatal and non-fatal strokes. Current recommendations suggest using metformin as the first-line treatment for diabetes, followed by GLP-1 receptor agonists if the priority is preventing vascular events, or SGLT-2 inhibitors if the priority is preventing worsening heart failure.
Infections can influence the pathogenesis of diabetes, affect blood glucose levels in individuals with pre-existing diabetes, and worsen diabetes-related complications. They are also a significant predisposing factor for diabetic ketoacidosis and hyperosmolar hyperglycaemic syndrome, making the identification of underlying infections crucial in managing acute hyperglycaemic complications.
The text includes several diabetes-related concepts and abbreviations. Key terms include: AACE (American Association of Clinical Endocrinologists), ACCORD (Action to Control Cardiovascular Risk in Diabetes), ACE (angiotensin-converting enzyme), ADA (American Diabetes Association), AICAR (5-aminoimidazole-4-carboxamide-1β-D-ribofuranoside), AMDCC (Animal Models for Diabetes Complications Consortium), ACR (albumin:creatinine ratio), BMD (bone mineral density), BMI (body mass index), BPH (benign prostatic hyperplasia), CDA (Canadian Diabetes Association), CDC (Centers for Disease Control and Prevention), CDE (Certified Diabetes Educator), CGM (continuous glucose monitoring), CI (confidence interval), CKD (chronic kidney disease), and CBT (cognitive-behavioral therapy). These terms relate to various aspects of diabetes such as risk factors (BMI, BPH), complications (CKD, CVD), diagnostic methods (CGM, ACR), treatment approaches (CBT, ACE inhibitors), and associated organizations and studies (ADA, AACE, ACCORD).
GLP-1, derived from the processing of proglucagon in the gut by prohormone convertase 1/3, plays a role in glucose regulation, which is relevant to diabetes management.
Islet transplantation can correct frequent hypoglycemia and glycemic lability, and may reduce the progression risk of diabetes complications if good glycemic control is achieved. However, this long-term benefit remains unproven. Diabetes complications assessed during patient evaluation include retinopathy, neuropathy (autonomic and peripheral), and vascular disease. Laboratory evaluation for transplantation includes testing for albuminuria, protein and creatinine clearance, serum creatinine, ECG, stress MIBI scan, and lipid panel. Ophthalmology reports are required, and if abnormalities are suspected clinically or through vascular testing, a coronary angiogram is performed.
Social determinants of health, such as financial constraints, psychosocial distress, and competing demands like work, act as barriers to effective diabetes self-management and are closely linked to socioeconomic status. Clinical guidelines now recommend that clinicians address these factors, including health literacy and food insecurity, as part of comprehensive diabetes care.
Overweight patients with diabetes who initiated oral antidiabetic therapy with metformin showed a 39% reduced risk of myocardial infarction compared to those receiving conventional treatment, and this benefit was not related to the dosage of metformin or its glucose-lowering effect. Metformin has been associated with favorable effects on atherothrombotic risk markers, including reduced carotid intima-media thickness, increased fibrinolysis, and decreased levels of plasminogen activator inhibitor-1. While some evidence suggests that combining metformin with a sulfonylurea may initially increase cardiovascular mortality, this could be due to the more severe metabolic disease in patients requiring combination therapy. Long-term follow-up data from the UK Prospective Diabetes Study indicate that the cardiovascular benefits of metformin are sustained over time.
Gastrointestinal symptoms such as nausea, vomiting, dyspepsia, heartburn, irritable bowel syndrome, constipation, and fecal incontinence do not show a significant difference in prevalence between individuals with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and age-matched controls. However, individuals with T2DM and men with T1DM use laxatives more frequently compared to controls. Additionally, people with T1DM have a lower prevalence of heartburn, as reported in a Finnish population-based study.
Device use is crucial for the effectiveness of continuous glucose monitoring (CGM) in managing type 1 diabetes, as illustrated by the relationship between the difference in CGM effect compared to capillary blood glucose monitoring and baseline glycated haemoglobin (HbA1c) values, particularly in a 40-year-old individual.
Insulin therapy in children with diabetes is typically managed through insulin pumps or basal bolus multiple daily injections. Nutrition planning is based on carbohydrate counting or exchange systems, with the macronutrient and micronutrient composition of the diet being similar to that of healthy children. Regular exercise is encouraged but requires careful insulin and nutritional management to prevent severe hypoglycemia, which remains the most common serious complication of childhood diabetes despite being largely preventable. Healthcare providers should support families in managing dehydration, uncontrolled hyperglycemia, and diabetic ketoacidosis during infections. The recommended target HbA1c level is below 58 mmol/mol (<7.5%), though a gap exists between recommended and actual levels, especially in adolescents. Psychological care should address family dysfunction, developmental issues, communication problems, disordered eating and sleep patterns, and psychiatric disorders in both patients and caregivers. Children with diabetes should also be screened for dyslipidemia, microalbuminuria, elevated blood pressure, retinopathy, celiac disease, thyroid disease, and Addison disease based on age and duration of diabetes.
Policy-level interventions to prevent diabetes include front-of-package nutrition labeling and taxation of sugar-sweetened beverages and energy-dense foods, which have been implemented in low- and middle-income countries, particularly in Latin America. Removing tariffs and taxes on medicines is another strategy that supports diabetes prevention and treatment. These measures require collaboration between the health sector and other government bodies, such as the ministry of finance, to both reduce diabetes risk and generate revenue for health initiatives, as demonstrated by examples from Hungary and Mexico where such taxes led to decreased consumption of sugary drinks and increased health funding.
Sulfonylurea therapy is a safe and effective long-term treatment for individuals with neonatal diabetes caused by KCNJ11 and ABCC8 variants, often allowing excellent glycemic control without severe hypoglycemia or serious side effects, even at high doses. This treatment may also improve neurological outcomes, particularly when initiated early, ideally within the first six months of life, and higher doses may lead to greater neurological improvement. The required daily dose for treatment is typically higher than that used for type 2 diabetes, with a median dose of 0.45 mg/kg/day and doses up to 1.5 mg/kg/day reported, although 1 mg/kg/day or less is usually sufficient. Side effects are generally mild and include transient gastrointestinal disturbances, especially diarrhea, and tooth discoloration. In contrast, neonatal diabetes resulting from INS variants requires insulin treatment.
Pioglitazone and rosiglitazone lower HbA1c by up to 1–1.5% (11–16 mmol/mol) with maximum doses in monotherapy, though response varies among patients. When added to sulfonylureas, metformin, or insulin, TZDs can further reduce HbA1c by 0.8–1.5% (9–16 mmol/mol). Combination pills of metformin with rosiglitazone or pioglitazone are available and may be beneficial for patients with insulin resistance, high BMI, central obesity, and hypertriglyceridemia, especially if they have preserved insulin secretion. TZD-secretagogue combinations, such as with glimepiride, are also available and effective in insulin-resistant patients with moderate insulin secretory reserve.
Type 2 diabetes is associated with elevated liver enzymes and hepatic steatosis, often leading to a diagnosis of NAFLD, especially when other causes of liver disease are excluded. Individuals with type 2 diabetes, obesity, hypertriglyceridaemia, and hypertension should undergo liver stiffness measurement using FibroScan, which can detect significant liver fibrosis (≥ F2 fibrosis). Management includes lifestyle modifications such as regular aerobic exercise, weight loss of 5–10%, sodium restriction, and replacing saturated fats and simple carbohydrates with polyunsaturated fats. Smoking cessation is also crucial. For suboptimal glycemic control (HbA1c ≥ 8%, 64 mmol/mol), adding a second glucose-lowering agent like pioglitazone or GLP-1 receptor agonists may be considered. If triglyceride levels remain elevated above 150 mg/dl (>1.8 mmol/l), fenofibrate or omega-3 PUFA supplementation can be added, and if blood pressure remains above 140/90 mmHg, adjustment of antihypertensive therapy, such as increasing ramipril dosage or adding another agent, is recommended.
Etanercept, when administered at a dose of 0.4 mg/kg (maximum 25 mg subcutaneously twice weekly), showed beneficial effects in individuals aged 7.8–18.2 years with diabetes, as indicated by a 39% increase in the 2-hour C-peptide AUC during a mixed-meal tolerance test compared to a 20% decrease in the placebo group after 24 weeks. Additionally, HbA1c levels were lower in the etanercept group (5.9% or 41 mmol/mol) compared to the placebo group (7.0% or 53 mmol/mol) at week 24, with a greater absolute percentage decrease from baseline in the etanercept group (0.41% vs. 0.18%).
Autoimmune type 1 diabetes was previously considered the main form of diabetes in children and young adults, but research now shows multiple genetic or acquired factors can influence islet and mitochondrial biology, leading to significant overlap between type 1 and type 2 diabetes phenotypes. Accurate diagnosis and management of atypical diabetes can be improved through detailed medical history, physical examination, laboratory testing, and evaluation of autoimmune and genetic markers to achieve better clinical outcomes.
In people with type 1 diabetes using multiple daily insulin or continuous subcutaneous insulin infusions, carbohydrate counting combined with insulin dose adjustment effectively lowers glycated haemoglobin (HbA1c), reduces hypoglycaemic episodes, and improves quality of life, body mass index, and waist circumference. However, accurate and consistent insulin dose adjustments require quality education and clinical support, as errors in carbohydrate counting or dosing are common and linked to poorer clinical outcomes. Carbohydrate counting and dietary advice should not interfere with weight management goals, and additional snacks are not always necessary, requiring individualized approaches. Structured education programs like DAFNE are recommended, ideally 6–12 months after diagnosis. For those on fixed or biphasic insulin regimens, maintaining consistency in carbohydrate intake is advised to reduce HbA1c levels.
Charcot joint is associated with diabetes and involves pathogenic mechanisms that include peripheral neuropathy leading to disordered weight-bearing and repetitive joint injury, as well as autonomic dysfunction causing vasodilatation and hyperemic bone resorption. Inflammation plays a key role, with increased expression of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin 1 in affected joints. Patients with Charcot joint exhibit increased osteoclast activity and enhanced osteoclast formation, particularly in acute phases of the disease. This osteoclastogenesis is mediated by receptor activator of nuclear factor κB ligand (RANKL), driven by local inflammation, suggesting potential therapeutic targets aimed at modulating osteoclast activity.
Inadequate awareness of hypoglycaemia refers to an inability to detect the onset of low blood sugar due to a lack of warning symptoms, a condition that is particularly relevant for individuals with diabetes who are at risk of hypoglycaemic episodes. This issue is significant in the context of assessing fitness to drive, as impaired or inadequate awareness can lead to dangerous situations. The condition remains poorly defined in terms of its precise clinical nature, severity, and methods of assessment.
Contraception should be used until glycaemic control is satisfactory, with near normalization of blood sugar targeted preconception and during the first 6–8 weeks of pregnancy. When planning pregnancy, oral antidiabetic agents must be switched to insulin at least three months before attempting conception, once an HbA1c level of less than 6.5% is achieved. Glycaemic control with an HbA1c of less than 6.5% must be maintained, and periodic assessments of complications such as renal function, cardiovascular status, and retinal evaluation must be conducted. Additionally, diabetes self-care skills and knowledge should be taught and assessed, along with nutrition assessment and adequate nutrition planning.
Raised plasma glucose levels during diagnosis of an acute coronary syndrome, particularly above 7 mmol/L, warrant further testing with fasting plasma glucose and HbA₁c to assess for diabetes. A fasting plasma glucose greater than 5.6 mmol/L during acute admission or an admission plasma glucose above 7.8 mmol/L has a sensitivity of nearly 90% and a positive predictive value of 44% for detecting diabetes. Hyperglycemia in this context indicates the need for prompt glucose control during the critical initial hours of the acute event, even though HbA₁c results may not be immediately available.
Self-monitoring of blood glucose (SMBG) provides immediate and daily documentation of hyperglycemia and hypoglycemia, helps determine daily insulin requirements, and assists in detecting and managing hypoglycemia. Blood glucose is best measured during the night, after the overnight fast, at anticipated peaks and troughs of insulin action, two hours after a meal, and during or after vigorous sport or exercise, typically performed 4–6 times a day. Increased frequency of SMBG is linked to improved HbA1c levels in patients with type 1 diabetes mellitus. Patient acceptance of SMBG may improve when alternative testing sites, such as the palm or forearm, are used alongside fingertips, although alternative sites may be slower in reflecting falling blood glucose levels.
Impaired awareness of hypoglycaemia is identified using tools like the Gold and Clarke scales in type 1 diabetes, though these have limitations. A Gold score of ≥ 4 is commonly used to define impaired awareness of hypoglycaemia, but variation in definitions across older studies complicates comparisons between populations, especially those differing in insulin treatment duration. Consistent definitions report a prevalence of impaired awareness of hypoglycaemia at ~25% in type 1 diabetes, increasing to ~50% after 25 years of insulin use. In type 2 diabetes, the prevalence is ~8–10%, rising in insulin-treated cases. Duration of insulin treatment is a key predictor of severe hypoglycaemia rates, which are comparable between type 1 and type 2 diabetes when matched for insulin treatment duration. Given that type 2 diabetes accounts for 90% of all diabetes cases globally, and with improved insulin access and longer life expectancies, hypoglycaemia remains a significant clinical challenge.
Hypoglycaemia in diabetes management is typically caused by an excess of insulin, either endogenous or exogenous, combined with impaired defenses against falling plasma glucose levels. Treatments associated with hypoglycaemia risk include insulin and insulin secretagogues such as sulfonylureas (e.g., glibenclamide, glipizide, glimepiride, gliclazide) and glinides (e.g., repaglinide, nateglinide). In early type 2 diabetes, certain drugs like metformin, thiazolidinediones, α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors may lower plasma glucose without increasing hypoglycaemia risk under normal conditions because they do not elevate insulin levels when glucose concentrations are low or normal. These drugs rely on endogenous insulin secretion, which appropriately declines as glucose levels normalize. GLP-1 receptor agonists and DPP-4 inhibitors enhance insulin secretion in a glucose-dependent manner, meaning they do not stimulate insulin release at normal or low glucose levels. However, all these drug classes can increase the risk of hypoglycaemia if combined with insulin or insulin secretagogues.
Several substances influence glucose metabolism by stimulating glucose uptake or suppressing glucose production, but their therapeutic use in type 2 diabetes mellitus (T2DM) is limited due to difficulty in control and broader physiological effects. Some compounds, such as deoxyfrenolicin, vitamin K5, spermine, diamides, and peroxides, produce insulin-like effects. Okadaic acid and phorbol esters initially mimic insulin's actions but later inhibit insulin responsiveness in tissues. Dichloroacetate and its esters enhance glucose oxidation by activating pyruvate dehydrogenase and reduce liver glucose output by inhibiting pyruvate carboxylase, though they may impair neural function by generating glyoxylate and oxalate.
As glucose levels rise during the progression from metabolic syndrome to type 2 diabetes, cardiovascular risk increases, with elevated glucose contributing to endothelial damage through oxidative stress. However, glucose is not the primary driver of ischaemic heart disease, as glucose-lowering interventions have shown limited effectiveness in reducing macrovascular complications, in contrast to its clear role in diabetic microangiopathy, which is directly caused by high glucose levels.
People with diabetes have a higher risk of infections compared to those without diabetes, with 46% of individuals with diabetes experiencing at least one hospitalization or outpatient visit for infections versus 38% of those without diabetes, resulting in a risk ratio of 1.2. The risk ratios for infection-related hospitalization and death are even higher at 2.2 and 1.9 respectively, which may be due to increased infection severity and complications. Population-based studies have shown that people with diabetes have elevated rates of pneumonia (1.3–1.7-fold), kidney infection (2.0–4.9-fold), skin infection (1.8–2.4-fold), osteomyelitis (4.4–15.7-fold), and general sepsis (2.1–3.2-fold). While some of this increased risk is linked to coexisting conditions like obesity, congestive heart failure, stroke, and peripheral artery disease, which are independent infection risk factors, the persistent difference after adjusting for these conditions suggests that chronic hyperglycemia and insulin resistance also play a role in the higher infection rates among people with diabetes.
Diabetes, of either type, is considered a risk factor for fragility fractures and should be included in clinical fracture risk assessments alongside other recognized factors such as age, gender, body weight, prior fractures, smoking, glucocorticoid use, and bone mineral density (BMD). Despite average BMD being higher in type 2 diabetes (T2DM), measuring BMD remains useful for assessing individual fracture risk. Thiazolidinediones (TZDs) should generally be avoided in T2DM patients at high fracture risk unless necessary. Managing skeletal health in diabetes involves reducing fall risk by addressing macrovascular and microvascular complications, preventing hypoglycemia, optimizing vision, and limiting use of fall-associated medications. While no interventional studies have specifically evaluated osteoporosis treatments in diabetes, it is presumed that fracture-preventing agents like bisphosphonates, effective in non-diabetic populations, will also benefit those with diabetes.
Atypical antipsychotics, or second-generation antipsychotics (SGAs), are associated with hyperglycaemic effects, with numerous reports indicating their potential to worsen existing diabetes, induce new-onset diabetes, and lead to hyperglycaemic crises. These effects can occur both acutely and chronically, and all SGAs marketed in the USA have been reported to cause elevated blood glucose levels, though the severity varies. Among them, olanzapine and clozapine have the highest propensity to induce hyperglycaemia, while newer SGAs such as aripiprazole, ziprasidone, paliperidone, lurasidone, brexiprazole, and cariprazine have the lowest potential, although clinical data on these are more limited. Quetiapine and risperidone exhibit a moderate risk for hyperglycaemia compared to other SGAs.
These drugs act on GLP-1 receptors on pancreatic β cells, enhancing glucose-induced insulin secretion, and are associated with weight loss and minimal risk of hypoglycaemia. They also activate GLP-1 receptors on vagal afferent fibers in the gastrointestinal tract and in the hindbrain, promoting satiety and reducing gastric emptying, which contributes to weight loss. Some POMC neurons express GLP-1 receptors and increase melanocortin signaling in response to GLP-1 stimulation, though it remains unclear if these central nervous system effects directly lower glucose levels independently of food intake and weight.
RAGE modulating agent TTP488 is being considered in phase II clinical trials for patients with diabetic nephropathy, and TP4000 will soon enter phase I clinical trials, though current efforts in RAGE antagonism do not focus on studies addressing cardiovascular disease in relation to diabetes.
Coping skills training programs improve diabetes management in adolescents on intensive insulin therapy by using a cognitive-behavioral model that teaches effective responses to social challenges affecting diabetes care, such as food choices. In structured group sessions led by trained facilitators, adolescents role-play scenarios and receive feedback, participating in six weekly sessions followed by monthly visits. Over 12 months, those receiving this training alongside intensive diabetes management showed significantly lower HbA1c levels (7.5% vs. 8.5%), higher self-efficacy, and reduced difficulty coping with diabetes and lower rates of depression compared to those receiving intensive management alone.
SGLT-2 inhibitors lower blood glucose levels in individuals with type 2 diabetes by blocking proximal tubular glucose reabsorption in the kidneys, thereby promoting renal glucose excretion. These medications also have a natriuretic effect, leading to reductions in blood pressure and body weight. Individuals with higher estimated glomerular filtration rate (eGFR) tend to experience greater HbA1c reduction due to increased glomerular glucose filtration, which is not reabsorbed in the presence of SGLT-2 inhibitors, resulting in a more pronounced glucosuric effect. However, the long-term clinical benefits of SGLT-2 inhibitors are unlikely to be primarily mediated by reductions in HbA1c.
Severe hypoglycemia and acute hyperglycemic episodes such as diabetic ketoacidosis (DKA) often require immediate medical management, with mortality rates from DKA ranging from 0.67–4.0% in high-income countries like Taiwan, the USA, and Denmark, but reaching as high as 25–33% in some African countries. The majority of acute diabetes complications occur in individuals with type 1 diabetes mellitus (T1DM), although around 10–12% occur in those with type 2 diabetes mellitus (T2DM), including atypical variants such as ketosis-prone T2DM in African populations. Long-term follow-up aims to improve blood glucose regulation and avoid precipitants of diabetic emergencies like infection, treatment noncompliance, missed meals, and alcohol abuse. In low-resource settings, barriers such as limited access to care, inadequate medications and equipment, and insufficiently trained staff contribute to poor glycemic control and increased mortality risk, with post-diagnosis life expectancy in some African regions being as low as one year following T1DM onset. Patient factors such as age and comorbidities, as well as healthcare resource availability and staff experience, also influence outcomes.
Type 1 diabetes mellitus (T1DM) involves a loss of immunologic tolerance leading to autoimmune destruction of pancreatic β-cells, potentially due to a disordered antigen-presenting mechanism. HLA class II molecules, expressed on antigen-presenting cells (APCs) such as macrophages, bind peptides from self-proteins or exogenous antigens to form a trimolecular complex that activates T-cell receptors. In T1DM, particularly in individuals with the high-risk HLA DQB1*0201*0302 genotype, macroages secrete excessive proinflammatory cytokines and prostaglandin E₂ upon non-antigenic stimulation, which can directly or indirectly damage β-cells by activating T and B lymphocytes. Antigen-presenting cells presenting β-cell autoantigens may drive an anti-self autoimmune response, contributing to insulitis, which involves APCs, CD4⁺, and CD8⁺ T lymphocytes in the pancreas. Autoreactive CD8⁺ T lymphocytes are considered to play a major role in β-cell destruction, with natural killer cells also showing abnormal activity and counts. The presence of autoreactive T lymphocytes in insulitis and circulation at diagnosis, along with the temporary effectiveness of immunosuppressive drugs like cyclosporine or anti-CD3 monoclonal antibodies in halting disease progression, supports the involvement of cellular immunity in β-cell destruction.
The effects of a 6.5-year difference in HbA1c during the DCCT on the incidence of retinopathy and nephropathy have persisted and even become more pronounced over 14 years of follow-up, with individuals in the standard therapy group continuing to experience a higher incidence of complications despite improved glycemic control during EDIC, while those in the intensive therapy group maintained a lower complication rate despite worsening glycemic control, a phenomenon known as "glycemic memory." Recent evidence shows glycemic memory also occurs in patients with type 2 diabetes mellitus (T2DM), as demonstrated by the UKPDS, where tight glucose control led to sustained reductions in microvascular risk and emerging risk reductions for myocardial infarction and death from any cause, even after early loss of glycemic differences, a concept referred to as the "legacy effect," with benefits evident during 10-year post-trial follow-up among overweight patients.
Gene variants associated with type 1 diabetes have undergone recent positive selection and are becoming more prevalent, with selection favoring alleles that increase susceptibility to type 1 diabetes, possibly due to an evolutionary benefit such as protection against viruses and bacterial infections. No similar link has been found for type 2 diabetes risk variants, which aligns with the lack of support for the thrifty genotype hypothesis in this context.
Clinical depression is more prevalent in individuals with type 1 diabetes mellitus (T1DM), with studies suggesting a prevalence of 12% compared to 3.2% in those without diabetes, although the increased risk is less evident when only high-quality studies with control groups and interview-based assessments are considered, showing a prevalence of 7.8% and a non-significant odds ratio of 2.4.
Diabetes is associated with several medical concepts and abbreviations, including RAGE (receptor for advanced glycation end-products), which plays a role in the complications of diabetes due to the accumulation of glycated proteins. RAI (rapid-acting analog) refers to types of insulin used in diabetes management that act quickly to lower blood glucose levels. RCAD (renal cysts and diabetes syndrome) is a genetic condition that includes both kidney cysts and diabetes. RT-CGM (real-time continuous glucose monitoring) is a method used to track glucose levels throughout the day and night, aiding in diabetes management. SMBG (self-monitoring of blood glucose) is a common practice for individuals with diabetes to check their blood sugar levels regularly. SGLT (sodium-glucose co-transporter) inhibitors are a class of medications used to lower blood glucose levels in individuals with diabetes. sRAGE (soluble receptor for advanced glycation end-products) acts as a decoy receptor and is related to the inflammatory processes seen in diabetes. SDH (sorbitol dehydrogenase) is an enzyme involved in the polyol pathway, which is implicated in diabetic complications such as neuropathy and retinopathy. SUR (sulfonylurea receptor) is involved in insulin secretion and is a target for sulfonylurea drugs used in treating type 2 diabetes.
Insulin dose modification is a strategy to combat exercise-related hypoglycaemia in individuals with diabetes. Those using insulin pumps can reduce basal insulin by 25–90 minutes before physical activity depending on its duration and intensity; for example, a 25% reduction is suitable for 30 minutes of mild aerobic exercise, while a 75% reduction is needed for heavy aerobic exercise. Intense anaerobic exercise, however, does not require a pre-exercise decrease in basal insulin. For individuals not using pumps, long-acting insulin should be reduced the evening before intense activity. Additionally, mealtime bolus insulin can be decreased by 25–50% before or after exercise. Rapid-acting insulin doses may need to be reduced by 25–75% depending on exercise intensity, particularly if activity occurs within an hour of eating or during evening exercise. In some cases, consuming 10–15 grams of fast-acting carbohydrate before activity can also help prevent hypoglycaemia.
Tight glycaemic management has established benefits in reducing microvascular disease, but its role in lowering cardiovascular events remains debated. In frail older individuals, the benefits of intensive glucose control diminish, particularly when other comorbidities are present. Blood pressure management may offer greater benefit than glucose control in older adults aged 75–79 years, and the effectiveness of both therapies declines with increased comorbidity and functional impairment. Tight glycaemic targets in frail older people may lead to harm, such as hypoglycaemia, emphasizing the need to individualize therapy based on patient preferences, life expectancy, comorbidities, and impact on quality of life. Anti-diabetes medications have varying advantages and disadvantages in older adults.
Diabetic complications involve interactions between hemodynamic pathways such as the renin angiotensin system (RAS) and metabolic pathways like hyperglycemia and the formation of advanced glycation end-products (AGEs). Research suggests that AGE accumulation can upregulate certain components of the RAS, particularly in the renal context. Angiotensin-converting enzyme (ACE) inhibition has been shown to provide end-organ protection, partly by reducing AGEs and increasing soluble RAGE (sRAGE). The status of the RAS may thus play a key role in modulating AGE-induced diseases. Additionally, other anti-atherosclerotic therapies, including angiotensin II receptor blockers (ARBs), peroxisome proliferator-activated receptor α (PPAR-α) and PPAR-γ agonists, and statins, have been found to exert vasculoprotective effects through inhibition of the AGE/RAGE pathway.
Autoimmune type 1 diabetes progresses through distinct stages, beginning with an aetiological stage linked to enterovirus infection in individuals with increased genetic risk. This infection may lead to prolonged viral shedding, which could trigger islet autoimmunity through unknown mechanisms. The first appearance of an autoantibody against islet antigen or glutamic acid decarboxylase marks the onset of islet autoimmunity, dependent on genetic risk factors. The progression to stage 1 of the disease occurs when a second autoantibody appears.
The ADA workgroups on hypoglycaemia indicate that individuals treated with insulin or insulin secretagogues are at risk of developing hypoglycaemia, particularly at a plasma glucose concentration of ≤3.9 mmol/l (≤70 mg/dl), which is considered a conservative alert value. This threshold aligns with the lower limit of the post-absorptive plasma glucose range in non-diabetic individuals and corresponds to the activation point of physiological glucose counter-regulatory mechanisms. Repeated exposure to such low glucose levels may reduce the body's glycaemic defenses against future hypoglycaemic episodes. Additionally, studies have shown that even complex functions like driving can be impaired at these glucose levels in people with type 1 diabetes, highlighting the clinical significance of maintaining adequate blood glucose. The threshold also accounts for the relative inaccuracy of glucose monitoring devices at low plasma glucose concentrations.
Resistance training and aerobic training both led to reductions in waist circumference, insulin dosage, and self-monitored blood glucose in individuals with type 1 diabetes mellitus (T1DM), although these changes were statistically significant only in the aerobic training group. Additionally, HbA1c levels increased significantly in the aerobic training group, while a non-significant decrease was observed in the resistance training group.
Young adults with type 1 diabetes, particularly those with poor glycemic control (HbA1c > 9% or 75 mmol/mol), may struggle with the transition to independent diabetes management due to a lack of formal preparation and a preference to delay taking full responsibility for their care. This transition period can be further complicated by competing social, emotional, educational, and work-related demands, which may take priority over self-care and healthcare visits. Additionally, some individuals feel uncomfortable disclosing their diabetes in new environments, making consistent diabetes management difficult. Successful transition requires strong self-efficacy and self-advocacy skills, which should be addressed during preparation for this critical phase.
Type 1 diabetes mellitus (T1DM) risk is significantly influenced by HLA class II DQ8 and DQ2 haplotypes, which are present in over 90% of patients diagnosed before age 30, and accounts for nearly 50% of the risk among first-degree relatives (FDR) of Caucasian patients. However, only 15% of children with T1DM have a family history of the disease, highlighting the need for general population screening, despite its low diagnostic sensitivity due to only 10% of individuals with disease-associated HLA genes developing the condition. Studies such as BABYDIAB, DAISY, DiPIS, and TEDDY are improving understanding of T1DM etiopathogenesis, and population differences in DR-DQ allele frequencies indicate the need for tailored screening strategies, as T1DM in Asians is associated with different HLA haplotypes than in Caucasians. Non-HLA genetic markers, including INS-VNTR, PTPN22, and IL2RA, have also been identified, though their relative risk is lower than that of HLA genes, and their role in islet autoimmunity remains under investigation. HLA and some non-HLA genes are linked to the presence of islet autoantibodies and progression to persistent autoimmunity, but combining genetic and autoimmune markers does not improve the sensitivity of autoantibody testing, despite potentially increasing positive predictive value.
Patients with known diabetes or hospital-related hyperglycaemia who are unable to take oral fluids or food and cannot adjust their own insulin regimen may require specialized management. Vomiting can occur but should exclude diabetic ketoacidosis. In cases where patients are nil by mouth and expected to miss more than one meal, or in severe illness such as sepsis where optimal glycaemic control is needed, careful monitoring and insulin adjustments are necessary.
SMBG (self-monitoring of blood glucose) should be performed three or more times daily for patients using multiple insulin injections or insulin pump therapy, and may also be useful for those on less frequent insulin regimens to guide treatment success and insulin dose adjustments. Additional blood glucose checks are recommended in situations that increase the risk of hypoglycemia, such as before exercise, driving, or when symptoms of hypoglycemia are present.
Type 2 diabetes, traditionally seen as irreversible and progressive, may arise from long-term excessive energy intake leading to liver fat accumulation, hepatic insulin resistance, hyperinsulinemia, ectopic pancreatic fat accumulation, and impaired β-cell function; weight loss sufficient to reverse these changes may result in durable remission of hyperglycaemia. A proof-of-concept study showed that a 600 kcal/day diet for eight weeks led to an average 15 kg weight loss, normalizing hepatic insulin sensitivity, β-cell function, and blood glucose while reducing liver and pancreas triacylglycerol stores. In a subsequent open-label, cluster randomized trial involving 306 participants with short-duration type 2 diabetes and BMI of 27–45 kg/m², 24% of those in a weight management program involving caloric restriction, total diet replacement, medication withdrawal, and structured support achieved ≥15 kg weight loss, and 46% achieved diabetes remission. Remission is defined as HbA1c < 6.5% (48 mmol/mol) measured at least three months after stopping glucose-lowering medications, a diagnostic criterion that is increasingly being applied in programs and studies on diabetes remission.
Thiazolidinediones, a class of medications used in diabetes management, have raised concerns due to their cardiovascular effects, including oedema, reduced haemoglobin levels, and congestive heart disease. While long-term cardiovascular events were reduced with pioglitazone in the PROactive study, safety concerns from rosiglitazone's cardiovascular risks diminished confidence in the drug class, and the TOSCA.IT study found no overall cardiovascular benefit with pioglitazone.
Adipose insulin resistance, particularly when both insulin receptor and type 1 IGF receptor are deleted, promotes lipodystrophy, diabetes, insulin resistance, increased beta-cell mass, and ectopic lipid accumulation. White adipose tissue plays a key role in post-prandial glucose storage and metabolic signaling, and its dysfunction contributes to metabolic disorders such as non-alcoholic fatty liver disease, which can progress to non-alcoholic steatohepatitis, fibrosis, and liver dysplasia. Insulin signaling in adipose tissue supports glucose influx, lipid synthesis, and anti-lipolysis, and disruption of this signaling leads to systemic insulin sensitivity or resistance depending on the extent and location of receptor deletion.
The prevalence of type 2 diabetes in China has increased rapidly, particularly in urban areas, with rates rising from as low as 0.3% in rural Guangdong in the 1980s to 5.5% by 2000–2001. Studies in regions like Da Qing showed a more than threefold increase from 1.0% in 1986 to 3.5% in 1994. A nationwide survey in 1995–1997 found an age-standardized diabetes prevalence of 3.2%, with higher rates in urban areas compared to rural regions. Impaired glucose tolerance is also widespread, affecting 7.3% of the population in 2000–2001, and individuals with impaired glucose tolerance or impaired fasting glycemia have an 11.7-fold increased risk of developing diabetes within three years. A significant portion of diabetes cases remain undiagnosed, with only 30% of the estimated 20 million affected individuals previously identified.
HbA1c ≤ 6.5% (48 mmol/mol) is a diagnostic threshold used in identifying diabetes, and in clinical studies such as SCALE Prediabetes, liraglutide 3.0 mg administered daily via subcutaneous injection, which belongs to the GLP-1 receptor agonist (GLP1-RA) class of medications, has been evaluated for its efficacy, with a reported response rate of 56.5% in achieving the target HbA1c level compared to other interventions.
Potential hazards for drivers with diabetes include hypoglycemia, visual impairment, and disability from severe neuropathy or leg amputation. Hypoglycemia can impair driving skills by causing cognitive dysfunction, mood changes, and reduced motor skills and judgment, often occurring without noticeable symptoms when blood glucose falls below 3.8 mmol/L; impaired awareness of hypoglycemia is a relative contraindication to driving. Visual acuity worse than 6/12 in the better eye precludes driving, though people with diabetes may still have significant visual impairments such as field loss, poor night vision, and reduced perception of movement due to retinopathy, laser treatment, or cataracts. Many countries require drivers with diabetes to declare their diagnosis for licensing and insurance purposes, with failure to disclose invalidating insurance claims. Driving licenses are often issued for fixed terms requiring medical review for renewal, and insulin-treated drivers are frequently prohibited from driving passenger-carrying or large goods vehicles.
α-Glucosidase inhibitors are contraindicated in patients with chronic intestinal disease, and high doses of acarbose may elevate liver enzyme levels, necessitating periodic monitoring of transaminase concentrations in patients on the maximum dosage regimen; if liver enzymes rise, reducing the dose typically leads to resolution, but if not, alternative causes of liver dysfunction should be investigated.
HNF1A maturity-onset diabetes of the young (MODY) is typically diagnosed between 10 and 30 years of age, with 63% of carriers diagnosed by age 25 and 79% by age 35, and the age of diagnosis is influenced by the location of the mutation within the gene. Patients initially may have normal fasting glucose levels during an oral glucose tolerance test but show a marked increase in glycemia at 2 hours, resulting in a large 2-hour increment of over 5.0 mmol/L, as insulin secretion remains appropriate for blood glucose values below 8.0 mmol/L but is significantly reduced above this level compared to non-diabetic non-mutation carriers. Glycemic control deteriorates with age, often requiring pharmacologic treatment, and microvascular complications are common when hyperglycemia is inadequately managed. Patients are generally lean and insulin-sensitive, with obesity rates similar to the general population.
For hypoglycemia management in diabetes, ensure safety and do not leave the individual alone; check blood glucose if possible and administer 15 grams of quickly absorbed carbohydrate such as sugar, glucose powder, or fruit juice, followed by 15 grams of slowly absorbed carbohydrate like rice or biscuits. Recheck blood glucose after 10 minutes and repeat treatment if levels remain below 72 mg/dL or symptoms persist. Identify and correct the cause of hypoglycemia and assess for any ongoing risk, providing guidance for its prevention.
Individuals with type 1 diabetes who participated in team sports during high school had a threefold lower risk of macrovascular disease and mortality compared to those who did not participate, although this benefit was not observed in women, potentially due to lower participation rates (24% in women versus 39% in men). Physical activity levels in adulthood were also predictive of mortality over six years, with sedentary men being three times more likely to die than active men. In the Finnish Diabetic Nephropathy (FinnDiane) study, involving 2369 individuals with type 1 diabetes followed for an average of 11.4 ± 3.5 years, exercise was linked to reduced risks of premature all-cause and cardiovascular mortality in both sexes, and also showed that physical activity lowers mortality risk in individuals with type 1 diabetes and chronic kidney disease.
Iatrogenic hypoglycemia is a major challenge in managing diabetes, particularly in individuals with type 1 diabetes mellitus (T1DM) and some with advanced type 2 diabetes mellitus (T2DM), leading to frequent health complications and occasionally death. It weakens the body's natural defenses against decreasing blood glucose levels, creating a cycle of recurring hypoglycemia. This condition also hinders the achievement of stable blood sugar levels over time, limiting the full vascular benefits that come with effective glycemic control.
Leptin inhibits glucose-stimulated insulin secretion by activating β-cell KATP channels or c-Jun N-terminal kinases, and may impair β-cell function by reducing β-cell mass. Resistin also inhibits glucose-stimulated insulin release and induces β-cell apoptosis in rats, although it is not considered a true adipokine in humans. Adiponectin enhances insulin sensitivity and has protective effects on β-cells, including stimulating insulin secretion, preventing apoptosis, and promoting regeneration through activation of Erk and Akt kinases and regulation of lipid metabolism genes. Other adipokines like adipsin, apelin, and chemerin may improve insulin secretion via β-cell G-protein-coupled receptors. Reduced adiponectin levels are linked to the development of type 2 diabetes.
SMBG (self-monitoring of blood glucose) should be used as part of a structured self-management program and only when it serves an identified purpose in diabetes management, with considerations including the frequency and timing of testing, its value for new and ongoing users, and how users respond to the results.
Health system interventions in low- and middle-income countries may improve glycaemic management in type 2 diabetes, with multicomponent clinic-based approaches showing the strongest evidence. Other effective strategies include pharmacist task sharing, diabetes education or support, and nursing case management. The WHO-PEN package provides protocols for managing noncommunicable diseases, including diabetes, along with essential diagnostic tools and medicines for primary care. Lessons from the COVID-19 pandemic, such as triage for prioritizing in-person visits, telemedicine, task sharing, decentralized medicine distribution, and redirecting patients to alternative facilities, may help address ongoing access-to-care challenges.
The prevalence of diabetes varies among different ethnic groups in the US, with higher rates observed in Latino people and African Americans compared to White people. In 1991, age-adjusted prevalence rates were 6% in White people, 9% in Cubans, 10% in African Americans, 13% in Mexican Americans, and 13% in Puerto Ricans. These disparities have persisted over time, with rising rates in all groups. Between 1987 and 1996, the 7- to 8-year incidence of type 2 diabetes mellitus (T2DM) tripled in both Mexican Americans and White people of Northern European ancestry, though the absolute rate was twice as high in Mexican Americans. T2DM is also more common in older Puerto Ricans (38%) and Dominicans (35%) than in White people of Northern European ancestry (23%). Economic disadvantage may contribute significantly to the higher prevalence of T2DM among African American women.
Neuropathic foot problems in diabetes arise due to sensory loss, which removes the warning signal of pain, leading patients to delay seeking medical attention. This lack of sensation can result in unnoticed injuries, such as ulcers caused by ill-fitting shoes, as pressure nerve endings may still be functional and give a false sense of normal fit. Management of such foot complications can be informed by practices used in treating leprosy patients, as both conditions result in similar sensory deficits and foot lesions despite different underlying causes. Clinicians should be alert to the possibility of neuropathy in patients with plantar ulcers who do not limp, and recognize that the absence of pain diminishes a patient's motivation to prevent or heal injuries.
Co-management and linkages of diabetes with diseases such as HIV/AIDS and tuberculosis should be integrated into health system responses, particularly in low- and middle-income countries (LMICs).
In patients with type 2 diabetes mellitus (T2DM), defects in insulin action on blood flow are not observed when tested at insulin concentrations within the physiologic range, but become apparent at grossly supraphysiologic insulin levels (600 mU/L). Insulin has a vascular effect involving vasodilatation of peripheral resistance vessels, partly mediated by enhanced nitric oxide (NO) production by the endothelium; however, this effect typically requires prolonged or high doses of insulin, raising questions about its physiologic significance.
Most children with diabetes are initially treated with a combination of intermediate-acting (lente) and short-acting (regular) insulins, administered 20 to 30 minutes before meals, typically using highly purified porcine or human insulins. The initial insulin requirement may range from 1 to 1.75 units per kilogram per day, followed by a partial remission phase where the requirement may decrease to 0.5 to 0.6 units per kilogram per day, known as the "honeymoon" period. Over time, insulin needs generally increase to reach a plateau. A common regimen is the split-mix approach, where two-thirds of the total daily dose is given before breakfast and one-third before dinner, with each dose consisting of two-thirds lente and one-third regular insulin. Insulin dosing adjustments are made based on blood sugar levels, urine sugar, ketone bodies in the urine, diet, and exercise. Premixed insulin formulations like Mixtard 30:70 are also available alongside short- and intermediate-acting insulins.
Increased concentrations of hormones such as human placental lactogen, progesterone, oestrogen, prolactin, and cortisol, along with elevated free fatty acid levels and changes in placental cytokines like tumour necrosis factor α (TNF-α), adipocyte fatty acid-binding protein, and leptin, appear to contribute to insulin resistance in late pregnancy, and increased visceral fat deposits also play a role in this insulin resistance.
Chronic hyperglycemia in diabetes alters renal sensitivity to vasopressin, reducing the sensation of thirst despite elevated plasma osmolarity, which can delay appropriate fluid intake. This mechanism is particularly relevant in undiagnosed diabetes and advanced age, where dehydration may progress unnoticed. In older individuals, polydipsia may be absent despite osmotic diuresis, making nocturia, especially an increase from habitual levels, the most reliable indicator of an osmotic presentation.
Repaglinide and nateglinide are prandial insulin releasers with chemical structures similar to glibenclamide (glyburide), indicating their related function in stimulating insulin release, which is relevant to the management of diabetes.
Employment can be restricted for individuals with diabetes due to the potential hazards of hypoglycaemia, particularly in jobs where such risks could endanger the worker, colleagues, or the public. The increasing prevalence of type 2 diabetes among working-age individuals and the greater use of insulin have become important considerations for occupational health assessments. Discriminatory employment practices and company-imposed restrictions may limit job access due to perceived risks associated with diabetes, including hypoglycaemia or visual impairment. Additionally, diabetes can lead to increased sick leave, absenteeism, and reduced productivity, with long-term effects on economic productivity and work capacity, especially among older employees who may face early retirement due to health-related disabilities.
Metformin is contraindicated in severe renal impairment with an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m². In Europe, the daily dose of metformin should not exceed 2000 mg for those with stage 3A chronic kidney disease (eGFR 45–59 ml/min/1.73 m²), whereas for individuals with stage 3B chronic kidney disease (eGFR 30–44 ml/min/1.73 m²), the maximal daily dose is 1000 mg. In the USA, initiation of metformin is not recommended with an eGFR between 30 and 45 ml/min/1.73 m². Annual monitoring of serum creatinine is required, and people with moderate renal impairment should be educated to withhold metformin during acute illness or if administration of iodinated contrast media is planned.
In both type 1 diabetes mellitus (T1DM) and advanced type 2 diabetes mellitus (T2DM) with absolute endogenous insulin deficiency, the pathophysiology of glucose counterregulation is similar but differs in timing. Iatrogenic hypoglycemia arises from therapeutic hyperinsulinemia leading to declining plasma glucose levels, impairing the normal decrease in insulin and increase in glucagon. Hypoglycemia also diminishes subsequent sympathoadrenal responses. In T1DM, rapid $\beta$-cell failure results in early development of defective glucose counterregulation and hypoglycemia unawareness, whereas in T2DM, these syndromes occur later due to slower $\beta$-cell decline. As T2DM patients approach the insulin-deficient stage, iatrogenic hypoglycemia becomes increasingly common.
Blood glucose monitoring systems must meet strict accuracy standards defined by ISO 15197:2013, ensuring that for readings above 100 mg/dl (5.6 mmol/l), deviations from a laboratory reference method do not exceed 15%, and for values below 100 mg/dl (5.6 mmol/l), 95% of measurements must fall within ±15 mg/dl (0.83 mmol/l) of the reference value.
Recommended care for diabetes is evidence-based and cost-effective in most nations with well-developed healthcare systems, aiming to be accessible to all people with diabetes. Healthcare systems should strive to provide this level of care, though variations in global resources necessitate different levels of care, including adaptations for low- and high-resource settings.
Individuals with overt type 2 diabetes have a consistently higher risk of developing NASH and advanced fibrosis, as well as serious liver-related complications such as cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Studies, including a large administrative health database of nearly 2.5 million Canadians, show that those with newly diagnosed type 2 diabetes have approximately a 2-fold increased risk of developing cirrhosis, liver failure, or requiring liver transplantation over 12 years compared to matched individuals without type 2 diabetes. Additionally, data from Northern Italy indicate that people with type 2 diabetes have about a 3-fold higher risk of dying from chronic liver diseases, primarily due to NAFLD.
Microangiopathy in diabetes is linked to reduced nerve conduction velocity and loss of myelinated nerve fibers. In normotensive individuals with mild diabetic sensorimotor polyneuropathy, treatment with trandolapril improved nerve conduction velocity, amplitude, and F-wave latency over 12 months. Additionally, candesartan has been shown to improve endothelial function and myogenic tone of resistance vessels in people with type 2 diabetes. The DEMAND trial demonstrated that a combination of manidipine and delapril was more effective in preventing the progression of diabetic sensorimotor polyneuropathy compared to delapril alone or placebo, with 23.5% progression in the combination group versus 28.9% with delapril and 38.6% with placebo over three years; furthermore, 33.3% of those with existing neuropathy at baseline showed regression with manidipine and delapril, compared to 28.9% with delapril and 8.3% with placebo.
The cloning of the insulin gene in the late 1970s led to the idea that non-insulin-producing cells could be transformed into insulin-producing substitute cells using a suitable promoter and insulin gene construct, potentially restoring insulin production in type 1 diabetes mellitus (T1DM) and some cases of type 2 diabetes mellitus (T2DM). Early experiments used cell lines and fibroblasts, but later studies extended to hepatocytes, myocytes, pituitary, and exocrine cells. A challenge in this approach is that most substitute cells do not express the prohormone convertases PC2 and PC3, which are necessary to convert proinsulin into insulin. This obstacle has been addressed by modifying the insulin gene to include a furin cleavage site, resulting in a construct known as INS-FUR.
Before insulin was available, most women with diabetes died within two years of diagnosis, and pregnancy was rare, with only one diabetic-related pregnancy recorded in 35,000 deliveries in 1920s London. Among those who became pregnant, approximately half of the mothers and babies died.
The Gocap device, which interfaces with an app, displays insulin administration type and timing, and allows data entry, has been used to assess insulin use in individuals on a multiple daily injection (MDI) regimen. In a study involving 75 participants, it revealed that 24% of bolus doses and 36% of basal doses were inaccurately dosed or timed. Additionally, the device has been paired with continuous glucose monitoring (CGM) to demonstrate how insulin dose and timing affect postprandial glucose levels, potentially helping healthcare providers and individuals with type 1 diabetes adjust bolus insulin regimens effectively.
Individuals with diabetes in hospital should be given the opportunity to decide whether they wish to self-manage their condition during admission, provided they are well enough to do so, with the key principle being that the person has primary responsibility for this decision. Suitable candidates for self-management in hospital are competent adults with a stable level of consciousness who successfully manage their diabetes at home, have the physical skills to self-administer insulin, are accustomed to performing glucose monitoring, and have adequate oral intake. If self-care is deemed unsafe or impossible, such as in critically ill or post-surgery patients or those unwilling to self-manage, there must be a governance arrangement to assess competency and, if necessary, override the individual's choice. Hospitals should implement a person-centred policy for diabetes self-management, supporting individuals to take as much responsibility as they wish and their clinical status allows, which can enhance their hospital experience. Institutions should provide written information to explain the responsibilities involved in self-management, and for elective surgical patients, this information may be given during the pre-assessment clinic along with an agreed care plan to establish the patient's preference for self-management and the circumstances under which it may not be feasible.
The class II HLA-DR-DQ haplogenotype DR3-DQ2 (DRB1*03-DQA1*0501-B1*0201) and DR4-DQ8 (DRB1*04-DQA1*03:01-B1*03:02) confers the highest risk for type 1 diabetes, with the heterozygous DQ2/8 genotype further complicating risk due to the potential formation of heterodimer molecules in trans by DQA1*05:01-B1*03:02 and DQA1*03:01-B1*02:01 haplotypes, which may contribute to disease risk through unique antigen-presenting capabilities.
Mortality in individuals with type 2 diabetes is linked to macrovascular disease, worsening microvascular disease, and diabetic sensorimotor polyneuropathy. Diabetic sensorimotor polyneuropathy, defined by reduced touch or pressure sensation, is associated with increased risk of non-fatal myocardial infarction, coronary revascularization, congestive cardiac failure, transient ischaemic attack, and stroke. The presence of neuropathy improves cardiovascular risk prediction beyond standard risk factors and is the strongest predictor of mortality in people with type 2 diabetes undergoing intensive glycaemic management with HbA1c < 6.0%. Neuropathy is also strongly linked to myocardial ischaemia detected via sestamibi single-photon emission computed tomographic imaging and is independently associated with mortality even in individuals without diabetes.
Impaired myocardial diastolic function and endothelial dysfunction are early manifestations of diabetes-related cardiovascular involvement, leading to reduced myocardial blood flow reserve. Hyperglycemia contributes to early myocardial and microcirculatory disturbances, which may be reversible with improved metabolic control, particularly through insulin-based glycemic management, as suggested by some observational studies. However, this hypothesis was not confirmed in the Diabetes mellitus And Diastolic Dysfunction (DADD) trial, which found no significant benefit of insulin versus oral glucose-lowering therapies in patients with type 2 diabetes and early diastolic dysfunction who were free from prior cardiovascular events or signs of congestive heart failure or coronary artery disease. The lack of effect may be due to the relatively healthy status of the study population, indicating a need for further research involving patients with more advanced disease stages, potentially using newer agents like incretins, while carefully accounting for confounding factors such as hypertension and other diabetes-related complications.
Elevated blood glucose levels on admission are associated with poorer outcomes in patients with troponin-positive acute coronary syndrome (ACS), with a 30-day mortality rate of 20.2% in those with blood glucose greater than 170 mg/dL (9.4 mmol/L) compared to 3.3% in those with lower levels. Approximately 10% of patients without a prior diabetes diagnosis had admission blood glucose exceeding 250 mg/dL (14 mmol/L). Not receiving intravenous insulin treatment was linked to a 56% increased risk of death at 7 days and a 51% increased risk at 30 days.
The average type 2 diabetes risk variant frequency in the general population is 54%, raising the question of whether type 2 diabetes is the default condition, and whether protective variants influence disease susceptibility. Studies have included controls with risk factors for type 2 diabetes but who remain disease-free to explore this. A rare (0.66%) loss-of-function mutation (R138X) in the SLC30A8 gene was identified in Finland and replicated in over 150,000 individuals from other European countries using Exome chip technology. Additionally, the DeCode group identified another loss-of-function mutation associated with type 2 diabetes and β-cell dysfunction. An ADCY5 variant is linked to two-hour insulin levels adjusted for two-hour glucose and to two-hour glucose/type 2 diabetes. MADD variants are associated with fasting proinsulin, fasting glucose, and HOMA-B, which measures insulin secretion. Variants in TMEM163 are also connected to fasting insulin, and TCF7L2 is associated with fasting and two-hour glucose levels.
Hypoglycaemia-associated autonomic failure is a dynamic functional disorder distinct from classic diabetic autonomic neuropathy, which is a common neuropathic complication of diabetes. While autonomic system failure is not present in hypoglycaemia-associated autonomic failure, an attenuated sympathoadrenal response to hypoglycaemia is a key feature and is also seen in diabetic autonomic neuropathy. Structural autonomic neuropathy typically occurs in individuals with long-standing diabetes, making it challenging to determine its specific contribution to counter-regulatory failure. A more precise term for the condition might be hypoglycaemia-associated counter-regulatory impairment to differentiate it from impairments caused by other factors like treatment duration, exercise, and sleep, although the term hypoglycaemia-associated autonomic failure is more commonly used.
People with type 2 diabetes, even without obesity, exhibit reduced hepatocellular ATP concentrations and lower flux rates through hepatic ATP synthase, which are linked to both peripheral and hepatic insulin sensitivity but not whole-body insulin sensitivity. Hepatocellular ATP and inorganic phosphate levels change differently in type 2 diabetes compared to type 1 diabetes within the first five years after onset, and these changes remain significant even after adjusting for liver fat content. Despite similar mitochondrial content, individuals with obesity, with or without steatosis, show significantly higher maximal mitochondrial respiration rates in the liver compared to lean individuals, while those with non-alcoholic steatohepatitis (NASH) have 30–40% lower maximal respiration rates, greater hepatic insulin resistance, increased mitochondrial uncoupling and leaking activity, elevated oxidative stress, reduced antioxidant defense, and heightened inflammation. These findings indicate an initial adaptive response in liver mitochondrial function during early obesity-related insulin resistance, which diminishes as non-alcoholic fatty liver disease (NAFLD) and insulin resistance progress. Supporting this, insulin-resistant individuals with steatosis and obesity experience a sixfold greater rise in hepatic ATP levels after a mixed meal compared to lean, insulin-sensitive individuals.
ZnT8Ab are present in 60-80% of patients with new-onset type 1 diabetes mellitus (T1DM) and are detected in approximately 26% of patients who are negative for conventional islet autoantibodies such as GAD65Ab, IA-2Ab, and IAA. These antibodies are found in only 2% of controls and less than 3% of patients with type 2 diabetes mellitus (T2DM), indicating their specificity for T1DM. ZnT8Ab are also present in 30% of patients with other autoimmune diseases associated with T1DM. Due to the high β-cell specificity of ZnT8 compared to other autoantigens like GAD65 and IA-2, and the fact that ZnT8Ab titers increase with age, they are considered valuable markers for predicting T1DM, particularly in older children.
Pramlintide, a molecule derived from the peptide AC137 with specific amino acid substitutions, was approved by the FDA in March 2005 for use in insulin-treated patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM). It is marketed under the tradename Symlin and has only been approved in the USA at the time of writing. Pramlintide has a plasma half-life of approximately 48 minutes when administered subcutaneously into the abdominal area or thigh, and it is primarily eliminated by the kidneys. For patients with T1DM, normal dosing during gradual titration is often 60–90 μg three to four times per day prior to meals, while those with T2DM may receive somewhat higher doses, typically administered subcutaneously twice per day. Proper titration of pramlintide is important to optimize efficacy and minimize transient nausea.
In individuals with type 2 diabetes, excessive postprandial hyperglycaemia arises from impaired suppression of glucose production and reduced hepatic glycogen accumulation, which is not solely due to impaired insulin secretion but involves defects in insulin-stimulated glycogen synthase activity. Hepatic lipid accumulation, known as steatosis and now classified under non-alcoholic fatty liver disease (NAFLD), is closely linked to hepatic insulin resistance and is commonly found in obesity, metabolic syndrome, and in women with a history of gestational diabetes or type 2 diabetes. Increased lipid availability can independently induce hepatic triglyceride storage and insulin resistance, as shown by studies using short-term lipid infusions that led to impaired insulin-mediated suppression of glucose production. Animal models further suggest that lipid intermediates like plasma membrane sn-1,2-DAGs inhibit insulin signaling in the liver, contributing to insulin resistance through mechanisms similar to those in skeletal muscle.
Corneal confocal microscopy (CCM) is a noninvasive imaging technique used to evaluate corneal nerve morphology and serves as a surrogate marker for peripheral neuropathies, particularly diabetic sensorimotor polyneuropathy. It allows direct visualization of peripheral nerves with high sensitivity and specificity, enabling diagnosis, prediction of development and progression, and assessment of repair after intervention. CCM correlates with intraepidermal nerve fibre density (IENFD) and has comparable diagnostic accuracy. It is used to quantify corneal nerve parameters such as corneal nerve fibre length (CNFL), corneal nerve branch density (CNBD), and corneal nerve fibre density (CNFD). CCM can detect subclinical small nerve fibre damage in individuals with impaired glucose tolerance and children with type 1 diabetes.
Type 1 diabetes is associated with the development of moderately and severely increased albuminuria and end-stage kidney disease (ESKD), although recent data suggest these complications may be less common than previously observed in some countries. Older studies indicated a lifetime risk of approximately 50% for moderately elevated albuminuria, typically occurring after 10–20 years of living with type 1 diabetes. In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, the cumulative incidence of persistent moderately elevated albuminuria (microalbuminuria) was 38% after 30 years in the conventional treatment group and 25% in the intensively treated group. The incidence of microalbuminuria appeared to plateau after 25–30 years in both groups, with the highest development rate occurring in the second decade of diabetes in the conventional group, a trend that was notably reduced in the intensive treatment group.
Many commonly used drugs can interfere with glucose homeostasis, leading to hyperglycemia in non-diabetic individuals or worsening glycemic control in those with diabetes. Glucocorticoids, for example, induce insulin insensitivity in a dose-dependent manner through post-insulin receptor mechanisms, and may lead to diabetes requiring treatment with oral hypoglycemic agents or insulin during continued glucocorticoid use. Oral contraceptive pills, particularly those containing high-dose estrogen or levonorgestrel, can rarely cause hyperglycemia, especially in women with a history of gestational diabetes. Imazide diuretics can impair insulin secretion at high doses, an effect linked to potassium depletion, though estrogen replacement therapy in postmenopausal women does not typically affect glycemic control.
Low-estrogen combination oral contraceptives affect glucose homeostasis primarily based on the type and dosage of progestogen, with monophasic levonorgestrel combinations having the most negative impact. Oral progestogen-only formulations cause only minor hyperglycemia in healthy individuals, but may lead to diabetes in women who previously experienced hyperglycemia during pregnancy. Long-acting progestogens like depot medroxyprogesterone and sustained-release levonorgestrel cause a statistically, though not clinically, significant decline in glucose tolerance in healthy women, without clear evidence of clinical harm. The WHO does not restrict the use of progestogen-only contraceptives in women with diabetes unless diabetes has been present for over 20 years or complications exist. In the UK, progestogen-only contraceptives, including Depo-Provera and progestogen-only pills, are more frequently prescribed to women with diabetes compared to those without. The Mirena coil has no proven association with changes in glucose metabolism.
A basal bolus regimen for diabetes management involves administering 40-60% of the total daily insulin dose as basal insulin analogs such as glargine or detemir, given in 1-2 daily doses. This is combined with rapid-acting insulin analogs taken 10-15 minutes before each meal. Soluble human insulin is a less preferred alternative and must be administered 20-30 minutes before meals. Other regimens include intermediate-acting human insulin twice daily with soluble human insulin before meals, or two daily injections of a mixture of short or rapid and intermediate-acting insulin before breakfast and the evening meal. Some approaches use three injections per day with variations such as a mixture of short or rapid and intermediate-acting insulin before breakfast, rapid or soluble insulin before the afternoon snack or evening meal, and intermediate or long-acting insulin before bedtime.
Painful diabetic neuropathy is a common complication affecting individuals with diabetes, with studies showing that a significant proportion of patients experience neuropathic symptoms but do not report them or receive treatment. In the UK, one-third of community-based individuals with diabetes had painful neuropathic symptoms, and in Germany, the prevalence of painful neuropathy was 13.3% among people with diabetes. Risk factors for neuropathic pain include age, obesity, and low physical activity. Treatments for neuropathic pain include antidepressants, anticonvulsants, opiates, and other drugs; however, opiates are of concern due to limited efficacy and risks of dependency and misuse. Pain relief is considered adequate with an 80–50% reduction in pain, while a ≥50% improvement is considered a good outcome, though neuropathic pain tends to persist in most individuals despite treatment.
Lifestyle interventions to improve glucose, blood pressure, and lipid levels and to promote weight loss or prevent weight gain are fundamental in managing diabetes, even when medications are required. Metabolic variables such as HbA1c, post-prandial blood glucose concentrations, serum triglycerides, and low-density lipoprotein cholesterol levels can guide the appropriate intake of carbohydrate-containing foods. Including vegetables, legumes, fruits, and wholegrain cereal-based foods in the diet is recommended due to their high dietary fiber content, low glycemic index or load, and provision of various micronutrients. For individuals treated with insulin or oral hypoglycemic agents, aligning the timing and dosage of medication with the quantity and type of carbohydrate consumed is important to prevent hyperglycemia or hypoglycemia, and blood glucose self-monitoring can support making informed dietary and treatment decisions.
GLP-1, GIP, and adiponectin are among the substances that stimulate insulin secretion, while ghrelin, leptin, resistin, SST-14, SST-28, norepinephrine, dopamine, NPY, and galanin are inhibitors of insulin secretion.
The diagnostic criteria for diabetes are the same in children and adults; in a symptomatic child, a plasma glucose level of ≥11.1 mmol/L (200 mg/dL) at any time of day or a fasting plasma glucose of ≥7.0 mmol/L (126 mg/dL) is diagnostic. Blood glucose results from a glucose meter should be confirmed in a laboratory before starting insulin treatment, unless there is marked hyperglycaemia and presence of blood or urinary ketones, in which case urgent treatment is required to prevent danger from developing diabetic ketoacidosis. In a well child, diagnosis should not rely on a single plasma glucose test or borderline glucose meter results; instead, it is advisable to measure HbA1c levels and, if normal, monitor fasting and/or two-hour post-prandial blood glucose over several days. Hyperglycaemia after dinner is typically the first detectable abnormality in children progressing to overt diabetes through self-monitoring of blood glucose at home. Oral glucose tolerance tests should be avoided if fasting, random, or post-prandial criteria are already met, as it can lead to unnecessary and excessive hyperglycaemia.
Serine-threonine phosphorylation of insulin receptors and IRS docking proteins negatively modulates insulin signal transduction by diminishing insulin receptor tyrosine kinase activity and reducing receptor-IRS coupling, leading to decreased glucose transport. This process involves multiple serine-threonine kinases such as PKC, JNK, and IKKβ, which are activated under conditions of nutrient excess, inflammation, and cell stress, contributing to insulin resistance, a key feature in diabetes.
Certain anti-diabetes therapies are relevant for people with diabetes and chronic kidney disease, including DPP-4 (dipeptidyl peptidase 4), GLP-1 (glucagon-like peptide 1), SGLT-2 (sodium-glucose cotransporter 2), and TZD (thiazolidinedione) inhibitors, with eGFR (estimated glomerular filtration rate) being an important factor in treatment considerations.
Men with diabetes should be offered effective oral therapies as first-line treatment for erectile dysfunction, with other treatment options reserved for cases where oral therapy is contraindicated or ineffective.
In diabetes, enteric nervous system abnormalities include reduced neuronal staining and neuronal loss, particularly of inhibitory neurons expressing nitric oxide synthase (NOS), which may contribute to impaired gastric accommodation and accelerated intestinal transit. Loss of NOS may also impair pyloric relaxation, leading to delayed gastric emptying. Additionally, loss of interstitial cells of Cajal (ICC), observed in animal models and case reports of diabetes, along with increased CD45 and CD68 immunoreactivity, are common neuropathological findings in diabetic and idiopathic gastroparesis, further contributing to gut dysmotility.
Exenatide and insulin glargine both reduce $\mathrm{HbA_{1c}}$ levels by a similar amount of 1.11% (12 mmol/mol) in patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled, though exenatide primarily lowers postprandial plasma glucose while insulin glargine mainly reduces fasting plasma glucose (FPG). Treatment with exenatide leads to a decrease in body weight by 2.3 kg compared to an increase of 1.8 kg with insulin glargine. Symptomatic hypoglycemia occurs at similar rates with both treatments, but nocturnal hypoglycemia is less frequent with exenatide (0.9 vs 2.4 events/patient-year). Gastrointestinal side effects, including nausea (57.1% vs 8.6%), vomiting (17.4% vs 3.7%), and diarrhea (8.5% vs 3.0%), are more common with exenatide than with insulin glargine. These findings suggest that exenatide may be a reasonable alternative to basal insulin therapy in patients with T2DM who are not far from glycemic goals, depending on the specific glucose control needs and tolerability.
Growth hormone (GH) has been associated with proliferative diabetic retinopathy, as evidenced by the resolution of retinopathy in a case of rapid-onset pan-hypopituitarism and supported by findings that GH inhibition ameliorated retinopathy in mice. However, patients with both diabetes and acromegaly do not show an increased incidence of diabetic retinopathy. The role of GH in diabetic retinopathy remains under investigation, with current data on treatment using pegvisomant or somatostatin analogs being contradictory, and larger trials are ongoing. Additionally, untreated GH excess in acromegaly may contribute to abnormalities in glucose metabolism that could lead to hypertension, a condition affecting over 50% of acromegaly patients.
Elevations in intracellular calcium are sufficient to initiate insulin secretion, and conditions that increase intracellular calcium typically stimulate insulin release. An increase in cytosolic calcium is essential for insulin secretion triggered by glucose and other nutrients, and blocking calcium influx, either by removing extracellular calcium or using pharmacological agents, prevents nutrient-induced insulin secretion. Glucose and other nutrients also activate $\beta$-cell phospholipase C (PLC), leading to the production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which act as second messengers. While IP3 causes the release of intracellular calcium, its role in secretory responses to nutrients is uncertain and may primarily serve to amplify the rise in cytosolic calcium caused by extracellular calcium influx.
Postpartum diabetes involves the interaction of modifiable and non-modifiable risk factors, with maternal age, family history of diabetes, glycaemic indices during pregnancy, weight, healthy diet, exercise, and breastfeeding identified as contributing factors. Women with the highest blood glucose levels at diagnosis of gestational diabetes mellitus (GDM), those requiring insulin treatment during pregnancy, those with impaired β-cell function, and those who are overweight and gain the most weight after their GDM pregnancy tend to develop type 2 diabetes earlier.
Rosiglitazone, a medication used in the management of diabetes, is metabolized by the hepatic microsomal enzyme CYP2C8, suggesting a potential for drug interactions with other agents processed by the same enzyme.
Gradually increasing urinary albumin excretion (UAE) over many years is characteristic of classical diabetic nephropathy. In type 1 diabetes, increased albuminuria may be present at diagnosis but often resolves as glucose levels normalize. Individuals who will not develop nephropathy typically maintain normal UAE, except during episodes of significant hyperglycemia or acute illness, which can cause temporary increases. Those who do develop diabetic nephropathy experience a gradual rise in UAE, with moderately elevated albuminuria usually appearing 5–15 years after diabetes onset. Without treatment, UAE increases by an average of 20% per year. About 1.5–2.5% of people with type 1 diabetes develop moderately elevated albuminuria annually, and half will develop persistent moderately elevated albuminuria at some point. Among those with moderately elevated albuminuria, approximately one-third progress to severely increased albuminuria over 5–15 years, one-third remain stable, and one-third revert to normal albumin levels, with short-term regression reported in 58% over six years.
Patients with diabetes do not show significant differences in measures of anxiety, depression, positive affect, emotional ties, loss of control, or overall mental health compared to those with other chronic conditions such as arthritis, renal disease, dermatologic disorders, or the general population. When assessed using the Medical Outcome Study (MOS-36) questionnaire, adults with diabetes reported more problems in physical and social functioning than individuals without chronic conditions but tended to function better than those with cardiovascular, pulmonary, or gastrointestinal disorders.
Successful transition from paediatric to adult diabetes care involves the family and is influenced by demographic factors, diabetes history, glycaemic control, self-management abilities, and a sense of self-efficacy. A successful transition is marked by the emerging adult's ability to self-manage diabetes, attend recommended healthcare appointments, maintain glycaemic levels, and avoid acute complications.
Soluble RAGE (sRAGE) has been shown to have therapeutic value in a model of diabetes-associated atherosclerosis using streptozotocin diabetic Apo E KO mice, where it suppressed atherosclerosis in a dose-dependent manner and reduced plaque complexity independently of glucose or lipid levels. In addition, sRAGE lowered AGE levels in diabetic mice to those seen in non-diabetic animals, and when used to block RAGE in established atherosclerosis, it decreased RAGE expression, reduced inflammatory cell infiltration, and lowered gene expression of TGF-β, fibronectin, and type IV collagen in both the aorta and kidney, leading to reduced plaque area. These findings indicate that RAGE activation plays a role not only in lesion formation but also in the progression of atherosclerosis in diabetes.
Exenatide twice daily and biphasic insulin aspart (70/30) were compared in patients with poorly controlled type 2 diabetes on metformin and sulfonylureas, showing that exenatide was non-inferior in reducing HbA1c, with a mean decrease of -1.04 ± 0.07% compared to -0.89 ± 0.06% for insulin aspart. Exenatide-treated patients experienced weight loss and nausea in 35%, while insulin aspart users gained weight, with a between-group difference of -5.4 kg. Both treatments significantly reduced fasting glucose levels.
A range of oral agents is available for managing diabetes, including metformin and thiazolidinediones, which counter insulin resistance, and sulfonylureas, meglitinides, and gliptins, which increase insulin secretion, while $\alpha$ glucosidase inhibitors slow carbohydrate digestion. Injected incretin analogs also enhance insulin secretion. These glucose-lowering agents are effective only if sufficient $\beta$-cell function remains. When adequate glycemic control cannot be achieved or maintained, prompt progression to the next treatment stage is necessary to prevent hyperglycemia. Insulin therapy should be considered when other treatments fail or are inappropriate. Effective diabetes management also involves addressing cardiovascular risk and comorbid conditions, with continuous monitoring and therapeutic adjustments to ensure efficacy, safety, and avoidance of hypoglycemia. Early, sustained glycemic control is crucial to reduce the risk of vascular complications later in life.
For diabetes management, target glucose levels are an important consideration. The table indicates that as age increases, target glucose levels also rise, ranging from 100–140 mg/dl for individuals younger than 6 years to 120–160 mg/dl for those aged 10–18 years. Additionally, the total daily insulin requirement varies with age, decreasing from 0.7–1.0 units/kg/day in children under 6 years to 0.5–0.7 units/kg/day in older children and adolescents.
Intermittent immunization with insulin or insulin-β chain combined with incomplete Freund adjuvant may prevent type 1 diabetes mellitus (T1DM) progression in NOD mice. An altered peptide ligand based on the immunodominant insulin-β chain:9-23 region, known as NBI6024, was developed as a vaccine and tested in humans following animal studies, as this region serves as a specific T-lymphocyte target antigen in NOD mice. A genetically engineered vaccine derived from this peptide was administered subcutaneously to adolescents and adults with recent-onset T1DM, showing in a Phase I trial the ability to shift IFNγ-producing T-helper (Th1) lymphocytes toward Th2 regulatory lymphocytes, though it did not demonstrate any preventive effect or improvement in metabolic control (NCT00873561).
ACE inhibitors do not cause hyperglycemia and do not adversely affect lipid metabolism; they may improve insulin sensitivity and lower blood glucose concentrations, sometimes leading to severe hypoglycemia. Some evidence suggests that ACE inhibitors could reduce the likelihood of new-onset diabetes, though this has not been consistently confirmed. Case-control studies have shown a threefold increased risk of severe hypoglycemia requiring hospital admission in patients with diabetes taking ACE inhibitors.
Some airlines provide "diabetic" meals, primarily intended for people with type 2 diabetes mellitus (T2DM), which are small and low in carbohydrate, potentially increasing the risk of hypoglycemia. Vegetarian meals may be more suitable for individuals with type 1 diabetes mellitus (T1DM), as they often contain pasta-based dishes or rice. In-flight meals may need to be supplemented with the patient's own supply of suitable carbohydrates, though carrying large quantities is impractical due to import restrictions. Consideration should be given to delayed flights or long intervals between meals, and factors like fatigue or travel sickness may reduce appetite.
Among children and adolescents with type 1 diabetes, the incidence of caries is very high (67%), and it is related to disease duration and the degree of hyperglycaemia. Caries growth may be higher in children with dysregulated type 1 diabetes than in healthy children, although evidence remains inconclusive. Increased caries activity and experience in diabetes may be linked to increased salivary glucose concentration, increased plaque incidence, changes in the oral microbiota, decreased salivary secretion rate, and lower pH in saliva. Studies have shown that the incidence of carious teeth is increased in individuals with diabetes, including those with dysregulated type 2 diabetes. Individuals with sub-optimally managed diabetes have an increased prevalence of periapical lesions compared to those with better-managed diabetes. Diabetes also appears to increase the extraction rate of root-filled teeth, despite the necessity of endodontic treatment involving removal of necrotic pulp tissue and filling of root canals.
Pheochromocytoma can lead to hyperglycemia through mechanisms involving the release of catecholamines, which increase lipolysis and the production of non-esterified fatty acids (NEFA), contributing to insulin resistance and impaired glucose metabolism.
Diabetes can lead to neuronal loss and gut dysmotility through mechanisms such as apoptosis, oxidative stress, advanced glycation end products, and neuroimmune processes. Hyperglycemia contributes to the loss of interstitial cells of Cajal (ICC), which is associated with reduced levels of heme oxygenase-1 and other protective mechanisms. The effects of diabetes on neuronal structure and function are reversible, as shown by improvements in glycemic control and autonomic nerve axonopathy following insulin or pancreas transplantation in diabetic rats. Insulin has been found to restore NOS expression and gastric emptying in animal models, and both insulin and insulin-like growth factors help prevent ICC loss in cultures, although these effects may not be direct since ICC do not express receptors for these hormones. Instead, the effects might be mediated by smooth muscle secretion of stem cell factor, which is crucial for ICC survival. Additionally, overexpression of glial cell line-derived neurotrophic factor in mice reversed hyperglycemia-induced apoptosis of enteric neurons and improved gastric and intestinal motility.
Health-related quality of life in adults with diabetes, assessed using the MOS-36 questionnaire, shows that people with diabetes experience more physical and social functioning problems compared to those without chronic conditions, though they tend to function better than individuals with cardiovascular, pulmonary, or gastrointestinal disorders. In type 1 diabetes, lower quality of life is linked to older age, biomedical complications, being female, reduced physical activity, and lower income. For type 2 diabetes, impaired quality of life is associated with being female, diabetes-related complications, non-diabetes comorbidities, and longer duration of the disease.
For hypoglycemia treatment, 15–20g of quick-acting carbohydrate such as 50–60mL of Ensure Plus juice, Fortijuice 25mL original, or 3–4 heaped teaspoons of sugar dissolved in water can be administered via a feed tube, followed by repeating capillary blood glucose measurement after 5–10 minutes. If blood glucose remains below 4mmol/L, the treatment can be repeated up to three times. If hypoglycemia persists after 15 minutes or three cycles, IV 10% glucose infusion at 100mL per hour may be considered. Once blood glucose exceeds 4mmol/L and the patient has recovered, a long-acting carbohydrate such as 200mL of milk (not soya) can be given, insulin should not be omitted, and regular capillary blood glucose monitoring should continue for 24–48 hours.
Gestational diabetes mellitus (GDM) screening strategies and diagnostic criteria vary in cost-effectiveness depending on population risk factors, with universal oral glucose tolerance testing (OGTT) being most cost-effective for populations with a risk greater than 4.2%, while using the IADPSG criteria has been found to be expensive but cost-effective in some studies.
Osteomyelitis in the diabetic foot can be diagnosed using a combination of clinical and laboratory findings, with features such as an ulcer area greater than 2×2 cm, a positive probe to bone test, elevated sedimentation rate, and abnormal radiograph being particularly helpful. MRI is increasingly used due to its high sensitivity, and a negative MRI significantly reduces the likelihood of osteomyelitis. Treatment options include long-term antibiotic therapy for localized cases, especially when confined to a single bone without joint involvement and in the absence of peripheral vascular disease, although localized bony resection after antibiotic therapy remains common. However, data from randomized controlled trials to guide treatment decisions are limited, highlighting the need for further research.
The diagnostic criteria for diabetes are the same in children and adults, with a symptomatic child being diagnosed by a plasma glucose level ≥11.1 mmol/L (200 mg/dL) at any time of day or a fasting plasma glucose ≥7.0 mmol/L (126 mg/dL). Blood glucose results from a glucose meter should be confirmed in a laboratory before starting insulin treatment, unless there is marked hyperglycemia along with blood or urinary ketones, in which case immediate treatment is necessary to prevent the development of DKA. In well children, diagnosis should not rely on a single plasma glucose test or borderline glucose meter results; if HbA1c levels are normal, further monitoring through fasting and/or 2-hour post-prandial blood glucose testing over several days is recommended. Hyperglycemia after dinner is often the first detectable abnormality in children progressing to overt diabetes through self-monitoring of blood glucose at home. OGTT is unnecessary if fasting, random, or post-prandial criteria are already met, as it may lead to excessive hyperglycemia.
In individuals without diabetes, insulin and glucagon levels change in a coordinated and reciprocal manner in response to glucose intake, but in those with type 1 diabetes mellitus (T1DM), carbohydrate consumption does not suppress glucagon levels, and protein intake often leads to an excessive increase in glucagon concentrations. This abnormal glucagon secretion in T1DM is believed to result from a lack of intra-islet insulin, as insulin infusion reduces glucagon secretion and blocking intra-islet insulin with anti-insulin antibodies increases glucagon levels. Administration of exogenous insulin quickly lowers glucagon concentrations in T1DM patients but does not restore the normal glucagon response to hyperglycemia.
Eplerenone, a mineralocorticoid receptor antagonist, has been shown to reduce morbidity and mortality in heart failure with reduced ejection fraction (HFrEF) and does not increase the rate of new-onset diabetes compared to placebo. In contrast, spironolactone increases HbA1c levels and appears to have worse metabolic effects than eplerenone, suggesting that eplerenone may have a more favorable metabolic profile in patients with HFrEF.
Supporting a person with diabetes to achieve excellent glycemic control is a crucial part of diabetes care, involving both short-term and long-term assessment methods. Short-term measures include self-monitoring of blood glucose, which may not be performed by all individuals with diabetes, but when used, healthcare professionals should discuss the results and their implications for future management. Long-term assessment involves measuring glycated hemoglobin, which provides an overview of glycemic control but may sometimes show discrepancies when compared to self-monitored blood glucose levels. These discrepancies can arise from various factors including biological differences such as genetically determined glycation rates, improper timing of glucose readings, or inaccurate record keeping, which might be indicated by a pristine testing log with no blood stains and use of a single pen color. Technology such as computers and glucose meters with downloadable results can help identify patterns of hyperglycemia, though it is important to ensure that the meter is not shared between individuals to maintain accurate monitoring.
High doses of vitamin D have been shown to have immunomodulatory effects and may prevent diabetes development in experimental animals when administered early. However, large-scale human studies have found no association between maternal or newborn vitamin D status, measured as circulating 25-hydroxyvitamin D, and the risk of type 1 diabetes in offspring. Despite mixed results from smaller studies, recent longitudinal research in high-risk cohorts suggests that higher vitamin D levels in early life are linked to a slightly reduced risk of islet autoimmunity or type 1 diabetes. Conversely, a large Mendelian randomization study found no significant association between vitamin D status and type 1 diabetes, indicating that the relationship may not be causal.
Bariatric surgery is a highly effective weight loss option for individuals with type 2 diabetes and morbid obesity, offering better glycaemic and metabolic control compared to lifestyle and medical interventions, while also reducing cardiovascular risk and potentially providing survival benefits. It often decreases the need for anti-diabetes medications, can induce diabetes remission, and may clear non-alcoholic steatohepatitis (NASH). The procedure is generally safe when conducted in experienced centers and is recommended for screened surgical candidates with BMI ≥40 kg/m², as well as those with BMI 35–40 kg/m² who fail to achieve lasting weight loss and improvement in comorbidities like hyperglycaemia through non-surgical means. It may also be considered for individuals with type 2 diabetes and BMI 30–34 kg/m².
High dietary energy density and unhealthy dietary patterns characterized by high intake of soft drinks, sugar-sweetened beverages, burgers, sausages, and snacks are associated with an increased risk of incident type 2 diabetes mellitus (T2DM), as demonstrated by two recent studies. In the Ely study, a population-based longitudinal study, the 10-year cumulative incidence of diabetes was reported at 7.3 per 1000 person-years.
TCF7L2 variants are associated with an increased risk of diabetes, potentially through impairment of incretin effects such as GLP-1 on islet functions, specifically reducing GLP-1-induced insulin secretion and  β-cell proliferation. TCF7L2 is essential for maintaining glucose-stimulated insulin secretion and β-cell survival, as its deletion in human islets leads to reduced insulin secretion and increased apoptosis, while its overexpression protects β-cells from apoptosis induced by glucose and cytokines. Clinical studies have linked the at-risk SNP rs7903146, located in an intronic region of TCF7L2, to defects in β-cell function and insulin release, with some evidence indicating increased TCF7L2 RNA levels in pancreatic islets of individuals with type 2 diabetes bearing the TT genotype. However, expression studies in adipose tissue and muscle have not shown a correlation between TCF7L2 expression and insulin sensitivity or BMI, and the exact functional mechanisms by which TCF7L2 influences glucose sensing and insulin release remain unclear.
The JDRF CGM trial evaluated 451 individuals with type 1 diabetes mellitus (T1DM) aged 8 to 74 years who had an HbA1c level below 10% (86 mmol/mol), assigning them to either real-time continuous glucose monitoring (RT-CGM) or a control group using capillary blood glucose monitoring. The study included patients using insulin pumps or injection therapy and allowed the use of three different CGM devices—Abbott Navigator, Dexcom Seven, and Medtronic Guardian/722 system—selected based on patient preference with investigator guidance. Participants were further categorized into two groups based on their HbA1c levels at randomization: those with HbA1c below 7.0% (<53 mmol/mol) and those with HbA1c between 7.0% and 10% (53–86 mmol/mol), with separate analyses conducted for each group.
Increased physical activity combined with dietary modification and intensive glycemic management reduces perinatal complications in women with gestational diabetes mellitus (GDM), and small clinical studies have shown that exercise programs involving upper arm exercises and resistance training can lower fasting and postprandial blood glucose levels in obese women with GDM, also decreasing insulin requirements compared to diet-only treatment.
Air travelers using insulin should carry an ample supply in hand luggage, with an additional supply kept by a relative or friend to prevent loss or theft. Medication and blood monitoring equipment should never be placed in checked luggage due to the risk of loss. Insulin can be stored during travel in an insulated cool bag or pre-cooled vacuum flask. Those on continuous subcutaneous insulin infusion (CSII) should carry insulin pens as a backup in case of pump failure and have the contact details of the pump manufacturer to obtain a replacement if needed.
GLP-1 receptor agonists have been shown to significantly reduce macrovascular complications in diabetes, including a 12% reduction in MACE, 11% reduction in cardiovascular death, 11% reduction in stroke, 9% reduction in myocardial infarction, 12% reduction in all-cause death, 9% reduction in heart failure, and 12% reduction in kidney disease, with no significant heterogeneity across studies, indicating a consistent class effect on cardiovascular and renal outcomes.
In diabetic ketoacidosis (DKA), despite overall potassium depletion, initial serum potassium levels are often normal or elevated due to shifts caused by acidosis and insulin deficiency. As treatment progresses with insulin therapy, rehydration, and correction of acidosis, serum potassium levels tend to drop, necessitating potassium supplementation once levels fall below 5.0 mmol/L, typically at a rate of 20–30 mmol per hour, assuming normal renal function. Frequent monitoring of potassium is required to guide ongoing administration, and in mild cases of DKA, oral potassium supplements may be used. Rapid bedside potassium analyzers help manage this process more effectively, as laboratory results may lag behind clinical changes.
Hyperthyroidism is associated with an increased risk of type 1 diabetes, particularly in the context of autoimmune hyperthyroidism such as Graves' disease, and thyrotoxicosis is linked to impaired glucose tolerance in about one-third of individuals. The hypermetabolic state of hyperthyroidism contributes to hepatic and peripheral insulin resistance, which can unmask glucose intolerance, especially in those with pre-existing risk factors like obesity or a family history of diabetes, and it can also worsen glucose levels in people with existing diabetes.
Diagnostic testing for monogenic diabetes is now widely available, with molecular genetic testing typically guided by clinical phenotype and population-specific variant prevalence. In cases with a clear clinical presentation, such as fasting hyperglycemia or renal cysts and diabetes, targeted testing like GCK or HNF1B sequencing may be sufficient. However, for conditions like transcription factor MODY or neonatal diabetes, predicting the affected gene based on clinical features alone can be challenging, historically leading to sequential gene testing and diagnostic delays. Advances in DNA sequencing now allow for simultaneous testing of multiple genes using next-generation sequencing, reducing both time and cost compared to traditional methods, and are increasingly replacing single gene testing. Nonetheless, targeted Sanger sequencing remains valuable in specific scenarios, such as in pregnant women with mild fasting hyperglycemia where a rapid GCK test result can inform pregnancy management.
Transition to adult diabetes services can be challenging due to differences in care approaches, as children's services involve the whole family and assume limited patient knowledge, while adult services emphasize individual responsibility, decision-making capacity, and self-management skills. Adolescents may struggle with the increased expectation for independence, especially if they have not been adequately prepared for self-care before transitioning, and may find it difficult to build new relationships with adult healthcare providers after long-standing pediatric care. A supportive transition approach involves identifying specific changes occurring, understanding how the individual is experiencing those changes, and considering how the person is responding or might respond.
In the early 1980s, over 90% of individuals with diabetes diagnosed young were considered to have type 1 diabetes due to autoimmune islet destruction, acute ketosis, and absolute insulin deficiency. Autoantibodies against pancreatic islet antigens, such as glutamic acid decarboxylase (GAD), are markers for type 1 diabetes. In the early 1990s, a form of adult-onset autoimmune diabetes resembling type 2 diabetes was described as latent autoimmune diabetes in adults (LADA), which was later recognized by the World Health Organization (WHO) in 2019 as a slowly evolving immune-mediated diabetes of adults under the category of hybrid forms of diabetes. LADA is often associated with other autoantibodies linked to coeliac disease and adrenal and thyroid disorders, suggesting it is part of a spectrum of autoimmune diseases. Recent studies suggest LADA may be a hybrid of type 2 diabetes and autoimmune diabetes, with individuals showing a high frequency of both type 1 and type 2 diabetes-susceptibility genotypes, indicating overlapping aetiologies. In the UK Prospective Diabetes Study (UKPDS), around 10% of individuals with type 2 diabetes had GAD autoantibodies, with most progressing to insulin dependency.
The diagnostic criteria for diabetes and impaired glucose tolerance (IGT) are based on epidemiologic evidence linking microvascular complications to specific levels of hyperglycemia, and these criteria have evolved over time, affecting the interpretation of epidemiologic studies. In 1999, the fasting glucose threshold for diagnosing diabetes was lowered from 7.8 to 7.0 mmol/L. A fasting glucose level between 6.0 and less than 7.0 mmol/L was previously classified as pre-diabetic, a condition referred to as impaired fasting glucose (IFG). Later, the "normal" fasting glucose level was further reduced to 5.6 mmol/L, expanding the population categorized as having "pre-diabetes." IGT is another state of intermediate hyperglycemia identified specifically through oral glucose tolerance testing.
Management of diabetes requires long-term care and follow-up by a trained interprofessional team, access to medicines and diagnostic tests, patient empowerment and education, prevention of cardiovascular disease, effective information management, treatment of complications with appropriate referrals, and coordination between all stakeholders. In low- and middle-income countries (LMICs), additional challenges include limited policy implementation, lack of trained healthcare professionals, staff shortages, low availability and high cost of medicines and diagnostic tools, consultation fees, and economic vulnerability of populations. Furthermore, health systems in LMICs need a paradigm shift from acute to chronic care, with resource availability being a key barrier to improving diabetes management globally.
Sitagliptin and vildagliptin are selective, competitive, and reversible inhibitors of DPP-4 with high bioavailability and rapid absorption, used in the treatment of diabetes. Sitagliptin has a plasma half-life of 8–14 hours, undergoes limited hepatic metabolism via CYP3A4 and CYP2C6, and is primarily excreted unchanged in the urine through renal tubular secretion. A 100 mg dose of sitagliptin nearly completely inhibits DPP-4 activity for around 12 hours and maintains about 80% inhibition up to 24 hours. Vildagliptin has a shorter plasma half-life of 1.5–4.5 hours, is mainly metabolized in the kidney with minimal involvement of CYP450 enzymes, and approximately 85% is excreted in the urine. A dose of 50–100 mg vildagliptin achieves almost complete DPP-4 inhibition for about 12 hours and roughly 40% inhibition after 24 hours.
MODY (Maturity-Onset Diabetes of the Young) should be considered in individuals diagnosed with diabetes before 25 years of age who do not clearly fit the phenotypes of type 1 or type 2 diabetes and have a strong family history of diabetes. Distinguishing MODY from type 1 diabetes is crucial as it can often be managed without injected insulin. Differentiating MODY from other diabetes types is challenging, prompting the use of strategies such as probability calculators, C-peptide and autoantibody measurements, and genetic testing using targeted next-generation sequencing to better identify individuals who require genetic analysis.
HLA DR3-DQ2 and DR4-DQ8 haplotypes are associated with an increased risk for type 1 diabetes, enabling the use of PCR-based typing methods to screen a large number of newborns for islet autoantibodies and potential diabetes development; additionally, at-birth screening using genetic risk scores has led to primary prevention trials involving oral insulin.
In patients with type 2 diabetes mellitus (T2DM) and nephropathy, the use of ACE inhibitors or ARBs is associated with protective effects, yet clinicians in conventional care settings may withhold or discontinue these medications due to concerns about side effects such as hyperkalemia and renal function decline, particularly in high-risk individuals. However, structured care delivered by a multidisciplinary team leads to higher persistence with ACE inhibitor or ARB treatment, contributing to improved outcomes including reduced rates of death and cardiorenal events compared to conventional care.
Diabetes is a significant metabolic disorder linked to carpal tunnel syndrome, with 16% of affected individuals having diabetes. People with either type 1 or type 2 diabetes show an increased risk of developing carpal tunnel syndrome, with prevalence rates rising from 14% in those with diabetes but no polyneuropathy to 30% in those with diabetic polyneuropathy. The condition is associated with the duration of diabetes and is more common in individuals with microvascular complications such as retinopathy, nephropathy, and polyneuropathy. Additionally, limited joint mobility in diabetes may contribute to a higher frequency of carpal tunnel syndrome due to accelerated thickening and fibrosis of the flexor tendon sheaths, possibly caused by glycation of collagen reducing connective tissue compliance. Microvascular disease may further heighten the risk of endoneural ischaemia as the median nerve passes through the carpal tunnel. Assessing carpal tunnel syndrome in individuals with diabetic neuropathy can be challenging due to atypical presentations and neurophysiological findings, but treatment options, including surgery, generally yield good outcomes.
AMPK activation enhances energy production by increasing glucose and fatty acid uptake and oxidation, while also potentially reducing gluconeogenesis through decreased PEPCK expression. Metformin, adiponectin, and thiazolidinediones activate AMPK, contributing to their glucose-lowering effects. AMP analogs like AICAR improve glycemic control in insulin-resistant diabetic animals, and other AMPK activators such as DRL-16536 are under development for diabetes treatment.
GLP-1RAs and SGLT-2 inhibitors show favourable cardiovascular effects in people with type 2 diabetes, but these benefits appear to be minimal in individuals with few or no cardiovascular risk factors, leading to a weak recommendation for their use in this population. Absolute treatment effects on cardiovascular and kidney outcomes are estimated to be very low in those with low baseline risk, highlighting the need to balance potential benefits against treatment burden and side effects. For people with low cardiovascular risk, therapeutic decisions often focus on managing glycaemia, body weight, or associated conditions like NASH. Metformin remains the first-line treatment for hyperglycaemia in most cases of type 2 diabetes due to its established efficacy, safety, and affordability. In cases involving obesity or NASH, specific agents such as GLP-1RAs, SGLT-2 inhibitors, or pioglitazone may be preferred.
GLP-1 is rapidly degraded by DPP-4, with only a small fraction reaching the pancreas in its active form, suggesting that its effects on insulin secretion may occur indirectly through activation of autonomic nerves, including vagovagal reflexes, particularly since GLP-1 receptors are present in the nodose ganglion and blocking autonomic ganglia can inhibit GLP-1's impact on insulin release.
Patients with type 1 diabetes typically present early in life, require ongoing insulin therapy, and often have autoimmune markers such as antibodies to glutamic acid decarboxylase (GAD). There are other forms of diabetes that resemble type 1 diabetes, including maturity-onset diabetes of the young (MODY) and other monogenic diabetes types caused by mutations affecting mitochondria, amylin, or pathways involved in pancreatic function.
Impaired glucagon secretion during hypoglycaemia closely mirrors a decline in C-peptide levels, which is a marker of endogenous β-cell function, in people with insulin-treated diabetes. Studies comparing individuals with insulin-treated type 2 diabetes to those on oral hypoglycaemic agents show no difference in peak glucagon response during hypoglycaemic clamps, likely due to relatively preserved β-cell function in insulin-treated participants. Another study found that those treated with oral hypoglycaemic agents had higher mean C-peptide levels and significantly higher glucagon responses after experimental hypoglycaemia compared to insulin-treated individuals with lower C-peptide levels. Observational studies also suggest that preserved C-peptide levels in people with type 1 diabetes and insulin-treated type 2 diabetes correlate with lower incidence of hypoglycaemia recorded by continuous glucose monitoring, supporting the intra-islet hypothesis.
Insulin resistance in various tissues contributes to hyperglycemia, hypertriglyceridemia, and low HDL cholesterol, which are common features in patients with type 2 diabetes mellitus (T2DM), who are also often hypertensive and abdominally obese. The cluster of abnormalities associated with insulin resistance, known as the metabolic syndrome, significantly increases cardiovascular risk beyond that of individual components alone. According to the International Diabetes Federation definition, metabolic syndrome is identified by central obesity plus any two of the following: elevated triglycerides, reduced HDL cholesterol, high blood pressure, or increased fasting plasma glucose. Approximately 20–25% of the global adult population meets the criteria for metabolic syndrome, which is associated with a twofold greater risk of developing T2DM and a twofold increased risk of death from cardiovascular disease compared to those without the syndrome.
A classification system for type 2 diabetes has been proposed to identify individuals at higher risk of complications and enable personalized treatment based on the most effective therapy for each individual. A study in Sweden analyzed 8980 people with newly diagnosed diabetes using six variables: GAD antibodies, age at diagnosis, BMI, HbA1c, β-cell function, and insulin resistance, identifying five distinct clusters. Cluster 1 (severe autoimmune diabetes) is characterized by early onset, low BMI, higher HbA1c, insulin deficiency, and presence of GAD antibodies. Cluster 2 (severe insulin-deficient diabetes) is GAD antibody negative, with early onset, low BMI, low insulin secretion, and higher HbA1c. Cluster 3 (severe insulin-resistant diabetes) involves high insulin resistance and high BMI. Cluster 4 (mild obesity-related diabetes) shows obesity without insulin resistance, while Cluster 5 (mild age-related diabetes) includes older individuals with modest metabolic disturbances similar to Cluster 4. Cluster 5 was the most common at 39.1%, and Cluster 1 the least at 6.4%.
The prevalence of diabetes is rising, especially among young adults, and is associated with increased morbidity and mortality due to microvascular and macrovascular complications. These complications contribute to higher healthcare costs and reduced economic growth. Medical expenditures for diabetes include hospital inpatient care, medications for treating complications and managing diabetes, diabetes supplies, and frequent clinic visits. The global health expenditure for diabetes in 2021 was estimated at $966 billion, with significant portions spent in North America and Asia. In the USA, the total costs of diabetes have risen sharply over time, reaching $327 billion in 2017, composed of direct medical costs and losses in productivity. The burden of diabetes extends beyond monetary costs, affecting quality of life, increasing disability and suffering, and impacting insurance premiums, earnings, and overall well-being of individuals and their families.
For frail older people or those with established cardiovascular disease, a safer HbA1c target around 58–64 mmol/mol (7.5–8.0%) is appropriate, as the presence of multiple comorbidities can reduce the benefits of tight glycaemic control. In a decision analysis, the expected benefits of maintaining tight glycaemic levels (HbA1c 53 vs 63 mmol/mol; 7.0% vs 7.9%) decreased with higher levels of comorbidities and functional impairment. A mortality index score was created by allocating one to two points for each comorbidity based on severity, and in people aged 60–64 years with new-onset diabetes, quality-adjusted days decreased significantly with increasing mortality index points, from 106 days (95% CI 97 to 117) to 44 days (range 38–50) with three additional points, and further to eight days (range 5–10) with seven additional points.
In women who need insulin, postpartum insulin requirements during breastfeeding are typically approximately 10% lower than before pregnancy, and for women with type 2 diabetes, metformin is approved during breastfeeding as the levels appearing in breast milk are low.
SGLT-2 inhibitors have significantly impacted the management of type 2 diabetes by reducing major cardiovascular events, with empagliflozin also showing benefits for all-cause mortality. These cardiovascular benefits occur early in treatment and may result from multiple factors including improved glycaemic control, weight loss, blood pressure reduction, lower uric acid levels, and changes in arterial stiffness. All SGLT-2 inhibitors consistently reduce hospitalizations for heart failure, partly due to natriuresis, and this risk reduction in worsening heart failure appears to be a class effect, observed even in individuals without type 2 diabetes. As a result, dapagliflozin and empagliflozin are now approved for the treatment of chronic heart failure.
Increased glucose levels lead to greater flux through the polyol pathway, which is implicated in the development of diabetic complications due to the accumulation of sorbitol and subsequent cellular damage.
Lower HbA1c levels were historically associated with an increased risk of hypoglycaemia, but advancements in diabetes technology, such as continuous glucose monitoring (CGM), insulin pumps, and hybrid closed-loop systems, now allow for more intensive insulin treatment while maintaining target HbA1c levels without significantly raising hypoglycaemic risk. Long-term data from Australia and Germany show a concurrent decline in average HbA1c and severe hypoglycaemic events over 20 years. The use of CGM and automated insulin delivery systems, including those with predicted low glucose suspend features, helps reduce the time spent in hypoglycaemia.
Hyperglycaemia drives microvascular complications in both type 1 and type 2 diabetes, making strict metabolic management essential for preventing retinopathy, nephropathy, and neuropathy. While effective treatments exist for retinopathy and nephropathy, ongoing research is needed to develop new biomarkers and therapies to better prevent and manage these complications.
Balance cards are used to help individuals with diabetes discuss the imbalances, challenges, and possibilities they experience in daily life, facilitating dialogue about living with the condition.
Orlistat has been shown to prevent progression to diabetes in the XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) study, and similar effects are seen with glucagon-like peptide 1 (GLP-1) receptor agonists such as semaglutide, which can reduce body weight by up to 10 kg.
Abnormal α-cell regulation in diabetes leads to elevated glucagon levels after meals instead of the usual postprandial decline, contributing to glucose intolerance. In people without diabetes, postprandial suppression of glucagon helps shift liver metabolism from glucose production to glucose clearance, a process that is disrupted in diabetes. Studies show that maintaining glucagon at fasting levels impairs glycemic regulation after meals, resulting in greater glycaemic excursions compared to when glucagon follows its normal postprandial decline.
MODY type 3 is associated with insulin promoter factor 1 (IPF-1), MODY type 4 involves hepatocyte nuclear factor 1β (HNF-1/TCF2), MODY type 5 is linked to NEUROD1/β2, and MODY type 6 involves the preproinsulin (INS) gene. Additionally, there are likely other unknown genes (referred to as MODY-X) related to the MODY phenotype that have not yet been identified in families where early-onset diabetes co-occurs with genetic markers outside the known MODY loci.
People with diabetes experience premature death, primarily due to cardiovascular disease, although the excess mortality rate decreases with age, particularly in those aged 65 years and older. The Verona Study showed a decline in the standardized mortality ratio from 2–3.5 in middle-aged individuals with diabetes to 1.75 in those aged 65–74 years and 1.3 in those older than 75 years, with a more pronounced impact in women. A systematic review found higher premature death rates in older individuals with diabetes, with cardiovascular disease accounting for 42% of overall mortality in the Verona Study. In contrast, the Melton Mowbray study reported increased excess mortality in people with diabetes over 65 years, and impaired glucose tolerance was linked to a relative risk of death of 1.7.
Potential contributions of the gut microbiota to the pathogenesis of metabolic syndrome and type 2 diabetes are increasingly recognized, with studies comparing intestinal microbial composition between individuals with and without type 2 diabetes traditionally using 16s rRNA characterization. Conflicting results regarding overall microbial diversity have been reported, with some studies showing no difference between type 2 diabetes patients and controls, while others indicate reduced microbial diversity in those with type 2 diabetes. Despite these discrepancies, most studies observe differences in the relative abundance of specific microbial taxa, including reduced levels of certain Bacteroidetes species such as Bifidobacteria and Bacteroides in people with type 2 diabetes. Limitations in earlier studies, including small sample sizes and the resolution of 16s rRNA methodologies, have hindered broader application of these findings.
In a study comparing liraglutide and exenatide for the treatment of diabetes, both drugs led to reductions in HbA1c levels, with liraglutide showing a greater decrease of 1.1% compared to 0.8% for exenatide, and both were associated with approximately 3 kg of weight loss. Nausea was a common side effect for both treatments, affecting around 25% of patients initially, but the incidence decreased more rapidly with liraglutide, dropping below 10% after 8–10 weeks, while remaining around 10% for exenatide. The rate of minor hypoglycemia was lower with liraglutide, and when patients previously on exenatide were switched to liraglutide, there was an additional 0.3% reduction in HbA1c after 30 weeks.
Diabetic dyspepsia refers to upper gastrointestinal symptoms such as bloating, postprandial fullness, and upper abdominal pain that occur when gastric emptying delay is not severe, in contrast to gastroparesis, which involves markedly delayed gastric emptying. Symptoms may also include non-severe vomiting and significant weight loss due to reduced caloric intake. In addition to delayed gastric emptying, impaired gastric accommodation and abnormal gastric sensation—either increased or decreased—can contribute to diabetic dyspepsia. The distinction between dyspepsia and gastroparesis is challenging due to the lack of a clear definition for moderately versus severely delayed gastric emptying, though emptying of less than 65% at 4 hours is often considered a significant delay, associated with nutritional consequences and potentially requiring nutritional supplementation, jejunal feeding, or gastric decompression.
During illness, insulin therapy should continue for children with diabetes, though the dose may need adjustment depending on food intake and symptoms such as vomiting. A fasting child still requires around 40% of their usual daily insulin dose in the form of long-acting basal insulin to meet basic metabolic needs and prevent ketoacidosis. In cases of infection with normal food intake, basal insulin may need to be increased by 10–15%. Additionally, rapid-acting insulin is often required to manage hyperglycaemia, prevent ketoacidosis, and avoid hospitalization, with doses repeated every 2–4 hours based on blood glucose and ketone levels.
Pregnancy in women with diabetes, particularly those with diabetic nephropathy or other vascular complications such as retinopathy, nephropathy, or pre-existing hypertension, is associated with increased risks of pre-eclampsia and abnormal fetal growth. Women with chronic kidney disease should be counseled on these risks. Inhibitors of the renin-angiotensin system should be discontinued before conception due to the increased risk of congenital malformations when used in the first trimester and fetopathy when used in the second and third trimesters. Alternative antihypertensive treatments such as methyldopa, labetolol, and nifedipine are considered safe in pregnancy and should be used instead. Strict control of blood glucose and blood pressure can improve outcomes for both mother and baby.
CGM devices include alarms for hypoglycaemia and hyperglycaemia, with alarm thresholds needing individualization based on clinical considerations. Setting alarms at target glucose levels, such as 5 mmol/l (90 mg/dl) for lows and 10 mmol/l (180 mg/dl) for highs, increases sensitivity in detecting glucose extremes but can result in frequent false alarms that may disrupt sleep and cause irritation, potentially leading to alarm fatigue and ignored alarms. Research by Buckingham et al. indicates that individuals awoke to only 29% of individual alarms and 66% of repeated alarms during sleep, highlighting the risk of alarms being unnoticed.
Patients with hyperglycemia undergoing cardiac surgery who were managed with an intravenous infusion titrated to achieve normoglycemia for three days postoperatively experienced improved mortality, a reduction in deep sternal wound infections, and a shorter length of stay, as observed in the Portland Diabetic Project, a non-randomized observational study of 5510 patients from 1987 to 2005.
There is limited research on the immune response to viral infections in children with a genetic predisposition to islet autoimmunity and type 1 diabetes, and it is possible that the pattern of an autoimmune response resembles that of an immune reaction to a virus. The development of IgG antibodies occurs within about 21 days, and understanding the immune response to potential triggers like coxsackie B virus may require more frequent blood sampling than is currently conducted in studies following children from birth. Advances in omics biomarkers, including genomics, transcriptomics, metabolomics, and single-cell sequencing, are being used to explore immune changes before the appearance of islet autoantibodies. Research has shown age-independent changes in natural killer cells prior to the first appearance of either insulin autoantibodies (IAA) or glutamic acid decarboxylase autoantibodies (GADA), and certain serum fatty acids and nutrients are linked to an increased risk of developing a first islet autoantibody. Additionally, mRNA sequencing in at-risk individuals has found upregulation of interleukin 32 in activated T cells and NK cells before seroconversion, suggesting that studying these early immune changes may lead to new biomarkers for predicting and understanding the onset of islet autoimmunity.
Metformin, a medication used in the management of diabetes, is rapidly but incompletely absorbed and is not metabolized, allowing it to remain largely unchanged during excretion. It achieves plasma concentrations of about $10^{-5} \mathrm{mol/l}$ and accumulates at higher levels in the gastrointestinal tract. The drug is primarily eliminated through renal excretion, with a plasma half-life of approximately 6 hours, and most of the dose is cleared within 12 hours. Its elimination relies more on tubular secretion than glomerular filtration, making it contraindicated in individuals with significant glomerular filtration impairment. Cimetidine can interfere with metformin's clearance, leading to increased plasma concentrations.
Type 2 diabetes often coexists with other risk factors for cardiovascular and kidney disease, including hypertension, hypercholesterolemia, obesity, and microalbuminuria. The primary goal of diabetes treatment is to correct hyperglycaemia to alleviate symptoms such as polyuria, tiredness, and blurred vision, while long-term objectives focus on preventing microvascular and macrovascular complications. Intensive glycaemic management has been shown to reduce the risk of complications like retinopathy, kidney disease, and cardiovascular disease in both type 1 and type 2 diabetes. However, optimal prevention of long-term complications requires managing additional risk factors such as obesity, hypertension, and hypercholesterolemia. Blood pressure control using ACE inhibitors provides micro- and macrovascular protection, and cholesterol reduction with statins lowers the incidence of cardiovascular events. The Steno 2 trial demonstrated that multifactorial risk factor management significantly improves cardiovascular outcomes and reduces the risk of kidney failure or mortality by 47% over 21 years, underscoring the importance of addressing multiple risk factors together rather than focusing solely on glycaemic control.
In type 1 diabetes, early signs of diabetic retinopathy such as microaneurysms and dot haemorrhages may appear at disease onset but often disappear, with progressive retinopathy typically emerging after about 10 years. The prevalence of retinopathy rises steadily, reaching nearly universal occurrence after approximately 20 years. Vision-threatening retinopathy increases in incidence until around 25 years, then declines, indicating that constitutional factors influence its development alongside metabolic dysregulation. In populations with organized screening and treatment, half of individuals with type 1 diabetes develop vision-threatening retinopathy, with two-thirds progressing to proliferative diabetic retinopathy and one-third to diabetic maculopathy.
The ESC guidelines recommend specific LDL cholesterol targets for individuals with diabetes, with a general goal of less than 2.6 mmol/l (100 mg/dl), and more intensive targets for those at higher cardiovascular risk. For individuals with diabetes duration of 10 years or more and any additional risk factor, the LDL cholesterol target should be less than 1.8 mmol/l (70 mg/dl). In very high-risk cases, such as those with target-organ damage, at least three major risk factors, or early onset of type 1 diabetes with duration exceeding 20 years, the LDL cholesterol target should be further reduced to less than 1.4 mmol/l (55 mg/dl), with a secondary non-HDL cholesterol target of less than 2.2 mmol/l (85 mg/dl).
Infections, particularly severe ones, can worsen hyperglycaemia through mechanisms such as the release of counter-regulatory hormones and cytokines like IL-1 and TNF, which increase insulin resistance. Infections are also a significant contributing factor to the development of diabetic ketoacidosis or hyperosmolar hyperglycaemia. Additionally, infections may cause hypoglycaemia when symptoms like anorexia, nausea, and vomiting lead to decreased food intake, and malaria treatment with quinine can also result in hypoglycaemia.
Younger children with diabetes tend to show better treatment adherence, possibly due to greater parental involvement, compared to adolescents. However, even when age is controlled, a longer duration of diabetes is linked to declines in adherence, particularly during adolescence. Factors that contribute to better adherence include strong family support, shared responsibility between the child and parent for self-care behaviors, higher cognitive maturity, greater knowledge of diabetes and its management, and better memory skills. The physician-patient relationship also plays a role, with doctor-centered discussions discouraging questions and increasing uncertainty, while patient-centered communication is associated with better self-reported adherence.
The dawn phenomenon refers to an early-morning rise in fasting blood glucose observed in individuals with type 1 diabetes, first described in 1981. It is attributed to reduced hepatic and peripheral insulin sensitivity caused by nocturnal growth hormone spikes. The phenomenon was more pronounced in older studies due to falling plasma insulin concentrations by dawn after a nocturnal dose of NPH or lente insulin. It is less pronounced with continuous subcutaneous insulin infusion (CSII) or long-acting insulin analogues, though it remains highly variable among individuals and occurs in approximately 50% of people with type 1 diabetes, often serving as a common indication for CSII therapy.
CSII may improve overall control and glycemic fluctuations in women with poorly controlled T1DM, though a study found no differences in glycemic control or pregnancy outcomes between women using CSII and those using MDI; however, the CSII group included women with more retinopathy and nephropathy, conditions that might predict poorer pregnancy outcomes.
In diabetes, significant defects in insulin secretion and action lead to elevated glucose concentrations, which must rise to balance glucose appearance and disappearance. Glucose appearance is increased due to the failure to suppress hepatic glucose production, as the systemic rate of appearance of ingested glucose remains similar to that in individuals without diabetes. Following a meal, glucose disappearance is often higher in people with diabetes compared to those without, largely due to increased urinary glucose excretion. However, despite being elevated, these rates of glucose disappearance are not sufficient relative to the existing glucose concentrations.
Gliptins, a class of medications used in the management of diabetes, have not been associated with any serious adverse effects based on clinical experience to date. In clinical trials lasting 6 to 12 months, the tolerability profile and adverse event rates were generally comparable to placebo or other comparator treatments. Some increases in liver enzymes were observed with the 100 mg dose of vildagliptin, but not with the 50 mg dose that is currently marketed. Additionally, there were nominal increases in reports of abdominal discomfort, suggesting a potential effect on gastric emptying; however, this is considered unlikely to have a significant clinical impact.
Baseline and incident metabolic syndrome identify individuals at risk for type 2 diabetes and cardiovascular disease, warranting evaluation in people starting antiretroviral therapy. Fasting plasma glucose should be assessed before therapy initiation and monitored every 3–6 months, particularly with treatment changes or risk factors for insulin resistance. Oral glucose tolerance tests may be necessary with risk factors or unclear glucose levels. General dietary guidelines apply for managing glucose disorders in HIV, with weight loss through activity and calorie reduction recommended for overweight individuals with HIV.
Patients with type 2 diabetes mellitus (T2DM) exhibit elevated concentrations of VLDL particles, which increase CETP-mediated exchange of cholesterol esters and triglycerides between VLDL and LDL particles, resulting in LDL particles with higher triglyceride content that are more susceptible to hepatic lipase activity, leading to increased density and the formation of small, dense LDL particles known to be highly atherogenic and linking insulin resistance to cardiovascular disease.
Akt, a key insulin signaling intermediate, contributes to a negative feedback loop by activating mTOR, which in turn promotes the phosphorylation of serine residues on IRS proteins, potentially impairing insulin signaling. Additionally, the membrane ectoenzyme glycoprotein-1 (PC-1/NNP1) binds to the insulin receptor and inhibits the conformational changes necessary for receptor autophosphorylation. These mechanisms represent potential targets for therapeutic intervention in diabetes.
Bile acid sequestrants reduce LDL cholesterol by approximately 20% and may slightly improve glucose levels in people with diabetes, although their effect on triglycerides tends to be increasing. However, these drugs have a poor side-effect profile, particularly gastrointestinal disturbances, and there is currently no evidence from cardiovascular outcome studies involving individuals with diabetes to determine their impact on hard clinical outcomes.
Individuals with type 2 diabetes exhibit overexpression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) in skeletal muscle and adipose tissue, which contributes to insulin resistance through interaction with the D4 domain of phospholipase D1 (PLD1). Targeting this interaction by disrupting the association between PLD1 and PED/PEA-15 using adenoviral-mediated overexpression of a soluble form of D4 in the liver, pancreas, and skeletal muscle improves insulin sensitivity and secretion, thereby restoring glucose homeostasis in diabetic transgenic mice and obese high-fat diet-fed wild-type mice.
Phobic disorders are more common in adults with diabetes compared to the general population, with research identifying injection or blood and injury phobia, and fear of hypoglycemia, as specific issues linked to insulin treatment. Studies show that a high percentage of adults with type 1 diabetes report phobic symptoms, and those with poorer glycemic control experience more fear of blood or injury, measure their blood glucose less frequently, and exhibit more symptoms of anxiety and depression. The relationship between poor metabolic control and reduced blood glucose monitoring appears to be influenced by fear of blood and injury, though estimates of the prevalence of this phobia vary widely depending on the assessment method and criteria used.
Increased production of pro-inflammatory cytokines such as TNF-α, IL-6, IL-8, and MCP-1 by pre-adipocytes and invading immune cells like activated macrophages contributes to insulin resistance and plays a role in the pathogenesis of type 2 diabetes.
Hypoglycaemia is less frequent in type 2 diabetes but becomes progressively more common as individuals approach the insulin-deficient end of the type 2 diabetes spectrum. Studies have shown that the frequency of hypoglycaemia in people with type 2 diabetes can become similar to that in those with type 1 diabetes when matched for duration of insulin therapy. Research by the UK Hypoglycaemia Study Group found that among people with type 2 diabetes treated with insulin, the prevalence of severe hypoglycaemia increased from 7% in those treated for less than 2 years to 25% in those treated for more than 5 years.
For patients with non-insulin-treated type 2 diabetes mellitus (T2DM), pre-fasting (pre-breakfast) blood glucose levels show low within-person variability, making them useful for assessing day-to-day control and evaluating the impact of lifestyle changes or therapy adjustments. However, the cost-effectiveness of this method relative to HbA1c testing is not established. Recommendations for the frequency of fasting blood glucose measurements in non-insulin-treated T2DM range from once a week to once a day, though there is a lack of strong evidence supporting any specific frequency.
Lidocaine plasters (5%) applied for 18 hours per day provide effective relief in painful diabetic neuropathy, with a systematic review showing significant pain reduction comparable to antitriptyline, capsaicin, gabapentin, and pregabalin, and with fewer and less clinically significant side effects compared to systemic agents.
Antigen-specific tolerance can be induced through various gene transfer methods, such as using lentiviral, non-viral, or AAV-mediated delivery of genes like IGF-I, insulin B chain 9–23 (InsB9–23), or MHC class I molecules to the liver, or through transient adenoviral expression of a soluble form of ICAM-1 following diabetes onset. These approaches have been shown to suppress autoimmune diabetes in NOD mice and transgenic mice overexpressing human interferon β in β cells, which are models for human type 1 diabetes. Additionally, retroviral-mediated expression of insulin or GAD65 in B lymphocytes, as well as vaccines based on viral vectors or plasmids encoding insulin, proinsulin, or GAD65, can induce immune tolerance and prevent type 1 diabetes development in mice.
Gene therapy involving the transfer of insulin and glucokinase genes to skeletal muscle in diabetic mice resulted in long-term restoration of normal blood glucose levels in both fed and fasted states, improved glucose tolerance, increased skeletal muscle glucose uptake, and normalized glucose metabolism in the liver, including increased glucose uptake, glycogen synthesis, and reduced hepatic glucose production, along with normalization of food and fluid intake and abdominal fat and skeletal muscle weight. This approach demonstrated that sustained basal insulin production and enhanced skeletal muscle glucose uptake can tightly regulate glycaemia in diabetic mice.
Studies in individuals with type 1 diabetes have shown inconsistent effects of exercise on fasting glucose levels, with no clear improvement in overall glycaemic control as measured by HbA1c. However, similar to healthy individuals, blood glucose tends to decrease around the time of exercise without causing hypoglycaemia. The absence of a clear glycaemic benefit may be due to rebound hyperglycaemia occurring immediately after exercise, suggesting that better management of this post-exercise response could be beneficial.
Genome-wide familial linkage studies conducted between 1995 and 2005 aimed to identify genes associated with common polygenic type 2 diabetes mellitus (T2DM) by detecting chromosomal regions linked to the disease in large family groups or sibling pairs. This method involved genotyping around 400 polymorphic markers, such as microsatellites, spaced at approximately 1 marker per 10 centimorgans, to find those with strong allele identity by descent in diabetic relatives. These studies enabled the positional cloning of susceptibility genes once linked chromosomal intervals were identified.
Hyperglycaemia and dyslipidaemia contribute to diabetes-associated atherosclerosis, as shown in a mouse model where destruction of pancreatic β cells mimics the autoimmune response in human type 1 diabetes. In these mice, atherosclerosis developed more rapidly even on a normal diet, indicating that hyperglycaemia alone can accelerate the condition, while a high-fat diet further worsened atherosclerosis, suggesting a synergistic effect between glucose and lipids. Additionally, features of plaque instability such as plaque disruption and intraplaque haemorrhages were observed in this model.
Addison disease is more prevalent in people with type 1 diabetes, affecting around 1% of this population compared to 1 in 10,000 in the general population. The presence of autoantibodies against 21 hydroxylase is more common in individuals with type 1 diabetes (1–2%) than in the general population and indicates an increased risk of developing Addison disease, with 15% of those having these antibodies progressing to the disease within a few years. Clinicians should maintain a high index of suspicion for Addison disease, especially when encountering unexplained hypoglycaemia, as it can present with mild symptoms including reduced insulin requirements and lower HbA1c levels in children. Diagnosis of adrenal insufficiency in this context relies on ACTH stimulation testing.
Hyperglucagonemia, as seen in the glucagonoma syndrome, contributes to hyperglycemia primarily through stimulation of hepatic gluconeogenesis and, in adequately fed individuals, glycogenolysis. Approximately three-quarters of individuals with glucagonoma syndrome develop diabetes, with the hyperglycemia often being mild and responsive to oral hypoglycemic agents in some cases, while in others, up to 75% may require insulin therapy.
Fixed-ratio combinations of GLP-1 receptor agonists and basal insulin, such as IDegLira (liraglutide with insulin degludec) and LixiLan (lixisenatide with glargine), are formulated into a single subcutaneous injection, offering complementary actions to target both post-prandial and basal hyperglycaemia. These combinations allow for greater reductions in HbA1c levels compared to either agent alone, while using lower insulin doses, avoiding weight gain, and reducing the risk of hypoglycaemia in type 2 diabetes.
Inflamed adipose tissue is insulin-resistant and overproduces free fatty acids, contributing to excess triglyceride storage in the liver, while adiponectin deficiency further decreases insulin sensitivity. Fatty liver leads to overproduction of glucose and VLDL, along with increased levels of plasminogen activator 1 and coagulation factors. Excess refined carbohydrate intake may enhance de novo lipogenesis in the liver, increasing intrahepatocellular triglyceride, and overeating with inactivity contributes to insulin resistance in skeletal muscle glucose uptake.
Increased temporary basal rates can be particularly useful during periods of acute illness, stress, or prolonged inactivity, such as during a long car journey, and increasing basal insulin delivery in these situations can be more effective at managing hyperglycaemia than administering multiple extra correction boluses.
Subcutaneous semaglutide has been associated with an increased incidence of diabetic retinopathy complications, although it remains uncertain whether this effect is due to the medication itself or a rapid decline in HbA1c levels. Given this potential risk, frequent retinal screening is recommended for individuals undergoing treatment with semaglutide to monitor and detect any progression of retinopathy.
Certain drug interactions can affect blood glucose levels by altering the effective concentrations of glucose-modifying medications. For example, clarithromycin can increase the concentration of disopyramide, and various drugs can either raise or lower the circulating levels of sulfonylureas. These pharmacokinetic interactions may lead to hyperglycemia or hypoglycemia, which are relevant considerations in the management of diabetes.
Variant carriers without diabetes may develop glycosuria after a glucose challenge even if glycaemia remains within normal limits, and individuals with HNF1A variants have a greater risk of liver adenomatosis and its complications, including acute intraabdominal haemorrhage.
Genetic linkages with diabetes and the age at onset of diabetes have been identified on chromosomes 3q27, 10q in Mexican American families, and 12q near TCF1 in Finnish type 2 diabetes mellitus (T2DM) families with insulin secretion defects. Additionally, evidence for an obesity-diabetes locus was found on chromosome 11q23–q25, and several chromosomal regions linked to prediabetic traits were observed in Pima Indians, who have a high prevalence of diabetes and obesity. Loci on chromosomes 1q21–25 and 20 have also shown evidence of linkage with diabetes in various populations, along with multiple other regions indicating weak or suggestive associations with diabetes-related traits.
Higher levels of physical activity and cardiorespiratory fitness are consistently linked to a reduced risk of developing type 2 diabetes mellitus (T2DM), with the most active individuals showing a 25–60% lower risk compared to the most sedentary, even after adjusting for confounding factors. This risk reduction is observed regardless of the presence of other diabetes risk factors such as hypertension, parental history of diabetes, and obesity. Additionally, walking offers similar risk reduction benefits as more vigorous activities when total energy expenditures are comparable.
Exendin-4, a synthetic version of which is known as exenatide (1-39), is resistant to DPP-4 cleavage and has a subcutaneous half-life of approximately 2.5 hours after injection, with peak action occurring 2–3 hours post-injection.
In type 2 diabetes and chronic kidney disease (CKD), metformin is recommended as the first glucose-lowering agent following lifestyle interventions, and SGLT-2 inhibitors are subsequently recommended regardless of HbA1c levels due to their organ-protective effects; however, in type 1 diabetes, the use of these agents may carry an increased risk of normoglycaemic diabetic ketoacidosis.
Dipeptidyl peptidase-4 inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin) are medications used in the management of diabetes that can be taken as normal under various clinical circumstances, though they should not be restarted until eating and drinking normally during situations like a VRIII (vomiting and reduced intake) episode. GLP-1 receptor agonists (e.g., exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide) are also diabetes medications that can generally be continued as normal across different clinical scenarios.
Antecedent hypoglycaemia, even when mild and occurring briefly twice weekly, can reduce counter-regulatory responses to subsequent hypoglycaemia for up to a week, contributing to impaired awareness of hypoglycaemia. Additionally, prior exercise and sleep can similarly diminish these counter-regulatory responses. These prolonged effects of previous hypoglycaemia can reset the glycaemic threshold at which the body activates counter-regulatory mechanisms, offering an explanation for why tight glycaemic control through intensive insulin therapy may lead to impaired hypoglycaemia awareness. The reduced sympathoadrenal response due to these stimuli results in fewer neurogenic symptoms, further contributing to transient impaired awareness of hypoglycaemia.
GLP-1 receptor agonists (GLP-1RAs) are a class of diabetes medications that have been studied for their cardiovascular effects in large-scale, double-blinded, randomized trials, with most approved GLP-1RAs evaluated for cardiovascular safety. These trials compare the cardiovascular impact of GLP-1RAs against placebo in addition to standard therapy, using a composite primary endpoint of major adverse cardiovascular events, which includes cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.
Autoimmune type 1 diabetes has seen significant changes in its described natural history, with improved understanding of its aetiology and pathogenesis, particularly in terms of genetic and environmental factors. HLA genetic risk for type 1 diabetes enables screening to identify neonates at increased genetic risk. Islet autoantibodies detected in standard radiobinding assays serve as reliable biomarkers for islet autoimmunity and can also be detected using methods such as double-sided ELISA, chemiluminescence, and ADAP. General population screening at birth for type 1 diabetes has been shown to be feasible and well tolerated.
Insulin pump therapy has been shown to provide better glycemic control with lower HbA1c levels and fewer episodes of severe hypoglycemia compared to multiple daily injections. It can enhance quality of life, especially in children who find injections challenging or desire more lifestyle flexibility, such as with sleep patterns, sports, and irregular eating habits. Insulin pumps are particularly beneficial for young children and infants who require multiple meals, snacks, and small doses of rapid-acting insulin throughout the day. Modern insulin pumps can deliver very low insulin rates, as little as 0.025 units per hour, although higher rates may be necessary when using diluted insulin to ensure consistent delivery. Common complications of insulin pump use include issues with insulin delivery due to displaced or blocked infusion sets, local skin infections, and the risk of diabetic ketoacidosis. Insulin pump therapy is also associated with higher costs compared to injection-based regimens.
Iatrogenic hypoglycaemia is a barrier to glycaemic management in people with diabetes, but this barrier can be reduced through the practice of hypoglycaemia risk factor reduction, which involves four steps.
ACE2 receptors are present on pancreatic beta cells, raising the possibility that viral infections, such as Covid-19, could induce diabetes through direct damage to pancreatic endocrine tissues. Clinical reports indicate that insulin requirements in people with Covid-19 were higher than expected given the level of physiological stress, and a high frequency of diabetic ketoacidosis was observed among hospitalized patients, suggesting virus-induced acute insulinopaenia and metabolic decompensation. Severe hyperglycaemia may also be attributed to interruptions in glucose-lowering medications during lockdowns and the use of high-dose corticosteroids in treatment. Some studies have found an increased incidence of diabetes following Covid-19, including a 1.5-fold higher risk of diabetes diagnosis in the USA and a 28% increased risk of type 2 diabetes in Germany compared to non-Covid-19 respiratory infections. However, a study in England found no increase in diabetes incidence after Covid-19 compared to non-Covid-19 pneumonia. The potential for Covid-19 to induce diabetes remains uncertain, and further research is needed to clarify its long-term metabolic effects.
People with diabetes have increased expression of angiotensin-converting enzyme 2 (ACE2), which may contribute to their higher susceptibility to SARS-CoV and SARS-CoV-2 infections. ACE2, found in the respiratory tract and other organs, serves as the primary receptor for these viruses, and its elevated levels could enhance viral entry. However, ACE2 also plays a protective role by counteracting the inflammatory and vasoconstrictive effects of angiotensin II through its conversion to angiotensin [1-7], which has antioxidant properties. The use of renin-angiotensin-aldosterone system (RAAS) inhibitors, which increase ACE2 levels, is associated with a reduced risk of pneumonia in individuals with or without diabetes, and current evidence suggests these medications have a neutral effect on mortality or critical outcomes in the context of COVID-19.
Insulin is stored in β cells as hexamers stabilized by zinc ions and disassembles into monomers when secreted into the bloodstream, which is the active form. In exogenous insulin administration, hexamer formation can be stabilized using additives such as zinc, phenolic preservatives (e.g., m-cresol and phenol), and buffers to maintain pH. After injection, fluid enters the insulin depot via osmosis, leading to dilution and dissociation of insulin molecules, a necessary step before insulin monomers cross capillary walls into circulation. Because this process is slow, people with diabetes are advised to inject soluble insulin 15–20 minutes before a meal to align insulin availability with meal absorption, though many find this difficult due to planning demands and potential inaccuracies in dose calculation, especially when meal preparation is outside their control. Insulin formulations aim to mimic the endogenous insulin response as closely as possible.
Risk factor–based screening for gestational diabetes mellitus (GDM) involves identifying women with specific clinical, obstetric, or demographic factors that increase their likelihood of developing the condition. Key risk factors include a family history of diabetes in a first-degree relative, a body mass index (BMI) greater than 30 kg/m², a history of delivering a large baby (greater than 4.5 kg), previous GDM, and belonging to certain ethnic groups such as those from Latin America, Africa, the Pacific Islands, Southeast Asia, or the Asian subcontinent. Additional factors include maternal age of 30 years or older and increased parity. The presence of multiple risk factors increases the positive predictive value for GDM, although individual factors such as prior GDM or macrosomia may influence parity as a risk factor. Despite these indicators, risk factor screening alone is only about 50% sensitive and specific, meaning many cases would be missed without universal testing. Studies suggest that no single combination of risk factors is superior for identifying GDM cases, and applying the NICE criteria would require approximately 67.2% of women to undergo oral glucose tolerance testing (OGTT), with a sensitivity of 78.2% and specificity of 31.7%. While NICE recommendations are largely influenced by cost considerations, analyses indicate that GDM screening can be cost-effective in populations where the prevalence of GDM exceeds 4.2%.
Short-chain fatty acids (SCFAs) are implicated in the pathogenesis of type 2 diabetes through their activation of G-protein-coupled receptors (GPRs) such as GPR41, GPR43, and GPR109A, which are expressed on the intestinal epithelium, adipose tissue, and immune cells. These SCFAs differentially activate various GPRs—propionate for GPR41 and GPR43, acetate for GPR43, and butyrate for GPR41 and GPR109A—triggering downstream signaling pathways that influence enteroendocrine cell function, immunity, and inflammation. These processes have the potential to affect insulin signaling pathways, linking the intestinal microbiome to metabolic regulation and type 2 diabetes.
Metformin, a medication commonly used in the management of type 2 diabetes, is associated with gastrointestinal side effects such as abdominal discomfort and diarrhea, which are usually temporary and can be minimized by taking the drug with food and gradually adjusting the dose. In some cases, symptoms may improve with dose reduction, although approximately 10% of individuals are unable to tolerate the medication at any dosage. A more severe but rare complication of metformin use is lactic acidosis, with an estimated incidence of 0.03 to 0.06 cases per 1000 patient-years, and about half of these cases are fatal. However, the baseline rate of lactic acidosis in people with type 2 diabetes is not well established, raising the possibility that some reported cases may have been due to other underlying causes rather than metformin itself.
Exenatide, when used in combination with metformin, sulfonylurea, or both, demonstrated a placebo-corrected reduction in HbA1c levels of 0.9–1.0% (10–11 mmol/mol) over 30 weeks in the AMIGO trials, with baseline HbA1c ranging from 8.3–8.6% (67–70 mmol/mol). Treatment with 10 µg exenatide twice daily also resulted in weight loss of 1.6–2.6 kg, with approximately 80% of subjects losing weight and greater weight reduction observed in those with higher baseline BMI. Exenatide treatment improved certain cardiovascular risk factors, including an increase in HDL cholesterol by 0.12 mmol/L, a decrease in triglycerides by 0.43 mmol/L, and a reduction in diastolic blood pressure by 2.7 mmHg, along with a significant decrease in postprandial triglyceride excursions after two weeks of treatment.
The references list historical developments related to diabetes and its treatment, including the discovery of insulin, the role of HC Hagedorn in Danish insulin production, the evolution of diabetes as a medical condition, and the development of oral hypoglycemic agents such as sulphonamides. It also references works on diabetes during pregnancy, historical substitutes for insulin, and broader cultural and medical histories of the disease.
Modulation of the bile acid pool by the intestinal microbiota influences the risk for diabetes, as bile acids contribute to glucose regulation. The microbiota in the large bowel catalyse reactions that produce secondary bile acids, which may affect bile acid synthesis and downstream processes through FXR and TCR5 signaling pathways. Studies in animal models show that the composition of the bile acid pool differs between germ-free and conventionalized animals, and antibiotic treatment shifts the pool towards primary bile acids while upregulating FXR signaling. In humans, short-term antibiotic interventions reduce faecal secondary bile acids and alter bile acid composition, which correlates with improved insulin sensitivity. Probiotic and prebiotic interventions also impact bile acid metabolism, with synbiotic supplementation reducing plasma concentrations of conjugated bile acids and certain probiotics increasing plasma deconjugated bile acids. These findings suggest that the intestinal microbiota, through its influence on bile acid metabolism and signaling pathways, may contribute to the risk for type 2 diabetes.
Treatment for young-onset type 2 diabetes should include lifestyle modifications, pharmacological treatment, and diabetes self-management education, as lifestyle changes alone are often insufficient to achieve and maintain glycaemic targets. The TODAY study, the largest clinical trial on managing type 2 diabetes in adolescents, enrolled 699 participants aged 10–17 years with recent-onset disease and found that after a run-in period with metformin, participants were randomized to metformin alone, metformin with lifestyle intervention, or metformin with rosiglitazone. Approximately half of the participants experienced loss of glycaemic control, defined as an HbA1c ≥ 8% (64 mmol/mol) for six months or metabolic decompensation requiring insulin, over an average follow-up of four years. The rosiglitazone plus metformin group had a ~25% reduction in the proportion reaching the primary outcome compared to the other groups, indicating better outcomes with combination therapy. However, rosiglitazone and other thiazolidinediones are not FDA-approved for use in children, highlighting the need for alternative effective pharmacological treatments in young patients with type 2 diabetes.
Nicotinamide (vitamin B3) was found to protect β-cells in rodent studies, leading to its evaluation in clinical trials such as the European Nicotinamide Diabetes Intervention Trial (ENDIT), where it was administered orally to islet cell antibody (ICA)-positive first-degree relatives (FDR) of patients with type 1 diabetes mellitus (T1DM), but it did not prevent progression to diabetes. High doses of nicotinamide were also tested in the DENIS study among high-risk children, which similarly showed no beneficial effects. Pilot studies combining nicotinamide with cyclosporine, vitamin E, or an intensive insulin regimen also failed to demonstrate a preventive effect against β-cell loss in high-risk subjects, indicating no significant protective benefits of nicotinamide in human trials despite positive results in animal models.
B-lymphocyte infiltration of pancreatic islets in humans is associated with more aggressive and earlier onset of type 1 diabetes. Depletion of B lymphocytes using an anti-CD20 monoclonal antibody has been shown to temporarily preserve β-cell function in individuals with recent type 1 diabetes onset, indicating a significant role for B lymphocytes in the autoimmune destruction of β-cells. The interaction between B and T lymphocytes is crucial for mounting an autoimmune attack, and targeting this T–B cell cross-talk is considered a potential therapeutic approach in type 1 diabetes.
Sulfonylureas are oral anti-diabetes medications that stimulate insulin release by binding to sulfonylurea receptors in pancreatic beta cells, inhibiting ATP-sensitive potassium channels, causing cell membrane depolarization, calcium influx, and insulin exocytosis. These drugs are effective in lowering glycated haemoglobin (HbA1c), particularly in early stages of diabetes when beta-cell function is still present. However, their glucose-lowering effect is not durable due to progressive decline in beta-cell insulin production, a process referred to as pancreatic exhaustion. First-generation sulfonylureas are no longer in use, having been replaced by second-generation agents such as gliclazide, glipizide, glibenclamide, and glimepiride, which offer longer duration of action and more convenient dosing.
Lixisenatide, a GLP-1 receptor agonist based on exendin-4 with structural modifications, was approved for use in Europe in 2013 and in the USA in 2016. Administered once daily at a dose of 20 μg, it has demonstrated efficacy in lowering HbA1c and moderately reducing fasting plasma glucose compared to placebo. It also shows effects on post-prandial plasma glucose when taken immediately before meals. Clinical trials indicate a dose-dependent decrease in body weight, although this effect was not consistently superior to placebo. Common side effects include gastrointestinal symptoms such as nausea and diarrhea, which are typical for GLP-1RAs. In comparison to exenatide twice daily, lixisenatide showed non-inferiority in HbA1c reduction, better tolerability with fewer gastrointestinal side effects and less symptomatic hypoglycemia, but was less effective in promoting weight loss.
During the management of diabetes in children, regular ambulatory visits are scheduled at least every three months, with more frequent visits if treatment goals are not met or if there is a change in treatment, such as starting insulin pump therapy. These visits include assessments of overall health, growth, and vital signs, along with physical examinations. Routine screening for diabetes-associated complications and comorbidities is conducted, and blood glucose records are reviewed, including HbA1c levels, medications, and school-related diabetes plans. Insulin doses may be adjusted based on these reviews, and ongoing diabetes education is provided, with evaluation of age-appropriate diabetes knowledge.
Continuous subcutaneous insulin infusion (CSII) has demonstrated greater improvements in glycemic levels and reduced glucose variability compared to multiple daily injection (MDI) therapy, particularly when MDI regimens use older basal insulin formulations. However, the benefits of CSII are less pronounced when MDI regimens include modern basal insulin analogues such as insulin glargine. Meta-analyses have shown small mean HbA1c differences favoring CSII over MDI, with a difference of 0.63% (7 mmol/mol) in short-term studies comparing glargine-based MDI with CSII. More recent analyses indicate that when rapid-acting insulin analogues are used in MDI regimens, the HbA1c improvement with CSII is more modest, showing differences of -0.29% (-3 mmol/mol) compared to -1.93% (21 mmol/mol) when regular human insulin is used. Overall, CSII provides a small but consistent reduction in HbA1c levels compared to MDI in both adults and children with type 1 diabetes, as confirmed by multiple studies and systematic reviews.
Increased physical activity improves cardiorespiratory fitness and lowers mortality rate in individuals without diabetes, and in people with diabetes, walking for two hours a week is associated with reduced cardiovascular mortality, with greater benefits seen when walking three to four hours a week. However, no randomized controlled trial has assessed the effect of improved physical fitness on mortality in type 2 diabetes.
Antipsychotics increase the risk of diabetes through several mechanisms, primarily due to their association with weight gain. All antipsychotics may lead to weight gain, though the extent varies significantly between drugs, with haloperidol, ziprasidone, and lurasidone being less problematic, while olanzapine, zotepine, and clozapine cause larger effects. In the first year of treatment, 15–72% of individuals may experience weight gain exceeding 7% of their body weight. The number needed to harm (NNH) for weight gain of ≥7% ranges from 6 for olanzapine and quetiapine immediate release to 67 for lurasidone. Weight gain is most pronounced in individuals who are antipsychotic-naive, being up to three- to fourfold greater compared to those with chronic illness, and occurs primarily early in treatment, though weight gain can continue for at least four years, albeit at a slower rate, eventually reaching a plateau.
Low glucose levels (less than 50 mg/dL or less than 2.8 mmol/L) can compromise behavioral defense mechanisms, potentially impacting cognition and the ability to respond to hypoglycemia, while higher glucose levels (2.8–3.1 mmol/L) may trigger defensive behaviors such as food ingestion.
During pregnancy, fasting glucose levels decrease early on due to insulin-independent glucose uptake by the fetus and placenta, but later in pregnancy, around 22 weeks, post-prandial glucose levels rise as insulin sensitivity declines, a change linked to the growth of the fetal placental unit and reversed after delivery. In late pregnancy, maternal lipolysis increases, making free fatty acids the primary maternal fuel, while glucose transfer to the fetus in the fasting state is enhanced. The inability of insulin to suppress lipolysis in adipose tissue occurs alongside increased maternal free fatty acid release and fatty acid oxidation, with reduced carbohydrate oxidation. This altered metabolism is influenced by placental hormones such as human placental growth hormone, supporting fetal nutrient supply and metabolic adaptations in the mother.
Familial partial lipodystrophies are autosomal dominant disorders characterized by insulin resistance in individuals who are otherwise slim, associated with the loss of peripheral subcutaneous fat and resulting in ectopic fat accumulation. Insulin resistance in these conditions contributes to the development of diabetes. The two main subtypes of this disorder are caused by variants in the LMNA and PPARG genes.
Neonatal diabetes, diagnosed within the first 6 months of life, is often monogenic rather than type 1 diabetes and is characterized by ketoacidosis and absent C-peptide. This condition is rare, affecting 1 in 100,000 to 200,000 live births, with about half of cases being transient neonatal diabetes mellitus (TNDM) that may remit spontaneously but can recur later in life, while the other half are permanent neonatal diabetes mellitus (PNDM) where diabetes persists. Neonatal diabetes arises from mutations in genes critical to β-cell development or function, and known genetic causes are summarized in relevant medical literature.
Nicotinamide has been used in combinations with intensive insulin, cyclosporine, or vitamin E in pilot studies for diabetes prevention or treatment, but these combinations have shown no effect. Additionally, orally administered nicotinamide at a dose of 1.2 g/m²/day has been studied in individuals with islet cell antibodies (ICA) and a family history of type 1 diabetes (FDR), who are at risk of developing type 1 diabetes within 3 years, but it also demonstrated no effect.
The use of menopause hormone therapy (MHT) in postmenopausal women, particularly with oral formulations, has been a concern for its potential effects on glucose homeostasis and glycaemic indices in women with diabetes. However, evidence from randomized placebo-controlled trials indicates that MHT does not adversely impact glucose metabolism or increase the risk of incident diabetes. In the Heart and Estrogen/Progestin Replacement Therapy Study (HERS), women taking MHT had a 35% reduction in incident diabetes compared to placebo over four years. Similarly, the Women's Health Initiative Hormone Trial found a 21% lower risk of diabetes at one year with conjugated equine oestrogens plus medroxyprogesterone, attributed to decreased insulin resistance. A meta-analysis of low-dose combination hormone replacement therapy also showed reduced diabetes incidence and improved metabolic measures in women with diabetes, suggesting that MHT can be safely used without negatively affecting glucose control.
In people with type 1 diabetes, severely increased albuminuria, and hypertension, adding an ACE inhibitor to non-ACE inhibitor antihypertensive therapy reduces the risk of a doubling of serum creatinine by 48% and lowers the risk of a composite endpoint including death, dialysis, or kidney transplantation by 50%, with both benefits occurring independently of blood pressure. Short-term studies show that angiotensin receptor blockers (ARBs) have similar effects on blood pressure and urinary albumin excretion (UAE) as ACE inhibitors in type 1 diabetes with severely increased albuminuria.
The evidence indicates that multiple abnormalities primarily affect β-cell function rather than β-cell mass in type 2 diabetes, with β-cell dedifferentiation and/or transdifferentiation, rather than apoptosis, playing a key role in reduced functional β-cell mass. This challenges the old concept of β-cell exhaustion and suggests the possibility of restoring insulin secretion through reprogramming. Supporting this view, β-cell dedifferentiation enhances degranulation, and experimental restoration of insulin granules has been achieved through lowering blood glucose, with recovery of insulin secretion even in islets from individuals with type 2 diabetes.
Impairment of glucose-induced insulin secretion, particularly in response to oral glucose, is common in elderly individuals with glucose intolerance. Glucose effectiveness, which refers to the ability of glucose to stimulate its own uptake without insulin, is reduced in healthy elderly subjects. Non-insulin-mediated glucose uptake (NIMGU) accounts for 70% of glucose uptake under fasting conditions, mainly into the central nervous system, and 50% of postprandial glucose uptake, especially into skeletal muscle, making it a potential target for therapeutic intervention.
CGM (continuous glucose monitoring) is becoming the gold standard for glucose management and is associated with improvements in diabetes-related outcomes, including reductions in HbA1c levels regardless of insulin delivery method (multiple daily injections or insulin pump), as well as decreases in both hyperglycemia and hypoglycemia. Advancements in CGM technology have led to increased global usage, although disparities exist, with lower adoption rates among youths from low socioeconomic backgrounds and racial and ethnic minority groups, particularly in less-resourced countries. In resource-limited settings, achieving the recommended SMBG frequency of at least five checks per day is difficult due to limited access to diabetes devices, prompting the development of tiered care guidelines to support more accessible, standards-based diabetes management.
Type 2 diabetes is causally associated with an increased risk of certain adult cancers, and in some Western countries, cancer is becoming the leading cause of death among people with diabetes as cardiovascular disease deaths decline. Two hypotheses for the link between diabetes and cancer include hyperglycaemia and hyperinsulinaemia. Earlier studies suggested that some anti-diabetes drugs might influence cancer risk—insulins, thiazolidinediones, and incretin-based agents were linked to increased risk, while metformin was associated with a decreased risk—but many of these findings likely overestimated the effect sizes. More recent, better-controlled reviews have generally weakened these associations. People with diabetes who develop cancer tend to have poorer treatment responses and reduced survival compared to those without diabetes. Important clinical considerations include cancer screening for individuals with diabetes, discussing cancer risk when starting new anti-diabetes medications, and managing cancer treatment-related effects in people with diabetes. Research is ongoing to better understand how diabetes, its treatments, and cancer biology interact, and whether diabetes has a direct adverse effect on tumor outcomes in clinical practice.
Clinical guidelines for diabetes management in low- and middle-income countries (LMICs) often face challenges in adaptation and implementation, with many guidelines being inadequate in clarity, dissemination, and contextualization, including socioeconomic and ethical-legal aspects. Compared to guidelines from high-income countries, those in LMICs tend to include a narrower range of elements and are developed through less optimal processes.
In diabetes, impaired NO production by autonomic nerve terminals due to autonomic neuropathy and by endothelial cells due to endothelial dysfunction leads to difficulties in achieving penile erection. Sildenafil and other PDE inhibitors enhance erections by inhibiting the breakdown of cGMP, the second messenger in the NO pathway, and are considered safe and effective treatments for erectile dysfunction in diabetic patients.
Transplantation of pancreatic tissue was first attempted in 1890 using fragments of a sheep's pancreas in a boy with diabetic ketoacidosis, though the procedure faced insurmountable immune barriers, especially due to the challenges of xenografts. In the 1960s, advancements in immunosuppression with steroids and azathioprine enabled successful renal transplantation, with steroids blocking cytokines and inhibiting antigen presentation while azathioprine impeded T cell activation by inhibiting purine synthesis. Cyclosporine A, a calcineurin inhibitor that impairs transcription in active T cells and blocks interleukin 2 activation, significantly improved graft survival. In 1972, it was demonstrated that chemical diabetes could be "cured" in mice through islet transplantation.
In diabetes, insulin-like growth factor 1 binding protein 1 (IGFBP-1) binds to insulin-like growth factor I (IGF-I), reducing its bioavailability and thereby decreasing the negative feedback inhibition that IGF-I normally exerts on the hypothalamus and pituitary, leading to increased growth hormone (GH) secretion; since IGFBP-1 expression is inhibited by insulin, this mechanism may be altered in the context of diabetes where insulin levels or signaling are affected.
Decretins are gut-derived factors released post-prandially to suppress insulin secretion and prevent post-prandial hyperinsulinaemic hypoglycaemia, and they may play a role in the pathophysiology of type 2 diabetes. Examples include SST-28, dopamine, and limostatin in Drosophila, which suppresses insulin-producing cells and reduces secretion of insulin-like peptides. Neuromedin U (NMU), a mammalian homologue of limostatin, is proposed to act as a decretin by suppressing glucose-induced insulin secretion through the β-cell receptor NMUR1, although studies in rats show conflicting evidence regarding its function. Most research on decretins has been conducted in rodent models, highlighting the need for further investigation, including human clinical studies, to fully understand their role in diabetes.
Insulin excess can result from relative or absolute insulin excess, including scenarios where insulin or insulin secretagogue doses are excessive, ill-timed, or inappropriate, or when exogenous glucose delivery is reduced such as after missed meals or during overnight fasting. Increased glucose utilization, such as during and after exercise, decreased endogenous glucose production as seen with alcohol ingestion, increased sensitivity to insulin, particularly at night or following weight loss and improved glycaemic control, and decreased insulin clearance due to renal or liver failure can all contribute to insulin excess. Hypoglycaemia-associated counter-regulatory impairment can occur due to absolute endogenous insulin deficiency, a history of severe hypoglycaemia or impaired awareness of hypoglycaemia, recent antecedent hypoglycaemia, prior exercise, sleep, and intensive glycaemic therapy characterized by lower glycated haemoglobin levels and lower glycaemic goals.
In fully developed type 1 diabetes mellitus (T1DM), where C peptide is negative, circulating insulin levels cannot decrease as plasma glucose levels fall due to therapeutic hyperinsulinemia, a result of beta-cell failure which also leads to loss of the normal increase in glucagon concentrations. This loss of glucagon response is attributed to the absence of intra-islet insulin and potentially other beta-cell secretory products, especially under low glucose conditions, thereby eliminating both the first and second physiological defenses against hypoglycemia. Additionally, the third defense, involving an increase in circulating epinephrine, is typically attenuated, leading to defective glucose counter-regulation, which increases the risk of severe iatrogenic hypoglycemia in T1DM by 25-fold or more. The reduced epinephrine response also indicates a diminished sympathoadrenal reaction, causing hypoglycemia unawareness due to fewer neurogenic symptoms, and is associated with a sixfold higher risk of severe hypoglycemia. Factors contributing to these attenuated responses include recent prior hypoglycemia, previous exercise, or sleep.
Elderly patients with diabetes may experience atypical symptoms such as "silent ischemia," which has a worse prognosis compared to non-diabetic individuals, and myocardial infarction (MI) can occur painlessly, presenting non-specifically as a fall, breathlessness, malaise, or hypotension.
A diabetes center can integrate clinical activities, allowing doctors and health professionals to work in a more coordinated and colocated manner, with roles that are interdependent. Initially, such centers focused on initiating insulin therapy and stabilizing diabetes without hospitalization, primarily led by diabetes nurses with doctor support. Over time, specialized services expanded to include screening and managing diabetes complications, treating diabetic foot disease, managing diabetes in pregnancy, addressing neuropathic pain, and utilizing insulin pump therapy. In many of these specialized areas, nursing and allied health professionals play a central role, often providing greater continuity of care than rotating doctors, making their involvement highly valued. While a single doctor could theoretically provide all these services, logistical challenges often make a team-based approach more practical, with specialists including non-doctors such as nurses playing key roles in diabetes management.
Tight glycaemic management in people with type 2 diabetes has shown limited impact on macrovascular outcomes, as indicated by studies such as the Diabetes Control and Complications Trial (DCCT) in type 1 diabetes and the UK Prospective Diabetes Study (UKPDS) in type 2 diabetes. Subsequent trials, including ADVANCE and ACCORD, further demonstrated no significant cardiovascular benefits from tight blood glucose control, with the ACCORD study even suggesting potential adverse cardiovascular effects associated with this approach.
The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial assessed the cardiovascular safety of once-daily lixisenatide, a GLP-1 receptor agonist, in 6068 individuals with type 2 diabetes and a recent acute coronary event. The trial demonstrated that lixisenatide was non-inferior, but not superior, to placebo in preventing the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina, with a hazard ratio of 1.02 (95% CI 0.89 to 1.17) over a median follow-up of 24 months.
In India, type 2 diabetes mellitus (T2DM) in youth often overlaps with monogenic forms of diabetes, fibrocalculous pancreatic diabetes, and diabetes associated with malnourishment, all of which are ketosis-resistant forms of youth-onset diabetes. In Indian patients with tropical calcific pancreatitis, the loss of endocrine function accompanying exocrine damage may contribute to the clinical manifestation of diabetes, especially in the presence of other stressors. Research using pancreatic specimens has shown significant correlations between BMI and relatively low beta-cell volume, with amyloidosis, inflammation, and fibrosis identified as common pathologic features.
Type 2 diabetes is linked to a heightened risk of hospital admission or death from chronic liver diseases, with the association influenced by factors such as liver disease type, sex, and socioeconomic status. Non-alcoholic fatty liver disease (NAFLD) elevates the risk of cardiovascular disease, cancer, and mortality in individuals with type 2 diabetes and also increases the likelihood of developing type 2 diabetes independently of common metabolic risk factors. A meta-analysis of 33 cohort studies involving over half a million middle-aged individuals found that NAFLD is associated with a 2.2-fold increased risk of developing diabetes over five years, with the risk rising as NAFLD severity increases, particularly with advanced liver fibrosis. In a retrospective study of Swedish individuals with biopsy-proven NAFLD, 51% of those with severe fibrosis (stages F3-4) developed type 2 diabetes compared to 31% with less severe fibrosis (stages F0-2) over 18 years.
Thiazide diuretics have been shown to have a dose-dependent modest effect on increasing fasting blood glucose levels and a negligible impact on HbA1c in people with hypertension. Long-term use of chlortalidone, a thiazide-like diuretic, has been associated with a higher incidence of new-onset diabetes compared to other antihypertensive medications such as amlodipine and lisinopril. Despite these effects, individuals with diabetes who were treated with chlortalidone demonstrated lower cardiovascular and total mortality rates compared to placebo controls over a 14.3-year follow-up period. These findings highlight the complex relationship between thiazide diuretics and glucose homeostasis, with both adverse glycaemic effects and potential cardiovascular benefits observed.
Patients with diabetes who are accustomed to self-managing their condition, including insulin adjustment, may find hospital admission disruptive. Guidelines from the ADA and Diabetes UK emphasize the importance of educating individuals with diabetes to ensure safe self-care in hospitals. For self-management to be permitted in a hospital setting, patients must be competent adults with stable consciousness, proven ability to manage diabetes at home, appropriate physical skills to self-administer insulin, experience in self-monitoring blood glucose, and adequate oral intake. If self-care is unsafe due to critical illness, surgery, or unwillingness, governance structures should assess competency and may override the patient's right to self-manage.
Neonatal diabetes mellitus (NDM) treatment aims to optimize glycemic levels using oral anti-diabetes agents or insulin, with variability in drug response influenced by genetic factors. Sulfonylurea derivatives, particularly glibenclamide, are commonly used as they promote insulin secretion by closing the $\mathrm{K_{ATP}}$ channel in pancreatic $\beta$ cells, though other sulfonylureas like gliclazide, glipizide, and glimepiride are less effective. Patients with transient NDM due to 6q24 methylation abnormalities respond well to low-dose sulfonylureas, while those with $\mathrm{K_{ATP}}$ channel mutations require high-dose sulfonylureas. Rapid-acting insulin analogs such as lispro, aspart, and glulisine are first-line for achieving $\mathrm{HbA_{1c}}$ targets. Children with NDM caused by insulin gene mutations may benefit from early aggressive insulin therapy to prevent insulin protein misfolding.
Oral anti-diabetes medications such as metformin or GLP-1 receptor agonists are not contraindications for vocational driving in the UK, though medical assessment is typically required. However, progression to insulin therapy often ends employment for bus and train drivers. Public transport companies frequently restrict employment of drivers with type 2 diabetes who use sulfonylureas. Taxi, ambulance, and police pursuit drivers fall outside statutory regulations, with taxi licensing and medical fitness assessments handled by local authorities, some of which apply Group 2 licensing standards. Employers in these sectors usually determine the employment of insulin-treated drivers based on advice from occupational health physicians.
Individuals with type 2 diabetes should undergo assessment for non-alcoholic fatty liver disease (NAFLD) using liver ultrasonography and non-invasive scores of fibrosis, as serum aminotransferase levels are not reliable for diagnosing or monitoring NAFLD in this population. It is recommended to assess people with type 2 diabetes every 2–3 years for NAFLD, utilizing non-invasive biomarkers such as FIB-4 score, NFS, or ELF test, followed by vibration-controlled transient elastography (FibroScan) if biomarker scores exceed a certain threshold to identify significant fibrosis (≥F2). In cases of diagnostic uncertainty or the need for precise staging of liver fibrosis, a liver biopsy may be performed. There is ongoing debate regarding the most appropriate diagnostic and monitoring algorithm for NAFLD in individuals with type 2 diabetes.
Screening for albuminuria should be performed, and if present, other causes of microalbuminuria must be excluded; if negative, yearly repeats are recommended. Positive results by dipstick or heat coagulation test require quantitative 24-hour urinary albumin excretion measurement, with follow-up every three months. Renal function tests including blood urea, creatinine, and electrolytes should be conducted alongside. Patients should be educated on primary, secondary, and tertiary prevention of diabetic nephropathy, along with the importance of glycemic control, blood pressure management, and awareness of illnesses that may worsen kidney function. Consideration of ACE inhibitors or ARBs is advised to slow disease progression, while protein restriction and phosphate-lowering agents may benefit select patients. Nephrotoxic medications such as NSAIDs should be avoided.
Glycemic control and the duration of diabetes exposure play a pivotal role in the development of microvascular complications, as demonstrated in the UK Prospective Diabetes Study (UKPDS). Recent studies have begun to more thoroughly investigate the impact of glycemic control on macrovascular disease, suggesting that HbA1c acts as an independent and continuous risk factor for macrovascular complications, though the association is not as strong as it is for microvascular issues. An increase in HbA1c from 5.5% (37 mmol/mol) to 9.5% (80 mmol/mol) corresponds to a tenfold rise in microvascular disease endpoints, while the risk for macrovascular disease endpoints increases only twofold.
Risk factors for diabetes include age ≥35 years, a family history of diabetes in a first-degree relative, certain racial or ethnic backgrounds such as African American, Latino, Indigenous American, Asian American, or Pacific Islander, physical inactivity, being overweight or obese with a body mass index ≥25 kg/m² or ≥23 kg/m² in Asians, hypertension defined as ≥140/90 mmHg or on therapy for hypertension, abnormal cholesterol levels such as high-density lipoprotein cholesterol <35 mg/dl (0.90 mmol/l) and/or triglyceride level >250 mg/dl (2.82 mmol/l), a history of cardiovascular disease, a history of gestational diabetes, polycystic ovary syndrome, previously identified pre-diabetes based on laboratory values, and other clinical conditions associated with insulin resistance such as acanthosis nigricans or severe obesity.
Men with diabetes experience functional impairment in autonomic and endothelium-dependent relaxation of corpus cavernosum smooth muscle, contributing to erectile dysfunction. Small nerve fibre damage, detectable via corneal confocal microscopy, is more strongly linked to erectile dysfunction than testosterone levels in individuals with type 1 diabetes, type 2 diabetes, and obesity.
Inhibiting the dephosphorylation of PIP3 has been explored as a strategy to enhance insulin action, with studies showing that blocking PTEN, a phosphatase that dephosphorylates PIP3, can improve insulin sensitivity and glycemic control in db/db and ob/ob mice when targeted with an antisense oligonucleotide. Additionally, adipose tissue-specific PTEN knockout mice exhibited increased insulin sensitivity, higher energy expenditure, and enhanced adipocyte mitochondrial biogenesis, although significant PTEN disruption may increase tumor risk. Another pathway involves SHIP-1 and SHIP-2, which convert PIP3 to phosphatidylinositol 3,4-bisphosphate; partial disruption of SHIP-2 in mice also improved insulin sensitivity, indicating a potential role for SHIP-2 inhibition in enhancing PI3K signaling in diabetes.
St. Vincent's Declaration outlines comprehensive strategies for diabetes detection, control, and complication prevention, emphasizing self-care and community support, while promoting awareness among the public and healthcare professionals. It advocates for age-inclusive diabetes education programs targeting patients, families, friends, colleagues, and healthcare teams, with specialized care for children and necessary emotional, economic, and social support for their families. The declaration supports strengthening existing centers of excellence in diabetes care and research, establishing new ones where needed, and promoting independence and societal integration for all individuals with diabetes. Specific measures are proposed to prevent costly complications, including reducing diabetes-related blindness, end-stage renal failure, and limb amputations by targeted percentages, as well as lowering morbidity and mortality from coronary heart disease through risk factor reduction programs. It also aims to improve pregnancy outcomes in women with diabetes to match those without the condition, implement advanced information systems for diabetes care quality assurance, and foster European and international collaboration through WHO and other agencies to advance diabetes research and program implementation.
Human insulin resistance, commonly seen in type 2 diabetes mellitus (T2DM), is associated with low-grade systemic inflammation, as indicated by elevated levels of inflammatory markers such as white blood cell count, CRP, adhesion molecules, IL-6, IL-8, and serum amyloid A. In obese individuals, insulin resistance correlates with macrophage infiltration in adipose tissue and paracrine interactions between macrophages and adipocytes involving cytokines and adipokines. These inflammatory mediators, including IL-1 and IL-6, contribute to the metabolic syndrome and impair insulin signaling. Specifically, IL-1β reduces IRS-1 expression, worsening insulin resistance, while IL-6 compromises insulin action through activation of Jak, STAT, and SHP-2 proteins, leading to ERK/MAP kinase pathway stimulation and increased SOCS gene transcription, which further impairs insulin signaling at the receptor or IRS protein level. Clinical evidence shows that treating T2DM patients with recombinant human IL-1 receptor antagonist can improve glycemic control.
Cushing syndrome can lead to hyperglycemia and diabetes through mechanisms involving elevated levels of non-esterified fatty acids (NEFA) and increased expression of phosphoenolpyruvate carboxykinase (PEPCK), which contribute to insulin resistance and impaired glucose metabolism.
These drug classes, including glucagon receptor antagonists, selective PPAR modulators, cellular glucocorticoid inhibitors, adiponectin receptor agonists, and fibroblast growth factor analogues, are under investigation for their potential roles in diabetes treatment.
Chronic hyperglycemia, indicated by microvascular complications such as proliferative diabetic retinopathy, is a strong risk factor for neurocognitive abnormalities in individuals with type 1 diabetes mellitus (T1DM). Longitudinal research shows that those with existing or developing retinopathy experience a notable decline in psychomotor efficiency compared to those without diabetes, while individuals without retinopathy do not show psychomotor slowing. Cognitive decline in this population is associated with four factors: presence or development of proliferative retinopathy, autonomic neuropathy, elevated systolic blood pressure, and longer diabetes duration, with a statistical model achieving 83% accuracy in predicting cognitive decline and explaining 53% of its variance.
In individuals with type 1 diabetes mellitus (T1DM), the absence of insulin-stimulated muscle glucose uptake leads to significant glucose disappearance through urinary excretion and non-insulin-mediated glucose uptake pathways. Following food intake, there is no corresponding increase in insulin or decrease in glucagon, resulting in inadequate splanchnic glucose uptake and reduced suppression of endogenous glucose production relative to blood glucose levels. Post-meal glycogen synthesis is significantly impaired, with most glycogen being formed through the indirect gluconeogenic pathway.
Sitagliptin administered at 100 mg/day as monotherapy or in combination with other antidiabetic agents typically reduces HbA1c by about 0.7–0.8% (8–9 mmol/mol) after 24–52 weeks in individuals with a baseline HbA1c of approximately 8% (64 mmol/mol), with those having higher baseline HbA1c often experiencing reductions greater than 1% (11 mmol/mol). Fasting plasma glucose concentrations are reduced by about 1.0–1.5 mmol/L, and postprandial glucose levels are also lowered as measured 2 hours after a standard mixed meal.
In diabetic ketoacidosis (DKA), serum potassium is typically elevated due to insulin deficiency, acidaemia, and water deficiency, which promote the movement of potassium from inside cells to the extracellular space. Serum sodium levels are usually low because hyperglycaemia causes water to shift from the intracellular to the extracellular compartment. Leucocytosis is frequently observed but does not necessarily indicate an active infection. Nausea, vomiting, and abdominal pain may occur, and in such cases, serum amylase should be measured to consider acute pancreatitis as a possible cause, although elevated amylase alone is not conclusive for pancreatitis in the context of DKA.
GLP-1 has been found to improve endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM) and coronary heart disease, and this effect on endothelial-dependent vasodilation has also been confirmed in healthy subjects. Functional receptors for GLP-1 have been identified on endothelial cells, and chronic administration of GLP-1 agonists in clinical settings is associated with small but significant decreases in blood pressure, which may be related to its vasodilatory actions observed in animal models.
Emphysematous pyelonephritis, a severe infection characterized by gas formation in the renal parenchyma, is highlighted in a 34-year-old woman with type 1 diabetes, showing gas in the right ureter and moderate hydronephrosis on computed tomography; the condition was caused by Escherichia coli and successfully treated with antibiotics, nephrostomy drainage, and ureteroscopy to remove obstructing necrotic slough.
Several long-term studies focus on diabetes autoimmunity and prediction, involving high-risk children and first-degree relatives in various countries. These studies include the German BABYDIAB, Australian BABYDIAB, Diabetes Autoimmunity Study in the Young (DAISY) in the USA, Diabetes Prediction and Prevention Program (DIPP) in Finland, Diabetes Evaluation in Washington (DEW-IT) in Washington, USA, Prospective Assessment of Newborns for Diabetes Autoimmunity Study (PANDA) in Florida, USA, All Babies in south-east Sweden (ABIS), Diabetes Prediction in Skåne (DIPI5) in Sweden, Environmental Triggers of Type 1 Diabetes Study (MIDIA) in Norway, and The Environmental Determinants of Diabetes in the Young (TEDDY), a multicenter study spanning Sweden, Finland, Germany, and multiple states in the USA. These studies aim to identify risk factors, environmental triggers, and early markers for diabetes, particularly in children with genetic predispositions or family histories of the disease.
Exenatide twice daily, a synthetic version of exendin-4, is used in the management of diabetes and is primarily cleared by the kidneys. It has a half-life of approximately 2.4 hours after subcutaneous injection, with detectable plasma concentrations up to 10 hours. It is recommended to start at 5 μg twice daily, increasing to 10 μg twice daily after one month if tolerated, and should be injected within 60 minutes before the two main meals to achieve maximum effect. Clinical trials, including the AMIGO studies, have shown that exenatide significantly reduces HbA1c levels compared to placebo, with a modest reduction in fasting plasma glucose and a notable blunting of postprandial plasma glucose excursions, mainly due to delayed gastric emptying. This postprandial effect is only observed during meals when the drug is administered. Exenatide is associated with an average weight loss of 1–4 kg and has mild to moderate side effects such as nausea, diarrhea, and vomiting. The risk of hypoglycemia is low unless exenatide is combined with sulfonylurea or insulin.
Diabetic peripheral neuropathy (DPN) commonly presents with lancinating or burning pain, often described as "burning/hot," "electric," "sharp," or "tingling," and tends to worsen at night or during periods of fatigue or stress. The most frequently affected areas are the feet (96%), particularly the balls of the feet (69%), toes (67%), dorsum of the foot (54%), and heels (32%), with involvement also seen in the hands (39%), plantar surface of the foot (37%), and calves (37%). Pain intensity averages around 5.75/10, with least and most pain scores of 3.6 and 6.9 respectively. Allodynia may occur, and while sensory loss can accompany the pain, patients with severe symptoms may show few clinical signs. Pain can persist for years, leading to disability and reduced quality of life, although partial or complete remission is possible, especially with sudden metabolic changes, shorter duration of diabetes or pain, preceding weight loss, and less severe sensory loss.
Prolonged and acute hyperglycemia can negatively impact $\beta$-cell function, and mechanisms behind this glucotoxicity include increased production of reactive oxygen species, oxidative stress-induced changes in gene transcription and protein expression, and elevated $\beta$-cell apoptosis. While improving glycemic control with secretagogues, insulin sensitizers, or insulin can enhance $\beta$-cell function in patients with type 2 diabetes mellitus (T2DM), impaired $\beta$-cell function is present even in genetically predisposed individuals with normal glucose tolerance, and optimal glycemic control does not fully reverse this dysfunction, indicating that glucotoxicity is a secondary but potentially accelerating factor in $\beta$-cell deterioration over time.
In individuals with diabetes, peripheral neuropathy can alter symptom presentation, potentially masking conditions like peripheral ischaemia, which may exist even in the absence of noticeable symptoms. This is particularly significant when a person with diabetes has a small ulcer or wound on the lower limb, as the lack of symptoms does not necessarily mean the issue is minor, especially if there is a risk of infection. Due to these concerns, healthcare professionals often recommend regular routine assessments of peripheral circulation in all individuals with diabetes to prevent complications such as diabetic foot infections.
Women with insufficient β-cell reserve, as seen in type 1 diabetes, type 2 diabetes, or gestational diabetes mellitus (GDM), experience impaired adaptation of carbohydrate, protein, and fat metabolism. Pregnant women with type 1 diabetes need increased insulin to address rising caloric demands, greater adiposity, reduced physical activity, and elevated anti-insulin hormones, with insulin requirements potentially tripling to maintain normal blood glucose and prevent ketosis. Type 2 diabetic women often require high-dose insulin during pregnancy due to obesity and inactivity. The feto-placental unit causes increased insulin resistance, leading to higher insulin needs, though this typically resolves shortly after delivery, while insulin requirements related to maternal weight gain may continue. Understanding these pathophysiological changes is essential for effective clinical management during pregnancy.
The shared care model for managing diabetes demonstrates better adherence to management guidelines compared to traditional specialist care, with a higher proportion of patients achieving an HbA1c within 1% (11 mmol/mol) of the normal range and/or blood pressure at target. This model suggests that most individuals with diabetes do not require regular specialist visits every 3–4 months to achieve similar quality of care. Additionally, the system is more cost-effective as specialist services, such as those provided by ophthalmologists and nephrologists, are utilized only when recommended by a diabetes specialist, while still maintaining effective glycemic control and complication monitoring.
The concept of "glycemic memory" refers to the lasting impact of early glycemic control on the future development of diabetic complications, where periods of poor glycemic management in the initial stages of diabetes can lead to or hasten complications later, even if control improves subsequently. Evidence from the DCCT/EDIC trial in type 1 diabetes and the UKPDS in type 2 diabetes demonstrates that poor glycemic control correlates with a higher later burden of complications. However, the VADT study in type 2 diabetes showed that intensive glucose control (6.9 vs. 8.4%, 52 vs. 68 mmol/mol) after prolonged exposure to hyperglycemia (12–15 years) did not significantly reduce cardiovascular risk, highlighting the importance of early glycemic control for long-term positive outcomes.
Approaches to restore $\beta$-cell mass in diabetes include stimulating regeneration from surviving $\beta$ cells, with techniques such as in vivo gene transfer using adenoviral or AAV vectors to deliver genes that promote replication and survival. Methods of delivery include intravenous, intraperitoneal, and local administration through the bile-pancreatic duct, while non-viral approaches like ultrasound targeted microbubble destruction have also been explored, though with transient expression. Genes and factors such as HGF, Sirtuin 1, angiopoietin-like protein 8, GLP-1, $\beta$-cellulin, Akt, and Nkx2.2 have shown the ability to reduce apoptosis, induce proliferation, and even reverse diabetes in animal models. Other promising candidates for gene therapy include IGF-I, Reg1, EGF, gastrin, and NGF. Specifically, AAV-mediated overexpression of IGF-I in NOD mice reduced diabetes incidence by preserving $\beta$-cell mass, decreasing apoptosis, lowering islet infiltration, and modulating islet autoimmunity through reduced expression of antigen-presenting molecules and inflammatory mediators.
CSII (Continuous Subcutaneous Insulin Infusion) may be beneficial for selected women with diabetes, particularly those experiencing a pronounced dawn phenomenon or recurrent hypoglycaemia, although there is limited evidence supporting its routine use during pregnancy. Studies comparing CSII to MDI (Multiple Daily Injections) have shown comparable glucose levels and pregnancy outcomes, but these studies were conducted before the use of insulin analogues became widespread and were limited in their ability to detect differences in neonatal outcomes. The UK NDIPA study found no difference in glycaemic control or maternal fetal health outcomes between women using insulin pumps and those using pens, with both groups showing elevated mean HbA1c levels after 24 weeks. Risks associated with CSII include the potential for hyperglycaemia or ketoacidosis in the event of pump failure, as well as increased costs. Women who were already managing their diabetes well with CSII prior to conception often continue its use during pregnancy.
SGLT-2 is highly expressed in the first segment of the proximal tubules of the kidneys, where it is responsible for the reabsorption of approximately 90% of glucose in the glomerular filtrate, and partial inhibition of SGLT-2 provides a non-insulin-dependent mechanism to reduce glucose reabsorption, eliminate excess glucose in the urine, and thereby reduce hyperglycaemia; this approach was initially explored using phlorizin, a naturally occurring inhibitor of sodium-glucose transporters found in apple tree bark, which was shown to reduce hyperglycaemia in partially pancreatectomized rodents with diabetes, although its rapid intestinal degradation limited its therapeutic use, leading to the development of chemically modified selective SGLT-2 inhibitors such as canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin.
Macroangiopathic complications are significantly associated with certain blood levels, indicating their role in the development or progression of these complications in diabetes.
Hyperglycemia, particularly when accompanied by ketones, requires prompt troubleshooting and treatment as it may indicate a pump malfunction. Interruption in insulin flow can lead to ketonemia within 4 hours, posing a significant risk, especially at night when there is no long-acting insulin present. To manage potential pump failure, patients should have syringes available for administering insulin via injection.
Elevations in intracellular calcium within pancreatic β-cells trigger the secretion of insulin through calcium-sensing mechanisms, including calcium-dependent protein kinases such as myosin light chain kinases, calcium/phospholipid-dependent kinases, and calcium/calmodulin-dependent kinases (CaMKs), with CaMK II specifically linked to initiating insulin secretion in response to glucose and enhancing secretion when intracellular calcium is elevated. Another β-cell calcium-sensitive enzyme, cytosolic PLA2 (cPLA2), is activated by calcium levels in stimulated β-cells and produces arachidonic acid (AA) by breaking down membrane phosphatidylcholine, and AA can stimulate insulin secretion independently of glucose and calcium, and is further metabolized into prostaglandins, thromboxanes, hydroperoxyeicosatetrenoic acids (HPETES), hydroxyeicosatetrenoic acids (HETES), and leukotrienes via cyclooxygenase and lipoxygenase pathways.
Hypoglycemia is associated with decreased cognitive functioning in children with type 1 diabetes mellitus (T1DM), especially those diagnosed before age 5–6 years, and even mild to moderate episodes can impair school performance and overall well-being. Chronic hyperglycemia also draws concern for its potential impact on cognitive function in young children. Reduced awareness of hypoglycemia increases the risk of injury and accidents, often leading to fear of hypoglycemia and subsequent decreases in insulin dosing, which raises HbA1c levels. Severe hypoglycemia can cause significant anxiety, poor sleep, emergency room visits, hospitalizations, and excessive insulin dose reductions that worsen glycemic control. Long-term follow-up from the Diabetes Control and Complications Trial (DCCT) showed no evidence of permanent neurocognitive changes due to hypoglycemia in adolescents and young adults, suggesting that the effects of severe hypoglycemia on neuropsychological functioning may depend on the age at exposure.
Iatrogenic hypoglycemia, a complication associated with diabetes management, leads to recurrent physical and psychological issues and can result in some mortality. It impairs the body's defenses against subsequent episodes of low blood sugar and hinders the maintenance of normal blood glucose levels over time. In the short term, it causes brain fuel deprivation, which can lead to functional brain failure, typically reversible once blood glucose levels are restored. Rarely, severe hypoglycemia may result in sudden death, possibly due to cardiac arrhythmia, or, if profound and prolonged, brain death.
In both type 1 diabetes and advanced type 2 diabetes, the pathophysiology of glucose counter-regulation is similar, though the progression differs, with type 1 diabetes involving a rapid loss of β-cell function leading to early development of defective glucose counter-regulation and impaired awareness of hypoglycaemia, while in type 2 diabetes these syndromes develop more gradually as β-cell failure progresses. Iatrogenic hypoglycaemia arises from therapeutic hyperinsulinaemia, which causes falling plasma glucose levels and prevents the normal reduction in insulin and compensatory glucagon secretion. Each hypoglycaemic episode further diminishes the sympathoadrenal response to future episodes, and as individuals with type 2 diabetes approach the insulin-deficient stage, their risk of iatrogenic hypoglycaemia increases.
Adiponectin levels in white fat decrease during pregnancy, which is linked to reduced insulin-stimulated glucose uptake rather than changes in lipid metabolism. Plasma leptin levels double in pregnancy, originating from both maternal adipose tissue and the fetoplacental unit, though its exact role in maternal metabolism remains unclear. The involvement of other adipokines such as leptin, adiponectin, interleukin-6, and resistin in insulin resistance during pregnancy is not yet fully understood.
In the development of diabetes, there is a stage known as pre-diabetes or intermediate hyperglycaemia, where blood glucose levels are elevated above normal but do not meet the diagnostic criteria for diabetes. Pre-diabetes includes impaired fasting glycaemia and impaired glucose tolerance (IGT), with the latter defined by the WHO as a fasting glucose value of less than 7 mmol/l (126 mg/dl) and a post-glucose challenge value between greater than 7.8 mmol/l (140 mg/dl) and a higher threshold. Both impaired fasting glycaemia and IGT increase the risk of progressing to type 2 diabetes, with approximately one-third of individuals with IGT developing the condition, and annual incidence rates ranging between 2% and 10% depending on population and risk factors. The term 'pre-diabetes' has been critiqued since not all individuals with intermediate hyperglycaemia progress to type 2 diabetes, and 'intermediate hyperglycaemia' is preferred by many. The diagnostic thresholds for pre-diabetes have evolved over time.
GLP-1 receptor agonists and SGLT-2 inhibitors are classes of medications studied for their effects on stroke risk in people with diabetes, though overall findings have shown limited impact. The REWIND trial demonstrated that dulaglutide, a GLP-1 receptor agonist, led to a small but significant reduction in non-fatal stroke risk without affecting fatal stroke rates.
Individuals with type 2 diabetes frequently experience comorbidities, which are more common in socially deprived populations and significantly affect quality of life. Type 2 diabetes shares risk factors with other non-communicable diseases (NCDs), leading to an increased likelihood of developing additional NCDs and mental health issues, particularly depression. While the interaction between depression and diabetes is well-studied in high-income countries (HICs), research on this comorbidity in low- and middle-income countries (LMICs) is limited, despite an estimated average depression prevalence of 36% among people with diabetes in LMICs, which is higher than the 25% observed in HICs.
When insulin levels are too low, it leads to reduced inhibition of hepatic glucose production and decreased stimulation of glucose uptake. Additionally, the counterregulatory response to exercise, involving hormones like catecholamines, glucagon, growth hormone, and cortisol, becomes more pronounced under insulin deficiency. This results in significantly increased liver glucose output and reduced glucose use by muscles, ultimately causing hyperglycemia.
Risk factors for counter-regulatory impairment in diabetes include endogenous insulin deficiency, a history of severe hypoglycemia, impaired hypoglycemia awareness, and associations between hypoglycemic episodes and recent antecedent hypoglycemia, prior exercise, or sleep, along with lower HbA1c levels. A history of severe hypoglycemia warrants consideration of regimen adjustment unless the cause is easily remediable, due to the high risk of recurrence. For impaired hypoglycemia awareness, a 2–3-week period of careful avoidance of hypoglycemia, without elevated glucose levels, may improve awareness, although studies show limited restoration of counter-regulatory hormone responses. Late post-exercise hypoglycemia or nocturnal hypoglycemia should lead to timed adjustments in treatment, such as reduced insulin action, increased carbohydrate intake, or both.
Omega-3 fatty acids' effects in type 2 diabetes have been studied in several trials with mixed results. Initial studies suggested benefits, but later trials such as the Outcome Reduction with Initial Glargine Intervention (ORIGIN) and A Study of Cardiovascular Events iN Diabetes (ASCEND) showed no benefit. Meta-analyses indicate no significant benefit of low-dose omega-3 fatty acid therapy $(< 1\mathrm{g})$ on cardiovascular disease (CVD) events in type 2 diabetes patients. However, higher doses of eicosapentanenoic acid (EPA), as tested in the Japan EPA Lipid Intervention Study (JELIS), showed a 14% reduction in CVD events in individuals with type 2 diabetes. In the Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trial (REDUCE-IT), 4g of an EPA derivative reduced CVD events by 23% in individuals with type 2 diabetes. In contrast, the STatin Residual risk with Epanova iN hiGb cardiovascular risk patients with Hypertriglyceridaemia (STRENGTH) trial found that 2g EPA-2g DHA reduced triglycerides by 19%, non-HDL cholesterol by 6%, and C-reactive protein by 14%, but had no effect on reducing CVD events and was associated with increased risk of atrial fibrillation and gastrointestinal side effects.
Men with diabetes and erectile dysfunction (ED) should be offered effective oral therapies as first-line treatment, with other options reserved for cases where oral therapy is contraindicated or ineffective.
MODY (Maturity-Onset Diabetes of the Young) can present with a non-ketotic mode and often involves abnormal pancreatic beta-cell function; some patients experience rapid deterioration in glycemic control after initial diagnosis, while others have mild hyperglycemia and may not require insulin even with long-standing disease.
Tricyclic antidepressants are used in the management of diabetic sensorimotor polyneuropathy, with amitriptyline being recommended as the drug of choice due to its greater efficacy according to a joint report from several medical associations. These medications are considered first- or second-line therapies in international pain management guidelines for diabetic neuropathy, although they require gradual dose increases over 6–8 weeks to achieve therapeutic effects, which can affect medication adherence. However, tricyclic antidepressants are contraindicated in patients with certain cardiovascular conditions, and their use should be cautious, especially in older individuals. There is currently insufficient evidence supporting the routine use of imipramine in this context.
Diabetes has been linked to an increased risk of cognitive impairment and dementia, with studies showing a 49% increased risk of mild cognitive impairment, 43% for all-cause dementia, 43% for Alzheimer's disease, and 91% for vascular dementia. Higher fasting plasma glucose levels, specifically above 7.75 mmol/l, are associated with a 20% increased risk of cognitive disorders. Diabetes is also connected to specific cognitive deficits, including impairments in episodic memory, logical memory, executive functions such as cognitive flexibility, and speed of processing, but not short-term or working memory. Some diabetes medications, like pioglitazone, may reduce dementia risk by up to 47% in individuals with diabetes.
Type 1a diabetes mellitus (T1aDM) is caused by an interplay of genetic and environmental factors, beginning with the development of islet autoimmunity, marked by the presence of islet autoantibodies, which is believed to be driven by one or more environmental triggers. The incidence of childhood type 1 diabetes mellitus (T1DM) has increased globally by 3–5% annually over the past 40 years, and eliminating the responsible environmental triggers would be the most efficient approach to primary prevention; however, there is no consensus on which environmental factors are involved. After the initiation of islet autoimmunity, most patients have a long preclinical period that offers an opportunity for secondary prevention. The presence of multiple autoantibodies combined with susceptibility HLA-DR,DQ genotypes identifies individuals at high risk of developing diabetes, and once tolerance is broken to more than one islet autoantigen, most progress to diabetes within 10 years. A period of mild asymptomatic hyperglycemia, detectable by oral glucose tolerance testing (OGTT) or HbA1c, may precede overt insulin dependence by months or years in those with islet autoantibodies, and intervention during this "dysglycemic" stage may theoretically preserve endogenous insulin secretion and prevent complications of T1DM. Preservation or regaining of residual insulin secretion after diagnosis might also be beneficial, although current immunomodulatory agents used in tertiary prevention may carry unacceptable long-term risks.
The UK Prospective Diabetes Study (UKPDS) found that a 0.9% (10 mmol/mol) reduction in HbA1c through intensive treatment did not reduce macrovascular complications in type 2 diabetes, although it significantly reduced microvascular complications such as retinopathy and neuropathy. A 10-year follow-up of the same cohort showed that the initial treatment effects persisted, with reduced microvascular complications, myocardial infarctions, and deaths from any cause. However, glycaemic management in type 2 diabetes has not been linked to a reduction in stroke risk.
AMPK activation increases insulin sensitivity in skeletal muscle and mediates contraction-induced glucose uptake during exercise, while in the liver, it suppresses gluconeogenic enzyme expression leading to decreased blood glucose levels. AICAR is used experimentally to study the effects of AMPK activation on glucose and lipid metabolism and insulin signaling pathways.
Exenatide once weekly is an extended-release formulation approved in Europe in 2011 and in the USA in 2012, containing exendin-4 encased in biodegradable microspheres, with its pharmacokinetic profile primarily dependent on absorption and sustained release over time. It was evaluated in the DURATION phase III clinical trial program, showing superiority in glucose lowering compared to the twice-daily exenatide formulation, with similar weight reduction and better tolerability. In a head-to-head trial with once-daily liraglutide, once-weekly exenatide 2mg resulted in less reduction in HbA1c and weight loss but was better tolerated. Nausea was the most common adverse event, occurring less frequently with the once-weekly formulation.
Seasonal variation in the diagnosis of type 1 diabetes mellitus (T1DM) shows a peak in the number of cases diagnosed during the autumn and winter, with fewer cases diagnosed in the spring or summer, a pattern observed in both the northern and southern hemispheres. The degree of seasonal variation is generally stronger among individuals diagnosed at age 10–14 years compared to younger children. Different analytical methods and limited data sets can affect the comparability of results, and the interpretation of seasonal variation must consider the long and variable preclinical period of T1DM, with speculation that viral or other periodic factors may influence the timing of disease onset in susceptible individuals.
Insulin units are used to measure and compare the blood glucose-lowering potency of insulin preparations, with one unit typically reducing blood glucose by about 50 mg/dl (2.8 mmol/l), though this can vary based on individual insulin sensitivity. Injecting large volumes of insulin, often necessary in insulin-resistant individuals, can slow absorption and decrease effectiveness, in addition to being more painful. To address this, splitting the dose across multiple injection sites or using more concentrated insulin may be beneficial. Insulin is commonly standardized at 100 units per milliliter, but concentrated forms like U500 human regular insulin have a prolonged action profile compared to standard U100 or NPH insulin.
Statins are recommended for cardiovascular prevention in older people with diabetes, as their effects emerge within 1–2 years, making them suitable for most individuals except those with very limited life expectancy. Chronological age alone should not determine therapy exclusion; instead, functional or biological age and the long-term impact of drug therapy on safety and quality of life should be considered.
In individuals with normal glucose tolerance, basal and glucose-stimulated insulin secretion declines at a rate of about 0.7–1% per year during adult life, but this rate is approximately doubled in those with impaired glucose tolerance (IGT) and reaches around 6% per year in patients with type 2 diabetes mellitus (T2DM), indicating a progressive loss of β-cell function that contributes to the development of diabetes, while age-related decreases in insulin sensitivity are likely influenced more by factors such as changes in body composition and physical activity rather than aging itself.
Hyperglycaemia increases the risk of infection by causing abnormal microcirculation, decreased phagocytosis, impaired leucocyte adherence, and delayed chemotaxis, leading to an immunocompromised state in people with diabetes. This contributes to higher susceptibility to skin infections, particularly fungal infections, which are more common in men than women. Skin and soft tissue infections occur more frequently in individuals with diabetes, with an adjusted incidence rate ratio 3.52 times higher compared to the general population, often resulting in increased infection-related hospitalizations. The foot is the most commonly affected anatomical site, and these infections contribute to morbidity and occasionally mortality.
Management of diabetes during labour requires adherence to an established protocol tailored to the time and mode of delivery, ideally in a facility with a dedicated NICU. Women with type 1 diabetes using continuous subcutaneous insulin infusion (CSII) should discuss and document a personalized glycaemic management plan with their physician prior to delivery. According to NICE guidelines, maternal blood glucose should be maintained between 4 and 7 mmol/L during labour to minimize the risk of neonatal hypoglycaemia and fetal distress. Hourly capillary glucose measurements are essential to monitor management effectiveness and guide insulin adjustments. Common approaches involve a continuous glucose infusion with separate insulin administration via a pump, and women on CSII may continue their basal insulin infusion, provided the attending midwifery and anaesthetic staff are knowledgeable about the regimen.
Certain diabetes medications carry a risk of hypoglycaemia, occasionally severe, though some have a lesser risk compared to sulfonylureas. Gastrointestinal side effects are common, and lactic acidosis, while rare, is a concern, particularly in individuals with compromised renal or hepatic function or those at higher risk of hypoxaemia. Some medications mainly reduce post-prandial hyperglycaemia with less effect on fasting glycaemia or HbA1c levels. Fluid retention, anaemia, and an increased risk of heart failure may occur in susceptible individuals, and there are rare reports of ketoacidosis. Monitoring liver function is important, especially with certain agents like vildagliptin, and adequate renal function should be ensured due to potential impacts on drug metabolism and elimination. Additionally, there is a possible risk of acute pancreatitis with some therapies.
Almost all diabetes in the timeframe of 9 months to 10 years is caused by islet autoimmunity, and the incidence of type 1 diabetes has been increasing, particularly in children and adolescents from racial and ethnic minority groups. There has also been a marked rise in the incidence and prevalence of type 2 diabetes in the last decade. At diagnosis, measuring autoantibodies to insulin, glutamic acid decarboxylase (GAD65), islet tyrosine phosphatase 2 (IA-2), and zinc transporter 8 (ZnT8), along with examining signs of insulin resistance, may be necessary to determine the diagnosis and guide long-term treatment.
Sulfonylurea derivatives lower blood glucose concentrations by stimulating insulin release from pancreatic β cells through inhibition of ATP-sensitive potassium (KATP) channels, leading to cell membrane depolarization, calcium influx, and insulin secretion. These medications may cause weight gain and hypoglycaemia, with hypoglycaemia being more common in individuals with impaired kidney function (eGFR < 60 ml/min/1.73 m²), for whom short-acting variants like gliclazide and glipizide are preferred. Men generally respond better to sulfonylurea derivatives, likely due to differences in cytochrome P450 activity between genders, and the drugs are primarily metabolized by the liver with CYP2C9 playing a key role. Some sulfonylurea derivatives have active metabolites excreted in urine, and their effectiveness is greater when initiated early after diabetes diagnosis, as a shorter diabetes duration correlates with improved response.
Glucagon, acting through both glucagon and GLP-1 receptors on β-cells, stimulates insulin release, and this effect is evident in both mouse and human islets. Antagonism of the GCGR in isolated human and rat islets impairs insulin secretion in response to elevated glucose levels, indicating a physiological role for glucagon in maintaining normal β-cell stimulus-secretion coupling. Paracrine regulation via α-cell products, including glucagon and proglucagon peptides, contributes to β-cell function, with dispersed β-cells showing increased glucose responsiveness when attached to α-cells. α-cell secretion stimulated by gastric inhibitory polypeptide (GIP) promotes glucose tolerance through α-to-β-cell communication, suggesting that α-cell signaling is a component of prandial insulin responses, which may have implications for understanding diabetes pathophysiology and treatment.
Persistent elevation of blood glucose above 200 mg/dL (11.1 mmol/L) with the presence of ketones indicates the need for supplemental insulin and fluids, reflecting insulin deficiency. However, when ketones appear with low or normal blood glucose, particularly during gastrointestinal illness, it suggests insufficient carbohydrate intake rather than insulin deficiency, representing a physiologic response where ketones like β-hydroxybutyrate serve as an alternative fuel for the brain, protecting against hypoglycemia. In such cases, insulin is contraindicated due to the risk of severe hypoglycemia, and treatment involves administering fluids with glucose.
Psychosocial and behavioural factors significantly influence the management and outcomes of type 1 diabetes, particularly in children and adolescents who are more likely to be diagnosed with psychiatric disorders, disordered eating, and neurocognitive issues compared to the general population. The demanding nature of managing type 1 diabetes can lead to increased general and diabetes-specific stress for both young patients and their families, with the initial period after diagnosis posing a risk for adjustment disorder. To address these challenges, routine and consistent psychosocial screening is recommended for all youths with type 1 diabetes to identify symptoms of depression, diabetes distress, disordered eating, parental distress, and other related factors. Effective care involves an interdisciplinary diabetes health team that includes mental health providers maintaining regular contact with patients and their families.
Children with new-onset diabetes tend to be taller, particularly if the disease develops several years before puberty, possibly due to elevated growth hormone and insulin levels during the preclinical phase, but growth may slow after diabetes onset, especially before age 10 and with poor glycemic control. The pubertal growth spurt may be blunted or delayed, particularly in girls, potentially leading to reduced final height. Growth failure in adolescents with type 1 diabetes mellitus (T1DM) is now rare, likely due to improved diabetes management, and intensified insulin treatment has been shown to increase IGF-I levels and growth velocity. Growth failure may also be associated with truncal obesity, hepatomegaly from glycogen or triglyceride deposition, and sexual infantilism in the Mauriac syndrome, a condition linked to poor glycemic control and high insulin doses, though it is now uncommon.
Medical therapy for diabetes focuses on achieving normoglycemia, particularly through intensive insulin regimens such as subcutaneous injections and external insulin pumps in individuals with type 1 diabetes mellitus (T1DM), aiming for HbA1c levels below 6.05% (42 mmol/mol) to prevent complications, as studied in the Diabetes Control and Complications Trial (DCCT).
Disruption of hepatic FOxO1 helps normalize the expression of numerous dysregulated hepatic genes and can restore glucose tolerance, though it does not directly restore hepatic insulin signaling. This effect may occur through the normalization of hepatokine secretion, such as Fst, which is a key FOxO1-dependent hepatokine that promotes white adipose tissue (WAT) lipolysis during hepatic insulin resistance. FOxO1-dependent gene expression or metabolites from hepatocytes may contribute to peripheral insulin resistance by influencing the delivery of metabolic intermediates like glycerol and free fatty acids from adipose tissue to the liver.
Type 2 diabetes prevalence varies across the African continent, with urbanized areas such as North Africa reporting increasing rates, while it remains comparatively rare in sub-Saharan Africa, a region still affected by poverty and malnutrition. The International Diabetes Federation estimated that approximately 4.5% of the adult population in Africa currently has diabetes, projected to rise to 5.2% by 2045. Type 1 diabetes incidence is generally low in the region except in Eastern Africa, where rates are higher. Atypical ketosis-prone diabetes occurs in Africa, initially presenting as type 1 diabetes with severe hyperglycaemia and ketosis but later entering long-term remission with a clinical course resembling type 2 diabetes. Another form, malnutrition-related diabetes mellitus, is an early-onset diabetes linked to past or present malnutrition and sometimes associated with pancreatic calcification. While infectious diseases remain the primary cause of mortality in sub-Saharan Africa, the growing prevalence of diabetes and other non-communicable diseases is expected to surpass infections as leading causes of death.
Bolus insulin dosing varies based on weight and blood glucose levels, with specific insulin sensitivity factors and correction factors provided for different age groups. For individuals under 5 years old, the insulin sensitivity ranges from 0.6 to 0.7 units per kilogram per dose, and 0.5 units are added per 100 mg/dL above the target glucose level. For those aged 5–12 years, the sensitivity increases to 0.7–1.0 units per kilogram per dose, with 0.75 units added per 100 mg/dL above target. In the 12–18 year age group, the sensitivity is 1.0–1.2 units per kilogram per dose, and 1.0–2.0 units are added per 100 mg/dL above the target glucose level.
Monogenic diabetes, which involves mutations in a single gene affecting $\beta$ cell function, can be differentiated from type 1 and type 2 diabetes. Type 1 diabetes is characterized by autoimmune destruction of $\beta$ cells, while type 2 diabetes is associated with insulin resistance and relative insulin deficiency. Monogenic diabetes is often misdiagninated as either type 1 or type 2 diabetes, but distinguishing features such as age of onset, family history, and specific clinical characteristics can help identify it. Genetic testing is required to confirm the diagnosis of monogenic diabetes.
Autoantibodies associated with diabetes include islet cell antibodies (ICAs), islet surface antibodies (ICSAs), and complement-dependent antibody-mediated islet cell cytotoxicity, with the 64K islet protein identified as glutamic acid decarboxylase (GAD), specifically the isoform GAD65. Autoantibodies to insulin were discovered in 1983, followed by those to islet antigen-2 (IA-2), a tyrosine phosphatase-like protein, in 1994, and to the zinc transporter 8 (ZnT8) in 2007. Unlike T-cell analyses, autoantibodies to GAD65, IA-2, and ZnT8 can be measured using standardized assays.
In diabetes, the polyol pathway becomes significant due to elevated glucose levels, as this pathway converts glucose to sorbitol via aldose reductase, an enzyme present in tissues like nerve, retina, lens, glomerulus, and blood vessel walls. In these tissues, glucose uptake is not insulin-dependent, leading to increased intracellular glucose concentrations during hyperglycaemia, which in turn activates the polyol pathway. Sorbitol is subsequently oxidized to fructose by sorbitol dehydrogenase, a process that generates NADH from NAD⁺.
Offspring of mothers with diabetes have an increased risk of obesity, as observed in a study by Dabelea et al. involving Pima Indian women, where infants born after the onset of maternal diabetes were heavier than those born before. Additionally, smoking during the intrauterine period also contributes to an increased risk for overweight at age 3 years, with an odds ratio of 2.16 and a 95% confidence interval of 1.05–4.47. Despite being smaller at birth, these infants tend to catch up in weight by age 3 years.
Most acute metabolic complications occur in people with type 1 diabetes, with the SEARCH for Diabetes in Youth study in the USA reporting that 29% of individuals under 20 years old with type 1 diabetes and 10% with type 2 diabetes presented with diabetic ketoacidosis (DKA) at diagnosis. The incidence of DKA in children and adolescents with type 1 diabetes remains high, at approximately 1–12 episodes per 100 person-years.
Islet transplantation has been explored as a treatment for diabetes, with early successes in achieving insulin independence. Intraportal islet infusion and allotransplantation of pancreatic microfragments into the spleen have demonstrated the potential for insulin independence in individuals with diabetes. Initial challenges included impure islet preparations, suboptimal immunosuppression, low islet masses, and complications such as thrombosis and immune rejection. Advances in islet isolation techniques, including intraductal collagenase perfusion, gentle mechanical dissociation, and density gradient purification, improved islet purity (>90%) and enabled post-transplant normoglycaemia in dogs after a single-donor islet transplant. A case involving a 36-year-old person with type 1 diabetes showed sustained insulin independence (at least five months) following an islet graft composed of fresh and cryopreserved islets with 75% purity, allowing for high-dose transplantation (>10,000 islets/kg) without complications.
Real-time continuous glucose monitoring (RT-CGM) devices include alarms for hypoglycemia and hyperglycemia, which are important for managing glucose levels. Adjusting alarm thresholds involves trade-offs, requiring individualization based on clinical needs. Setting alarms at ideal glucose levels, such as 5 mmol/L (90 mg/dL) for lows and 10 mmol/L (180 mg/dL) for highs, increases sensitivity in detecting glucose extremes but may result in frequent false alarms. These false alarms can cause irritation, disrupt sleep, and lead to "alarm fatigue," where patients may ignore the alarms.
DNA vaccination has shown potential in preventing the progression of type 1 diabetes mellitus (T1DM) in high-risk individuals before autoimmune β-cell destruction begins. Studies in mice indicate that vaccination with a glutamic acid decarboxylase 65 (GAD65) gene construct can generate a protective humoral immune response and delay diabetes onset. Research using a preproinsulin/GAD65 (Ins-GAD) fusion construct in non-obese diabetic (NOD) mice introduced more autoantigenic epitopes, and when combined with B7-1wa, which engages CTLA-4 to promote negative signaling, it produced protective regulatory T-cells and improved disease outcomes. Both insulin and GAD65 are considered key autoantigens in T1DM, and inducing tolerance through DNA vaccination may prevent β-cell destruction.
In individuals with type 2 diabetes and overweight or obesity, the intestinal lipase inhibitor orlistat (120 mg three times daily with meals) can reduce dietary fat absorption by up to 30%, leading to an additional weight reduction of 2–3 kg and further decreases in HbA1c levels by 0.28–1.1% (3–12 mmol/mol).
Monogenic diabetes, caused by genetic mutations affecting insulin synthesis and secretion pathways, can result in young-onset diabetes with an atypical presentation. In young Chinese patients, there is a higher prevalence of a parental history of diabetes (32-47%), especially maternal history, compared to those with late-onset disease (12-19%). Some families show a progressively earlier age of onset in successive generations. These patients may display a mixed phenotype, including young age at diagnosis, insulinopenia, normal body weight similar to type 1 diabetes, and a non-ketotic state typical of type 2 diabetes, despite the absence of insulin resistance and metabolic syndrome.
A target systolic blood pressure of approximately 140 mmHg is reasonable in older people with diabetes, as maintaining systolic pressure between 130 and 140 mmHg is associated with reduced adverse cardiovascular outcomes. Tighter control to below 130 mmHg is not recommended in older individuals with diabetes due to an increased risk of adverse events, as shown in the INVEST study where stricter control did not improve cardiovascular outcomes and was linked to a nonsignificant increase in mortality. Similarly, targeting systolic pressure below 120 mmHg was not beneficial and was associated with adverse outcomes in older people with diabetes. The ONTARGET trial also found no benefit from tight blood pressure control in older individuals, including those aged over 65 years. While the SPRINT study demonstrated benefits of intensive blood pressure treatment to below 120 mmHg in older adults without diabetes, it excluded individuals with diabetes along with other conditions, indicating that such intensive treatment may not be safe or beneficial for older people with diabetes.
The data indicates varying prevalence rates of type 2 diabetes mellitus (T2DM) and impaired glucose tolerance (IGT) across different countries and populations in the Middle East during the 1990s and early 2000s, with notable differences between urban and rural areas as well as between genders. In Saudi Arabia, the prevalence of T2DM increased from 11.8% in males and 12.8% in females in 1995 to 26.2% in males and 21.5% in females in 2000. In Oman, T2DM prevalence in 2000 was 11.8% in males and 11.6% in females, while IGT or impaired fasting glucose (IFG) was higher in males (7.1%) than in females (5.1%). In Iran, urban females had a higher prevalence of IGT (14.9%) compared to urban males (8.9%) and rural populations (7.2%). In Lebanon, T2DM prevalence was 13.2% in 1998 with an IGT prevalence of 6%.
Because of the physiologic lag of interstitial glucose behind blood glucose, sensor glucose readings can show normal levels even when actual blood glucose is low, particularly during rapid declines, which has implications for hypoglycemia detection and treatment. Patients should perform a fingerstick blood glucose measurement before driving if the sensor glucose reading is normal but the trend graph or rate-of-change arrows indicate a declining glucose level. Additionally, if a patient feels hypoglycemic or suspects declining glucose despite conflicting sensor data, they should disregard the sensor reading and confirm with a fingerstick measurement.
In emergency surgery for diabetic patients, the operation is postponed until the patient's blood biochemistry, ketone bodies, and glucose levels are assessed. If abnormalities are found, corrections are made using a GIK (glucose-insulin-potassium) regime supplemented by other measures. Correcting conditions such as ketoacidosis, dehydration, and hyperkalemia takes priority over achieving a specific blood glucose level before surgery. Once these issues are addressed, the patient can undergo surgery while continuing the GIK regime, which is also maintained in the postoperative period.
The regulation of insulin secretion involves phospholipase C (PLC), which is activated by receptor agonists such as acetylcholine and cholecystokinin through the Gq protein. PLC hydrolyzes PIP2 into IP3 and DAG, with IP3 mobilizing calcium from the endoplasmic reticulum and DAG activating protein kinase C (PKC), both of which enhance insulin secretion. Nutrients can also activate PLC in a calcium-dependent manner, though the role of IP3 and DAG in nutrient-induced insulin secretion remains uncertain.
Diagnosis of glucokinase MODY is crucial in young individuals who might otherwise be misdiagnosed with type 1 diabetes and unnecessarily treated with insulin. In glucokinase MODY, hyperglycaemia remains mild, $\beta$-cell antibodies are typically negative, and fasting C-peptide remains detectable with a much smaller post-meal rise in glucose compared to type 1 diabetes. Distinguishing glucokinase MODY from type 2 diabetes can be difficult due to similarities such as mild hyperglycaemia and family history, but features like lack of obesity, absence of insulin resistance, a raised fasting glucose with only a mild post-prandial increase, $\mathrm{HbA_{1c}}$ levels between 40–60 mmol/mol (5.8–7.6%), and stable disease progression over time are indicative of glucokinase MODY.
Hypoglycaemia in diabetes can range from causing unpleasant symptoms to severe complications such as seizures and coma, and although permanent neurological damage is rare, recurrent episodes may lead to chronic cognitive impairment. Severe hypoglycaemia is particularly harmful to the developing brain, with early-onset type 1 diabetes patients experiencing cumulative effects that may result in poorer cognitive performance in adulthood. Long-term studies, such as the 32-year follow-up of the DCCT trial, show that both higher HbA1c levels and frequent severe hypoglycaemic episodes are linked to greater cognitive decline, with a dose-response relationship observed between the number of episodes and reduced psychomotor function and mental efficiency, especially in later life. Additionally, the psychological impact of fearing hypoglycaemia can hinder achieving optimal glycaemic control.
Risk factors for type 2 diabetes mellitus (T2DM) include family history, advancing age, overweight or increased waist-to-hip ratio, and a sedentary lifestyle, with morbidity increasing as the number of risk factors rises. Specific risk factors for coronary artery disease (CAD) in T2DM include lipid abnormalities such as small, dense, easily oxidized low-density lipoprotein (LDL) particles, low high-density lipoprotein (HDL) cholesterol, and elevated triglycerides, along with poor glucometabolic control indicated by high fasting plasma glucose and elevated HbA1c. Hypertension is another significant risk factor, with studies showing a link between fasting and post-load glucose levels and the subsequent risk for hypertension, independent of age, BMI, and weight gain. Patients with both diabetes and congestive heart failure (CHF) tend to have increased ischemic heart disease (IHD), higher systolic blood pressure, lower diastolic blood pressure, and elevated HbA1c compared to those without diabetes, highlighting overlapping risk factors between CHF and glucose abnormalities.
Innovations in diagnostic tests, including those integrated with mobile devices, can improve diabetes care in low- and middle-income countries (LMICs), as can mobile phone–attached devices for screening eye complications. Other promising tools include foot thermometry and mHealth applications for preventing foot ulcers, though many of these solutions are still in pilot stages and require further evidence and scalability assessment. Innovations in diabetes management also involve heat-stable insulin, self-monitoring equipment, and monitoring tools tailored to LMIC settings. Equally important is innovation in the delivery of care and ensuring equitable access to diabetes technologies, as insulin, despite being discovered 100 years ago, remains unavailable to many people who need it.
Dapagliflozin has been shown to reduce the risk of kidney outcomes, all-cause mortality, and cardiovascular mortality or hospitalization for heart failure in patients with chronic kidney disease, including those both with and without type 2 diabetes, as demonstrated in the DAPA-CKD trial.
Vanadium salts have shown potential in improving glycemic control and reducing insulin requirements in individuals with type 1 and type 2 diabetes mellitus. This effect may be due to enhanced insulin sensitivity, partly through inhibition of protein tyrosine phosphatases such as PTP-1B, and suppression of glucose 6-phosphatase. Additional mechanisms contributing to their antidiabetic activity include appetite reduction and decreased intestinal glucose absorption. To overcome challenges like poor absorption and toxicity, derivatives such as low-dose peroxovanadiums, pervanadates, and organic vanadium complexes have been explored, with intermittent dosing considered viable due to the prolonged antidiabetic effects observed after discontinuation of treatment.
In patients with type 1 or type 2 diabetes without nephropathy, protein intake up to 20% of total energy intake does not need modification, but in those with established nephropathy, protein intake should be restricted to 0.8g/kg of normal body weight per day. Dietary recommendations include restricting saturated and trans-unsaturated fatty acids and cholesterol while encouraging oils rich in monounsaturated fatty acids and oily fish containing n-3 polyunsaturated fatty acids. Moderate alcohol intake is advised, and foods rich in dietary antioxidants, trace elements, and vitamins are encouraged. Routine supplementation and special diabetic foods are not recommended. Individual dietary advice from healthcare professionals and structured nutritional training are essential components in the ongoing management and education of individuals with type 1 or type 2 diabetes.
Short sleep duration is associated with an increased risk of type 2 diabetes mellitus (T2DM), with studies showing a 57% increase in diabetes risk among women with short sleep duration over a 10-year period, and a 47% increase in diabetes incidence among individuals sleeping 5 hours or less. The mechanism linking sleep restriction to diabetes risk may involve activation of the sympathetic nervous system, decreased cerebral glucose utilization, and dysregulation of the hypothalamic-pituitary-adrenal axis along with other neuroendocrine changes.
L-783,281, a non-peptide molecule derived from a Pseudomassaria fungus, mimics the glucose-regulatory actions of insulin by activating the tyrosine kinase activity of the β-subunit of the human insulin receptor in CHO cells, leading to downstream effects such as tyrosine phosphorylation of IRS1, increased PI3K activity, and Akt phosphorylation. It interacts selectively with the β-subunit without requiring insulin binding to the α-subunit and is not an inhibitor of protein tyrosine phosphatases. At low concentrations, it elicits about half the maximum tyrosine kinase activity of insulin and induces insulin-like effects in tissues, including increased glucose uptake in rodent adipocytes and skeletal muscle. When administered orally, it lowers blood glucose in insulin-resistant obese-diabetic db/db mice, demonstrating therapeutic potential despite limitations for clinical development.
In older people with diabetes, the acute-phase response involves hypersecretion of interleukins, C-reactive protein, and TNF-∇·a→, which can reduce insulin secretion. Additionally, disturbances in gut-derived incretins, specifically gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), may contribute to β-cell dysfunction. These peptides normally enhance insulin secretion after meals and play a role in maintaining β-cell growth, proliferation, and inhibition of apoptosis. However, aging is associated with decreased levels and impaired function of these incretin peptides.
Diabetes, particularly type 1 and type 2 diabetes mellitus (T1DM and T2DM), is associated with perforating dermatoses, a skin condition predominantly affecting African-American patients on dialysis. This condition presents with pruritic hyperkeratotic papules, typically on the extensor surfaces of the lower limbs but sometimes on the trunk and face, and can develop at sites of trauma due to the Koebner or isomorphic phenomenon. Histologically, the lesions show an atrophic epidermis surrounding a plug of degenerate material made up of elastin and collagen, suggesting a disorder of keratinization where the epidermis proliferates to eliminate abnormal tissue. Microvasculopathy has also been observed in the underlying dermis of biopsy specimens, indicating a possible link with diabetes-related vascular complications. The condition is challenging to treat, though topical steroids or retinoids may help, and phototherapy can be a useful alternative when these treatments fail.
Hypoglycaemia, defined as a blood glucose level below 4.0 mmol/L (70 mg/dL), is a common consequence of efforts to maintain near-normal maternal blood glucose levels in women with diabetes. In a study of 108 women with type 1 diabetes, 45% experienced severe hypoglycaemia during pregnancy, occurring 3–5 times more frequently in early pregnancy compared to the period immediately before pregnancy. Factors predicting severe hypoglycaemia requiring external assistance include impaired hypoglycaemia awareness, a history of severe hypoglycaemia, long duration of diabetes, low HbA1c levels in early pregnancy, fluctuating glucose levels, and excessive use of supplementary insulin between meals. Impaired hypoglycaemia unawareness, which results from a diminished counter-regulatory response to low blood glucose, is more pronounced in pregnant women with diabetes and poses an additional clinical challenge.
GLP-1 (glucagon-like peptide 1) plays a key role in glucose-dependent stimulation of insulin secretion and biosynthesis, with its islet actions being glucose dependent, making it a safer treatment option compared to sulfonylureas or insulin. Additionally, GLP-1 suppresses glucagon and regulates appetite in humans, contributing to its importance in diabetes management.
Mini-dose glucagon can be used to achieve euglycaemia in cases of mild or impending hypoglycaemia, particularly when associated with conditions like nausea, vomiting, diarrhoea, or inadequate oral carbohydrate intake or absorption. It is administered subcutaneously using an insulin syringe, with a dose of 1 unit per year of age, ranging from a minimum of 2 units (~20 μg) for children under 2 years to a maximum of 15 units (~150 μg), and can be repeated every 2–4 hours.
For individuals with type 1 diabetes mellitus (T1DM), carbohydrate intake during exercise is important to manage blood glucose levels. A general recommendation is to consume approximately 15g of carbohydrate before exercise and 15–40g at 30–60 minute intervals during prolonged activity. Carbohydrate supplementation is particularly advised if pre-exercise blood glucose is below 5.6 mmol/L, though the amount needed varies between individuals and should be adjusted based on blood glucose monitoring. Some may not require supplementation, while others may need larger amounts, especially during strenuous activity, where part of the intake can come from a sucrose-containing beverage. When exercise occurs after a meal, less carbohydrate is typically needed, but larger snacks may be required if several hours have passed since the last meal. The risk of hypoglycemia decreases as the time since the last insulin injection increases.
In patients with type 1 diabetes mellitus (T1DM), treatment with the ACE inhibitor ramipril or the ARB losartan for 3 weeks has been shown to improve endothelial dysfunction, potentially mediated by increased bradykinin levels with ACE inhibition or increased levels of angiotensin 1-7 (AT 1-7) with ARB use.
There are no evidence-based treatments or comprehensive protocols that lead to sustained improvements in glycaemia and diabetes-related outcomes in people with type 1 diabetes and eating disorders, so current advice is based on existing guidelines for diabetes or eating disorders with some integrated, pragmatic approaches. For instance, NICE guidance for eating disorders includes principles for managing diabetes, and NICE guidance for type 1 diabetes highlights the need for healthcare professionals to be alert to bulimia nervosa, anorexia nervosa, and insulin dose manipulation in adults with concerns about body shape, low BMI, hypoglycaemia, and poor glucose control. A key strategy involves a multidisciplinary and multiprofessional team approach integrating physical and mental health aspects of both conditions, with ongoing clinical research and quality improvement projects in the UK focusing on this integrated care model, including step-wise re-insulinization, psychotherapy, and close monitoring.
Thiazolidinediones (TZDs) increase the production and circulation of adiponectin, a hormone released by fat cells that enhances AMPK activity in the liver, adipose tissue, and skeletal muscle. Reduced adiponectin levels are associated with type 2 diabetes mellitus (T2DM) and may play a role in promoting insulin resistance and elevated blood glucose levels. The improvement in insulin sensitivity and favorable lipid effects seen with TZDs may be attributed to both adiponectin stimulation and direct AMPK activation. Additionally, low adiponectin levels may serve as a predictor of response to TZD therapy, while genetic variations in the PPAR-γ gene might account for differences in treatment effectiveness and diabetes progression.
Skin infections, particularly those caused by Staphylococcus aureus, are more common in individuals with diabetes, especially when diabetes is poorly controlled. Severe otitis externa, a serious infection caused by Pseudomonas spp., occurs in elderly patients with diabetes and can progress to cellulitis, osteomyelitis, meningitis, and cerebritis, carrying a high mortality risk.
Insulin is synthesized in pancreatic β cells as proinsulin and processed by PCSK1 to form the bioactive A- and B-chains, and its structure includes three α-helices with specific residues involved in dimerization and hexamer formation in the presence of zinc. The insulin receptor binds insulin through two asymmetrical sites, the primary site (S1) and the secondary site (S2), each involving distinct residues from the A- and B-chains, with S1 having high-affinity binding and S2 binding at high insulin concentrations with lower affinity.
Hypoglycaemia can lead to a reduced sympathoadrenal and glucagon response to subsequent episodes in both type 1 and type 2 diabetes, impairing an individual's ability to perceive hypoglycaemia symptoms. The degree, duration, and frequency of hypoglycaemia contribute to the extent of this diminished response. Over time, people with long-standing insulin-treated diabetes may experience a progressive impairment in these counter-regulatory responses, though it is not entirely clear if this is solely due to repeated hypoglycaemia. Clinically, many individuals with longstanding diabetes have difficulty recognizing hypoglycaemia symptoms, a condition now referred to as impaired awareness of hypoglycaemia rather than hypoglycaemia unawareness, as absolute unawareness is rare.
Thiazolidinediones, a class of medications used in diabetes management, have raised concerns due to their cardiovascular effects, including edema, reduced hemoglobin levels, and congestive heart disease. Rosiglitazone, a member of this class, has been associated with an increased risk of myocardial infarction during the initial treatment period according to a meta-analysis, though this risk has not been confirmed by large treatment databases or long-term prospective studies. In contrast, pioglitazone has demonstrated a reduction in long-term vascular events in a large prospective study.
Diabetes management involves various drug classes that lower blood glucose through distinct mechanisms. Biguanides like metformin counter insulin resistance, particularly by decreasing hepatic glucose output, and enhance insulin-dependent and -independent actions involving AMPK, mitochondrial respiratory chain, and insulin receptor signaling. Sulfonylureas such as glibenclamide stimulate insulin secretion for 6–24 hours by binding to SUR1 receptors on pancreatic β cells, closing ATP-sensitive potassium channels. Meglitinides like repaglinide also stimulate insulin secretion but with faster onset and shorter duration, acting on the benzamido site of SUR1 receptors. DPP-4 inhibitors (e.g., sitagliptin) increase prandial insulin secretion by inhibiting the DPP-4 enzyme, thereby prolonging the action of incretins like GLP-1. Thiazolidinediones (e.g., pioglitazone) improve insulin sensitivity, especially in peripheral tissues, by activating PPAR-γ receptors in adipose tissue. SGLT-2 inhibitors such as empagliflozin increase glucose excretion in urine by blocking renal glucose reabsorption via SGLT-2 transporters. α-Glucosidase inhibitors (e.g., acarbose) slow carbohydrate digestion by competitively inhibiting intestinal α-glucosidase enzymes. Dopamine agonists like bromocriptine reduce hepatic glucose production through central dopaminergic effects. GLP-1 receptor agonists (e.g., semaglutide) enhance insulin secretion, reduce glucagon secretion, delay gastric emptying, and promote satiety through central mechanisms by activating GLP-1 receptors in the pancreas, gastrointestinal tract, and brain.
Somatostatinomas cause diabetes due to the dual inhibition of insulin and glucagon secretion, resulting in mild, non-ketotic hyperglycaemia in most cases, although some individuals may present with hypoglycaemia instead. Insulin treatment is rarely required in these patients.
The progression from multiple autoantibodies without dysglycaemia (stage 1) to clinical onset of type 1 diabetes (stage 3) is influenced by the number of islet autoantibodies, with higher levels of IAA and IA-2A increasing the risk for progression, particularly in children with persistent autoantibodies. Risk scores have been developed to predict the time to stage 3 among individuals with multiple islet autoantibodies. Islet autoantibodies serve as biomarkers for stages 1 and 2 of type 1 diabetes but should be combined with β-cell function tests such as glucose tolerance tests or continuous glucose monitoring. Glycated haemoglobin (HbA1c) is a specific but not sensitive early indicator of stage 3 type 1 diabetes, particularly when diagnosed by glucose tolerance tests or asymptomatic hyperglycaemia. Additional biomarkers such as C-peptide and plasma glucose are needed to improve prediction of clinical onset in order to implement timely interventions that may halt disease progression at stage 1 or 2.
Erectile dysfunction is prevalent among men with diabetes, with studies indicating that a significant percentage experience erectile problems, which are often linked to depressive symptoms, anxiety, and reduced quality of life. In men with type 2 diabetes, erectile dysfunction has been associated with a dramatic increase in depressive symptoms, while nearly half of those with diabetes report constant thoughts about their condition, and a substantial proportion feel it severely impacts their quality of life and relationships. A study of men with diabetes, mostly type 1, found that two-thirds had erectile dysfunction, and almost half had not sought help, with many also experiencing high rates of depressive symptoms, anxiety, and relationship difficulties. Treating erectile dysfunction has been shown to improve self-esteem, confidence, and depression scores.
SGLT-2 inhibitors can weakly suppress SGLT-1 transporter activity, which is involved in glucose absorption in the intestine and accounts for approximately 10% of glucose reabsorption in the renal proximal tubules. Canagliflozin may delay intestinal glucose absorption by interacting with SGLT-1, though it is unclear if it reaches sufficient concentrations in the kidney to inhibit SGLT-1 there. Sotagliflozin, a more potent inhibitor of both SGLT-1 and SGLT-2, is being studied for its effects in individuals with type 2 diabetes.
Microalbuminuria screening should be conducted annually in children with diabetes who have reached puberty or are at least 10 years old, whichever comes first, and who have had diabetes for more than five years. If initial results are borderline or rising, more frequent testing is advised, and abnormal findings should be confirmed by repeating the test. A diagnosis of microalbuminuria requires two out of three abnormal urine samples collected over 3–6 months. Once confirmed, non-diabetic causes of kidney disease must be ruled out, and treatment initiated, typically with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), even in the presence of normal blood pressure. Persistent microalbuminuria increases the risk of end-stage renal disease and macrovascular complications. In females of reproductive age, the teratogenic risks of ACE inhibitors and ARBs necessitate counselling and appropriate contraceptive measures. Effective glycaemic control and smoking cessation are emphasized for children and their families. While ARBs are not approved for paediatric use, they may be used off-label in certain cases.
Thiazolidinediones, such as rosiglitazone and pioglitazone, require monitoring of liver function through serum alanine aminotransferase (ALT) levels before and during therapy due to the risk of hepatotoxicity associated with this class of drugs, as seen with troglitazone. Pre-existing liver disease, clinical hepatic dysfunction, or ALT levels exceeding 2.5 times the upper limit of normal are contraindications for thiazolidinedione use. Despite these risks, recent studies suggest that thiazolidinediones may be beneficial in treating non-alcoholic steatohepatitis due to their ability to reduce hepatic fat.
Average hourly insulin dose is calculated by totaling the last 6 hours' doses and dividing by 6, with the result multiplied by 20 to estimate the total daily dose (TDD) of insulin. For a basal:bolus regimen, the TDD is split 50:50 between basal and bolus insulin, with the basal portion typically administered as a long-acting insulin like Lantus, and the bolus portion divided into three mealtime doses using short-acting insulin such as Novorapid. In a twice daily fixed mixture regimen, insulin is administered as a 60:40 ratio in the morning and evening, using premixed insulins like Humalog Mix 25 or Novomix 30.
DPP-4 inhibitors are weight neutral, while GLP-1 mimetics like exenatide lead to significant weight loss in many patients.
Intensive glycaemic management can prevent or delay the progression of neuropathy in people with type 1 diabetes, as shown by several landmark studies. A decrease in HbA1c levels is linked to a reduced incidence of diabetic sensorimotor polyneuropathy, with a 20% decrease in incidence reported for a 2% (22 mmol/mol) reduction in HbA1c over four years. The DCCT demonstrated a 64% risk reduction for incident diabetic sensorimotor polyneuropathy with intensive glucose management over 6.5 years. The EDIC study highlighted the concept of metabolic memory, showing that despite similar HbA1c levels (8.1% vs. 8.2%, or 65 vs. 67 mmol/mol) five years after the DCCT, individuals who received intensive therapy had significantly lower prevalence and incidence of diabetic sensorimotor polyneuropathy and cardiac autonomic neuropathy compared to those on standard therapy. Factors such as HbA1c, smoking status, and high-density lipoprotein cholesterol are associated with the development of neuropathy.
Type 1 diabetes has historically shown higher incidence rates in populations of European origin compared to non-European populations. In South America, standardized registry data indicate lower incidence rates than among Latino people in the USA and Spaniards in Spain. In the USA, from 2002 to 2015, white youths had the highest incidence (25–27 per 100,000 per year), while Black and Hispanic youths had similar rates (15–17 per 100,000 per year by 2010), with Black youths showing a sharper increase to nearly 20 per 100,000 in 2015. Asian Pacific Islanders and American Indian youths had much lower incidence rates (approximately 5–10 per 100,000 per year). Some studies suggest that ethnic differences in incidence within the USA may be less pronounced in certain regions or groups, potentially due to admixture with European ancestry diluting distinctions between ethnicities.
The American Diabetes Prevention Program involved 3234 individuals with impaired glucose tolerance who were assigned to placebo, metformin, or a lifestyle-modification program. The lifestyle intervention included 16 lessons during the first 24 weeks, focusing on diet, exercise, and behavior modification, delivered individually, along with at least two supervised exercise sessions per week and monthly contact with study personnel afterward. The cumulative incidence of type 2 diabetes was 11.0 per 100 person-years in the placebo group, 7.8 per 100 person-years in the metformin group, and 4.8 per 100 person-years in the lifestyle group. The risk of type 2 diabetes was 58% lower in the lifestyle group compared to the placebo group and 39% lower compared to the metformin group.
Urban areas in India have consistently shown higher prevalence rates of diabetes compared to rural areas, with studies indicating a progressive increase in diabetes prevalence with greater urbanization. For example, in Chennai, diabetes prevalence was reported as 2.4% in rural areas, 5.9% in semiurban areas, and 11.6% in urban areas, while more recent data showed 18.6% in urban Chennai, 16.4% in towns, and 9.2% in peri-urban villages. A nationwide study across 77 centers found the standardized prevalence of diabetes to be 5.9% in urban populations and 2.7% in rural populations. Although urban areas continue to have higher rates of diabetes and impaired glucose tolerance (IGT) than rural areas, the difference between urban and rural prevalence appears to be decreasing over time.
Metformin should be omitted on the day of a procedure and for the following 48 hours if contrast medium is used and the estimated glomerular filtration rate (eGFR) is less than 60 ml/min/1.73 m². In cases where there is likely to be a reduction in oral intake prior to a procedure, such as before a colonoscopy, metformin should be omitted starting on the day of the reduced intake, which may include the day prior to and the day of the procedure. Additionally, SGLT2 inhibitors should be stopped 72 hours prior to a planned procedure according to US and other guidelines.
Continuous glucose monitoring (CGM) devices are important for improving glycaemia, though more research is needed to identify barriers to their effective use. In adults with type 2 diabetes not using insulin, the value of blood glucose monitoring is debated, as some studies show little clinical benefit, likely due to variability in study design and implementation, including education, frequency, and follow-up actions. Simply monitoring blood glucose without using the data to adjust medications has limited impact on long-term glycaemia, but individuals who are motivated to monitor can derive considerable personal benefit. A structured approach to blood glucose monitoring in adults with non-insulin-treated type 2 diabetes has shown clinical benefits, including reduced HbA1c levels, particularly among those adhering to the monitoring protocol, as well as improved emotional well-being and confidence in diabetes self-care.
Cognitive effects in individuals with type 2 diabetes mellitus (T2DM) are comparable to those seen in younger adults with type 1 diabetes mellitus (T1DM), particularly in domains such as information processing speed, memory, and attention and executive function. Research has shown that poorer metabolic control, indicated by higher HbA1c levels, is the strongest predictor of worse cognitive performance, while the duration of diabetes and severity of peripheral neuropathy do not appear to correlate with cognitive outcomes. Elevated HbA1c levels have been linked to declines in psychomotor speed, memory, and executive function, highlighting the impact of glycemic control on cognitive health in diabetic individuals.
Thiazolidinediones act as PPARγ agonists in adipocytes, binding to the nuclear PPARγ receptor which forms a heterodimer with RXR. This binding leads to the release of repressors, recruitment of co-activators, and activation of the receptor complex, enabling it to bind to the PPRE DNA sequence and initiate mRNA transcription for genes involved in glucose and lipid metabolism. These genes include those encoding FATP, aP2, acyl-CoA synthase, lipoprotein lipase, and GLUT4, all contributing to the biological effects of thiazolidinediones, which are relevant to diabetes treatment. Additionally, activation of PPARγ by these compounds also induces expression of proteins with anti-inflammatory and vascular effects, further supporting their therapeutic role in diabetes.
The ADA recommends screening for cardiac autonomic neuropathy at diagnosis in type 2 diabetes and after five years in type 1 diabetes, particularly in those with microvascular complications or hypoglycaemia unawareness. Cardiac autonomic neuropathy can present with symptoms and signs listed in Table 45.4, though symptoms often weakly correlate with autonomic deficits. It may initially be asymptomatic, manifesting only as reduced heart rate variability during deep breathing, potentially progressing to resting tachycardia (>100 bpm). In cases of resting tachycardia and a history of poor glucose control, where cardiac autonomic neuropathy is highly suspected, no further testing is advised. Other conditions such as idiopathic orthostatic hypotension, syncope, and postural orthostatic tachycardia syndrome should be ruled out.
Type 1 diabetes risk in offspring is 2–4% if the mother is affected and 5–8% if the father is affected, with a sibling relative risk of 15. Concordance in monozygotic twins is approximately 40%, varying with age of diagnosis, and the age at diagnosis is highly correlated in identical twins (RR = 0.94) compared to non-identical twins (RR = 0.59). The condition arises from the interaction of genetic, epigenetic, and environmental factors, with over 200 genetic loci identified, explaining about 80% of heritability. Environmental factors linked to type 1 diabetes include enterovirus infections, particularly from the picorna family, which occur more frequently in individuals with new-onset type 1 diabetes and precede autoantibody development, as well as environmental pollutants, variations in gut flora, and vitamin D exposure.
Individuals with diabetes are categorized into risk groups based on their health status and potential complications during fasting. Those in the very high-risk category may have a history of severe hypoglycaemia, diabetic ketoacidosis, or hyperosmolar hyperglycaemic coma within the past three months, suboptimally managed type 1 diabetes, acute illness, pregnancy in pre-existing diabetes or gestational diabetes treated with insulin or sulfonylureas, chronic dialysis, advanced kidney disease, or significant macrovascular complications. People in this category should receive structured education, be monitored by a diabetes team, regularly check blood glucose, adjust medications as needed, and be ready to break or stop fasting if necessary. High-risk individuals may include older adults, those with sustained hyperglycaemia, optimally managed type 1 or type 2 diabetes on certain treatments, pregnant women with gestational diabetes managed by diet or metformin, and those with stable macrovascular issues or other comorbidities. These individuals should also receive education, monitor blood glucose, and adjust medication as advised.
Hepatic insulin sensitivity decreases during sleep and increases upon waking, aligning with the circadian rhythm, and a subset of GABA-producing neurons in the suprachiasmatic nucleus has been identified as underlying this variation. Normal glucose tolerance relies on the proper coupling of insulin secretion to insulin sensitivity, and it remains to be determined whether the brain governs adaptive β-cell responses to daily changes in insulin sensitivity, which could extend existing knowledge on how the brain influences insulin secretion and sensitivity during conditions like cold exposure.
Lack of insulin leads to diabetic ketoacidosis (DKA), and insulin treatment is essential. In adults, insulin therapy can be administered via infusion at a rate of $0.1\mathrm{IU / kg}$ body weight per hour or 6 units per hour. A bolus of $0.15\mathrm{IU / kg}$ body weight (or 10 IU) of regular insulin may be given initially, though it is not strictly necessary since rehydration contributes significantly to initial metabolic improvement. Alternatively, a $0.15\mathrm{IU / kg}$ (or 10 IU) bolus can be administered every hour, or a 20-unit intramuscular bolus followed by 6 units every hour. Dosage adjustments are made based on insulin sensitivity or resistance, with increased doses for resistance and decreased doses for sensitivity. Due to the short half-life of intravenous insulin, it must be given at least every hour regardless of blood glucose levels.
Insulin deficiency along with elevated counter-regulatory hormones causes the release of free fatty acids and glycerol from adipose tissue, leading to increased ketone body production in the liver, including acetone, acetoacetate, and beta-hydroxybutyrate. Acetone contributes to the characteristic fruity or pear-like breath odor in diabetic ketoacidosis (DKA), while the acidic ketone bodies acetoacetate and beta-hydroxybutyrate accumulate, resulting in metabolic acidosis, decreased serum bicarbonate, and a high anion gap. The severity of DKA is determined by the extent of acidosis and associated mental status changes, with severe and prolonged acidosis potentially causing irreversible damage, coma, or death.
Mature exocrine cells of the pancreas can be reprogrammed in vivo into β-like cells using three transcription factors, and these induced cells closely resemble natural islet β-cells in structure, molecular profile, and function; however, challenges remain for clinical application, including the inability of induced β-cells to organize into islets, the need for safer reagents to deliver reprogramming factors, and the difficulty of pancreatic biopsies, which suggests that reprogramming in vivo or using more accessible cell types like liver cells or skin fibroblasts may be more feasible for generating β-cells.
The generation of functional β cells from human embryonic stem cells, adult stem cells, or through lineage reprogramming offers potential for treating diabetes, but several challenges must be addressed before clinical application. Immune rejection remains a major concern, although immunosuppressive strategies and the use of patient-specific induced pluripotent stem (iPS) cells may help overcome this issue. Additionally, the risk of neoplasia must be eliminated by ensuring that derived cells are not transformed and are free from undifferentiated cells that could form teratomas. The presence of pathogens, especially those associated with xenotransplantation due to the use of murine feeder cells, must also be ruled out. Long-term stability and functionality of transplanted β cells, as well as the inclusion of pancreatic stem cells for sustained regeneration, are essential for successful cell-based therapies in diabetes.
As children with diabetes grow into adolescence, parental involvement in diabetes management typically decreases, often leading to worsening glycemic control. Parents remain crucial in providing regular meals and managing hypoglycemia, especially at night. Moving away from home can create challenges for individuals with T1DM, particularly when living alone or relocating, due to potential social isolation, increased access to alcohol and recreational drugs, new sexual health considerations, and unfamiliar exercise opportunities. Additionally, separation from familiar healthcare support during this transition can limit immediate access to diabetes-related medical advice when it is most needed. Notably, "living alone" has been linked to a more than fourfold increased risk of mortality from acute metabolic complications in individuals with diabetes.
MODY (Maturity-Onset Diabetes of the Young) is frequently caused by mutations in the HNF1A gene, which account for up to 70% of cases, with nearly 200 different mutations identified. The HNF4A gene is the next most common cause, responsible for approximately 3% of MODY cases.
Various microRNAs (miRNAs) regulate insulin signaling components in different tissues during metabolic stress, with several showing increased expression in mouse liver under high-fat diet conditions, correlating with reduced insulin receptor expression; miR-222 suppresses IRS1 in liver and adipose tissue during high-fat and sucrose feeding, while resistin upregulates miR-145 to inhibit IRS1 levels; miR-29a and miR-29c reduce IRS1 expression in muscle tissue of individuals with type 2 diabetes or in high-fat diet-fed mice; IRS1 downregulation by miR-126 in mouse endothelial cells disrupts angiogenesis; additionally, chronic angiotensin-II-induced hypertension elevates miR-487b in rat aorta, suppressing IRS1 and contributing to cardiovascular disease and aortic aneurysm formation.
Insulin stimulates muscle glycogen synthesis, which accounts for approximately 90% of whole-body glucose disposal and nearly all non-oxidative glucose disposal in healthy individuals. Incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) enhance glucose-induced insulin secretion from β-cells when glucose levels exceed 4–5 mmol/l and also suppress glucagon secretion in a glucose-dependent manner. The gastrointestinal microbiome, composed of over 1000 bacterial species, influences glucose metabolism through mechanisms that are not yet fully understood. The brain coordinates glucose regulation by integrating responses from the pancreas, liver, and other tissues. Additionally, the kidney contributes to glucose homeostasis by reabsorbing glucose from the renal tubules after glomerular filtration and possesses gluconeogenic enzyme activity, making it a significant contributor to gluconeogenesis alongside the liver.
Dietary management for diabetes emphasizes limiting saturated fatty acids and trans-fats by choosing smaller portions of fatty meats, sausages, cheese, spreads, and fatty baked goods, while preferring lower fat alternatives. Vegetable oils such as olive, rapeseed, and soybean oil, along with nuts and seeds, are recommended for better fat quality. Oily fish should be consumed 2–3 times weekly, and the diet should include ample dietary fiber and micronutrients through five daily servings of fruits and vegetables, legumes, and whole grains. Sugar is not prohibited but should be consumed in moderation, with non-caloric sweeteners being a safe alternative when used within daily limits. Alcohol intake should be moderate, limited to 1–2 small glasses of wine or beer, with caution against consumption on an empty stomach due to hypoglycemia risk. Special dietetic foods are unnecessary, as people with diabetes can follow regular diets tailored to individual therapeutic needs, personal preferences, and cultural considerations.
Poor sleep quality and insomnia symptoms in adults with type 2 diabetes are associated with suboptimal diabetes self-care behaviours, including less healthy diets, deviations from meal plans, and difficulties with exercise and medication adherence, with studies showing significant correlations and effect sizes. Disruptions in sleep continuity, such as frequent nighttime awakenings, along with fatigue and daytime sleepiness, may impair self-regulatory capacities, leading to poorer diabetes self-management.
Somatostatin (SST) is expressed by islet δ-cells and inhibits insulin and glucagon secretion through activation of SSTR5 and SSTR2, respectively, playing a role in the regulation of glucose homeostasis. SST-14, generated in islets and the central nervous system, and SST-28, the major circulating form in humans produced in the gastrointestinal tract, both act via inhibitory G-protein-coupled receptors that reduce adenylate cyclase activity and cyclic AMP formation, leading to β-cell membrane hyperpolarization and decreased intracellular calcium levels.
Hospital diabetes clinics originated from the need to supervise insulin treatment and gradually included many non-insulin-treated individuals, increasing clinic workloads over time. As primary care now manages most diabetes cases, specialists focus on acutely ill patients, such as those with diabetic ketoacidosis, acute myocardial infarction, or those in intensive care and renal wards requiring precise insulin management. Specialists also manage individuals with type 1 or type 2 diabetes on complex insulin regimens, including high-dose insulin or combinations with newer therapies. Many diabetes specialists work in hospitals, providing leadership for multidisciplinary teams and supporting community diabetes services through education and coordination. In some regions, community-based diabetes consultants have been employed to organize and deliver diabetes care outside hospitals.
Insulin therapy can restore fat and muscle mass in individuals with diabetes who are newly diagnosed or suboptimally treated, but it may also cause excessive weight gain, which is a significant concern, especially for those with type 2 diabetes and existing overweight who require insulin due to failure of oral anti-diabetes agents. Weight gain is also a growing issue in type 1 diabetes, limiting the adoption of intensive insulin therapy. This weight gain can be mitigated through personalized insulin regimens that align insulin delivery with mealtime needs, along with dietary guidance. However, overly aggressive insulin adjustments that result in low blood glucose can increase appetite and contribute to weight gain. Managing diabetes becomes particularly challenging in some individuals, especially young women, when insulin doses are intentionally reduced to control body weight, leading to suboptimal glycemic control.
β-cells respond to various signals such as hormones, neurotransmitters, and neuropeptides, which influence insulin secretion in relation to circulating nutrients, and complex interactions between islet cells, the autonomic nervous system, and gastrointestinal incretin hormones help regulate the balance between metabolic fuel intake, usage, and storage.
Most children with type 1 diabetes who experience severe hypoglycaemia typically have isolated events, though some may have recurrent episodes, with the risk of recurrence increasing after a severe episode, potentially lasting up to four years. Recurrent hypoglycaemia requires evaluation for impaired awareness of hypoglycaemia and possible coexisting autoimmune disorders such as subclinical hypothyroidism, coeliac disease, and Addison's disease. Unexplained hypoglycaemia, especially in adolescence, may be factitious, often indicating psychological distress.
In patients with type 2 diabetes mellitus (T2DM), the normal post-meal suppression of endogenous glucose production is incomplete due to hepatic insulin resistance, deficient insulin secretion, and excessive glucagon secretion. Hepatic insulin resistance, which is linked to increased liver fat content, results in a reduced ability of insulin to decrease hepatic glucose production. This defect contributes to sustained postprandial hyperglycemia. Although glucose utilization in skeletal muscle and the brain remains similar to normal conditions due to the compensatory effect of hyperglycemia itself, the liver's inability to fully suppress glucose production after meals is the primary cause of elevated blood glucose levels in T2DM.
Stress-induced intestinal barrier disruption may play a role in the development and/or course of type 1 diabetes, along with other autoimmune diseases. Population-based studies suggest an association between type 1 diabetes and negative life events early in life, including life events requiring difficult adaptation, child behavioral deviances, and chaotic family functioning. In the ABIS study, childhood experiences of serious life events were linked to a higher risk of developing type 1 diabetes (hazard ratio [HR] 3.0; 95% confidence interval [CI] 1.6 to 5.6). Additionally, a nationwide Danish study showed that a higher number of childhood adversities had a small but significant effect on increasing the risk of type 1 diabetes in women (adjusted HR per adversity increase: 1.07), but not in men (adjusted HR per adversity increase: 0.99). However, these observational findings must be interpreted cautiously due to potential methodological issues such as selection bias, recall bias, residual confounding, and multiple testing errors.
New antidiabetes drugs require a dedicated cardiovascular outcomes trial for regulatory approval, a policy change influenced by concerns over muraglitazar and triggered by findings from a meta-analysis showing that rosiglitazone increased the risk of myocardial infarction compared to placebo and other diabetes treatments. Subsequent cardiovascular outcomes trials have primarily focused on DPP-4 inhibitors, GLP-1RAs, and SGLT-2 inhibitors.
Epinephrine impairs glucose utilization in muscle through direct $\beta_{2}$-adrenergic effects and is more potent than norepinephrine in producing hyperglycaemia due to its higher affinity for $\beta_{2}$-receptors. Hepatic gluconeogenesis, fueled by precursors such as lactate, alanine, and glycerol, is partly generated by $\beta_{2}$-adrenergic stimulation of muscle and adipose tissue lipolysis, with lipolysis also stimulated via $\beta_{1}$- and $\beta_{3}$-adrenoceptors. Activation of epinephrine release plays a key role in correcting hypoglycaemia, following inhibition of insulin and increased glucagon secretion, as part of the counter-regulatory responses.
Eruptive xanthomas can occur at the initial presentation of type 1 diabetes when there is insulinopaenia, as insulin is a stimulatory factor for lipoprotein lipase, and its absence leads to impaired clearance of very low-density lipoproteins and chylomicrons. Correcting hypertriglyceridaemia through lipid-lowering drugs, dietary modification, or improved glycaemic levels results in slow regression of the lesions over months.
Islet transplantation is considered for patients with type 1 diabetes who experience recurrent severe hypoglycemia or have poor glycemic control despite optimal medical therapy, and it may also be indicated for those with severe complications related to diabetes such as nephropathy or retinopathy; however, contraindications include active infections, cancer, and significant organ dysfunction that would increase the risk of the procedure or immunosuppressive therapy.
Glycaemic management in people with HbA1c ≥9% (75 mmol/mol) is cost-saving across all regions and has the highest feasibility and priority for implementation. Blood pressure control in people with pressure >160/95 mmHg and footcare for those at high risk of ulcers are also cost-saving and highly prioritized. Lifestyle interventions for preventing type 2 diabetes have varying costs per QALY across regions and a moderate feasibility and priority. Influenza vaccinations, annual eye examinations, smoking cessation, and ACE inhibitor use for people with diabetes have increasing costs per QALY and moderate to high feasibility. Metformin intervention for preventing type 2 diabetes, cholesterol management for those with total cholesterol >200 mg/dl (5.2 mmol/l), intensive glycaemic management for HbA1c ≥8% (64 mmol/mol), screening for undiagnosed diabetes, and annual screening for microalbuminuria have higher costs per QALY and lower implementation priority, though some interventions have higher feasibility.
GLP-1 receptors are present in the heart, and recent studies in mice lacking the GLP-1 receptor suggest a physiological role for these receptors.
Urinary tract infections are more common in individuals with diabetes, with asymptomatic bacteriuria occurring at a prevalence rate of 26% in women with diabetes compared to 6% in those without diabetes. Postmenopausal women with diabetes on insulin therapy also show increased asymptomatic vaginal E. coli colonization, potentially due to enhanced bacterial adherence to uroepithelial cells, impaired cytokine secretion, or reduced inflammatory response. Despite this higher prevalence, antibiotic treatment for asymptomatic bacteriuria in people with diabetes has shown no benefit in preventing symptomatic UTIs, pyelonephritis, or hospitalizations, leading to the conclusion that routine screening or treatment for asymptomatic bacteriuria is not warranted in diabetes, although this remains a topic of debate.
Hyperglycemia associated with volume depletion can lead to persistent refractory hyperglycemia and metabolic deterioration in individuals with diabetes. Recurring fasting hyperglycemia greater than 300 mg/dL that does not respond to outpatient therapy indicates significant metabolic instability. Severe hypoglycemia, defined as blood glucose levels below 50 mg/dL, can occur repeatedly despite interventions. Fluctuations between hypoglycemia and fasting hyperglycemia highlight unstable glucose control. Additionally, recurring diabetic ketoacidosis in the absence of infection or trauma suggests underlying metabolic dysregulation associated with diabetes.
DPP-4 inhibitors were the first anti-diabetes medications assessed in cardiovascular outcome trials mandated by drug regulators. These trials involved individuals with high cardiovascular risk and demonstrated that DPP-4 inhibitors do not elevate the risk of major cardiovascular events such as non-fatal myocardial infarction, stroke, or cardiovascular death. However, treatment with saxagliptin, a DPP-4 inhibitor, was associated with an increased risk of hospitalization due to worsening heart failure.
Insulin exerts both pro- and anti-atherogenic effects, and pathway-specific insulin resistance may contribute to the proatherogenic effects by impairing antiproliferative and antithrombogenic signaling via phosphatidylinositol-3-kinase (PI3K), leading to reduced nitric oxide (NO) production, which normally decreases oxLDL and vascular smooth muscle cell (VSMC) proliferation. In contrast, VSMC proliferation and migration are mediated through the Ras/Raf/MEKK/MAPK pathway, which is further activated in hyperinsulinemia. Additionally, IL-6 decreases insulin-stimulated NO production in endothelial cells by enhancing TNF-α production, while paradoxically increasing insulin-stimulated glucose uptake in skeletal muscle and adipose tissue without increasing TNF-α expression in these tissues.
Reduced insulin signaling during fasting or insulin resistance leads to increased nuclear FOXO1 activity in the liver, where it promotes hepatic glucose production by upregulating genes such as glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1). FOXO1 also increases follistatin (Fst), which contributes to white adipose tissue insulin resistance and lipolysis, providing substrates for hepatic glucose production. In muscle, nuclear FOXO1 promotes autophagy and protein breakdown, supporting liver glucose production and contributing to muscle mass loss and elevated blood glucose levels in chronic insulin resistance. In the liver, FOXO proteins regulate numerous genes involved in glucose and lipid homeostasis and systemic insulin sensitivity. Under severe starvation, FOXO1-mediated expression of insulin-like growth factor binding protein 1 (IGFBP-1) reduces IGF-I bioavailability, which may further impact metabolic regulation.
Insulin binding to its receptor relieves the inhibition of the receptor's catalytic activity, which is initially blocked by interactions between Tyr984 in the juxtamembrane domain and a hydrophobic pocket formed by an α-helix (αC) and a five-stranded β-sheet in the N-terminal lobe of the receptor tyrosine kinase. This inhibition prevents the α-helix from adopting its active position and suppresses transphosphorylation of adjacent receptor tyrosine kinases. Upon insulin binding, the ectodomains converge, facilitating transphosphorylation in the A-loop, which leads to multisite phosphorylation that lifts multiple inhibitory mechanisms, enabling the receptor to activate downstream signaling pathways critical for glucose metabolism.
In Europe and North America, 1 in 300 children develops diabetes by the age of 20 years, with an estimated 700,000 children affected worldwide and 100,000 new cases diagnosed annually. Diabetes is a heterogeneous disease, and its causes vary by age group: newborns and infants rarely develop diabetes, typically due to monogenic causes rather than autoimmune factors, while from 9 months to 10 years of age, diabetes is almost exclusively caused by islet autoimmunity. Type 1a (autoimmune) diabetes mellitus accounts for over 90% of cases in older children of European ancestry, but in other ethnic groups, 20–70% may have type 2 diabetes mellitus. The rising prevalence of obesity has led to a significant number of children with type 1a diabetes presenting with a phenotype resembling type 2 diabetes, and diagnosis can be supported by measuring autoantibodies to insulin, GAD65, IA-2, and ZnT8.
Gestational diabetes mellitus (GDM) is defined by the American Diabetes Association (ADA) as carbohydrate intolerance of varying severity with onset or first recognition during pregnancy, regardless of whether insulin is used for treatment or if the condition persists after pregnancy. Screening for GDM is universally recommended after 24 weeks’ gestation using a 100 g oral glucose tolerance test (OGTT), often preceded by a 50 g glucose challenge test, with diagnostic criteria based on the Carpenter and Coustan modification of the O’Sullivan and Mahan criteria. It has been increasingly recognized that GDM may include women who had previously undiagnosed diabetes before pregnancy.
The text provides data on various anti-diabetes agents and their cardiovascular outcomes from multiple clinical trials. Pioglitazone, a thiazolidinedione, is associated with a reduced risk of major adverse cardiovascular events in the PROACTIVE study but shows an increased risk of hospitalization for heart failure. DPP-4 inhibitors, including Alogliptin, Liragliptin, Saxagliptin, and Sitagliptin, demonstrate neutral effects on major adverse cardiovascular events in some studies, while Saxagliptin is linked to a higher risk of heart failure hospitalization. GLP-1 receptor agonists such as Dulaglutide, Exenatide LAR, Liraglutide, and semaglutide show cardiovascular benefits, particularly in reducing major adverse events and all-cause mortality in certain trials. SGLT-2 inhibitors, including Canagliflozin, Dapagliflozin, Empagliflozin, and Ertugliflozin, are associated with reduced cardiovascular events and hospitalization for heart failure, with Empagliflozin showing a significant decrease in all-cause mortality. Basal insulin analogues like Degludec and Glargine U-100 show neutral or mixed cardiovascular outcomes, with Degludec indicating a possible lower risk of major adverse events compared to Glargine in the DEVOTE study.
In patients with type 2 diabetes mellitus (T2DM), an increasing HbA1c level despite normal or near-normal fasting glucose values indicates significant postprandial glucose spikes, suggesting the need for mealtime insulin. This can be addressed by adding prandial insulin with the main meal, and as needed, before every meal. Alternatively, switching from basal insulin to premixed insulin, which is typically administered twice daily at breakfast and the evening meal, or increasingly initiated once daily with the main meal and escalated up to three times daily, may be considered.
Early insulin therapy is typically necessary for managing diabetes, and unlike other transcription factor diabetes types, HNF1B diabetes does not show sensitivity to sulfonylureas. Annual diabetes screening is recommended for nondiabetic mutation carriers.
In individuals with advanced type 1 and type 2 diabetes mellitus, compromised defenses against falling plasma glucose levels create a higher risk of iatrogenic hypoglycemia, making insulin therapy effective but not always safe. Despite concerns about hypoglycemia, poor glycemic control should not be justified by these concerns. Data from the DCCT demonstrate a curvilinear relationship between microvascular complications and mean glycemia, indicating that some degree of glycemic control significantly reduces the risk of complications compared to minimal or no control.
Individuals with diabetes experience similar cardiovascular disease (CVD) event reduction benefits from LDL cholesterol-lowering therapies as those without diabetes, with a 17% event reduction per 1 mmol/l LDL cholesterol reduction. Certain therapies that reduce triglycerides (TGs) can increase measured LDL cholesterol levels, particularly through increased conversion of very low-density lipoprotein (VLDL) to LDL particles, an effect influenced by baseline TG levels. Omega-3 fatty acids increase LDL cholesterol by 6%, while sodium-glucose cotransporter 2 (SGLT-2) inhibitors raise LDL cholesterol by 0.1 mmol/l (3%) and non-HDL cholesterol by 0.09 mmol/l (2%). The clinical significance of these LDL cholesterol increases remains uncertain, as these therapies demonstrate lipid-independent effects on CVD risk.
The conventional risk factors for hypoglycemia in diabetes are based on the premise that absolute or relative therapeutic insulin excess is the sole determinant of risk. Absolute therapeutic insulin excess can occur when insulin secretagogue or insulin doses are excessive, ill-timed, or of the wrong type, or when insulin clearance is reduced, as in renal failure. Relative therapeutic insulin excess occurs when exogenous glucose delivery is decreased, such as after missed or low carbohydrate meals and during the overnight fast, when glucose utilization is increased, such as during and shortly after exercise, when endogenous glucose production is decreased, such as after alcohol ingestion, and when sensitivity to insulin is increased, such as after weight loss or improved glycemic control and in the middle of the night. People with diabetes and their caregivers must consider each of these risk factors when addressing the problem of iatrogenic hypoglycemia.
Prolonged hGH replacement in individuals without diabetes typically causes increases in fasting plasma glucose and glycated hemoglobin, though these levels generally remain within the reference range. In those with preexisting impaired glucose tolerance, these markers tend not to rise further above pretreatment levels. The effects of hGH on insulin sensitivity are complex, involving interactions with IGF-I and body composition changes, such as reduced fat mass and increased lean body mass, which over time may improve insulin sensitivity. However, rhGH initially acts as an insulin antagonist, highlighting the need to avoid overdosing and to monitor glycemic control during treatment.
Insulin, produced by the β cells of the pancreatic islet, is the key hormone involved in regulating cellular energy supply and macronutrient balance, and increases the uptake and storage of glucose in the liver, adipose tissue, and skeletal muscle. The liver, skeletal muscle, and adipose tissue are the key insulin-sensitive tissues, with the liver being the principal organ for glucose homeostasis. In the post-absorptive state, the liver stores glucose as glycogen and can produce glucose through glycogenolysis or gluconeogenesis for use by other tissues. Several hormones, including glucagon, catecholamines, corticosteroids, and growth hormone, antagonize insulin's actions and are known as counter-regulatory hormones. Normal physiological conditions maintain blood glucose levels within narrow limits, a regulation crucial because some tissues like the brain are highly dependent on glucose as an energy source.
Individuals with diabetes and chronic kidney disease often develop anaemia, which can affect $\mathrm{HbA_{1c}}$ values; erythropoietin deficiency and iron-deficiency anaemia may increase $\mathrm{HbA_{1c}}$ due to elongated erythrocyte lifespan, while reduced red blood cell survival, increased erythrocyte turnover, or erythropoietin administration can decrease $\mathrm{HbA_{1c}}$, with non-iron-deficiency anaemia also potentially causing falsely low levels, leading to erroneous results in glycaemic monitoring or in the diagnosis of type 1 diabetes.
Minkowski's experiments did not immediately establish the pancreatic origin of diabetes, and for the next two decades, diabetes was considered a heterogeneous disorder with multiple subtypes involving the brain, pancreas, and liver in its pathogenesis. In 1901, Blum discovered that injection of an adrenal extract caused glycosuria, implicating other glands in diabetes and leading to Carl von Noorden's polyglandular theory, which proposed that carbohydrate metabolism was controlled by the thyroid, pancreas, adrenals, and parathyroids.
Diabetes is associated with an increased risk of heart failure, with studies showing higher prevalence rates in diabetic populations compared to controls. In patients with diabetes, heart failure prevalence ranges from 11.8% to 22.3%, and the incidence of heart failure is higher in people with diabetes compared to those without, particularly in women. Heart failure incidence in diabetic individuals is reported at 3.3 per 100 person-years in one study, and in another, 9–14 per 1000 person-years depending on sex. Factors predictive of heart failure in diabetes include age, female sex, duration of diabetes, insulin use, ischemic heart disease, creatinine levels, and glucose levels. Additionally, a 1% (11 mmol/mol) increase in HbA1c is associated with an 8% increased risk of heart failure. Diabetes also increases mortality risk in patients with heart failure, with a relative risk of 1.5 observed in one study. Conversely, heart failure is associated with an increased risk of developing diabetes, with an annual incidence of 9.6% in heart failure patients compared to 6.1% in controls, and an odds ratio of 2.0 for the association between diabetes and heart failure. Other predictive factors for diabetes include heart failure itself, with an odds ratio of 1.4.
Hyperglycaemia may resolve after delivery, but 5–10% of women may continue to have diabetes, most often type 2 diabetes, requiring treatment with lifestyle changes and appropriate anti-diabetes agents. Women with gestational diabetes should be screened for diabetes immediately postpartum and again at 6–12 weeks postpartum using non-pregnant OGTT criteria. HbA1c cannot be used in the immediate postpartum period but is effective for screening from 12 weeks postpartum where accurate measurement is available. Women with gestational diabetes are at risk of future diabetes outside pregnancy and should be offered annual screening, with those showing impaired glucose regulation treated through lifestyle interventions and, in some cases, metformin.
Preventing acute symptoms of hyperglycaemia involves addressing dehydration, thirst, polyuria, blurred vision, and increased infections, while also preventing acute complications such as hyperosmolar non-ketotic state. Efforts to prevent, defer, or reduce the severity of chronic complications focus on microvascular and neuropathic issues like retinopathy, nephropathy, and neuropathy, as well as macrovascular conditions including coronary, cerebrovascular, and peripheral vascular disease.
α-Glucosidase inhibitors delay carbohydrate digestion and glucose absorption by competitively inhibiting α-glucosidase enzymes in the intestinal brush border, with different inhibitors showing varying affinities for specific enzymes such as glycoamylase, sucrase, maltase, and dextrinases; for example, acarbose preferentially inhibits glycoamylase, while miglitol is a stronger inhibitor of sucrase.
Elevated free fatty acids can directly impair insulin action, and obese individuals as well as those with type 2 diabetes mellitus (T2DM) exhibit high intramyocellular lipid accumulation, which is a key feature of insulin resistance. Excessive lipid supply to skeletal muscle leads to intramuscular accumulation of neutral fatty acids and lipid-derived metabolites such as ceramide, diacylglycerol, and fatty acyl coenzyme A (CoA). This lipid accumulation activates a serine-threonine kinase cascade, resulting in the phosphorylation of insulin receptor substrate 1 (IRS-1) and IRS-2, which impairs insulin signaling, including reduced activation of phosphoinositide-3 kinase and other downstream components. Chronic overnutrition with high dietary fat intake contributes to and worsens this condition, making increased fatty acid availability the most critical factor in disrupting insulin action in obesity.
The most common causes of death among people with diabetes include cardiovascular disease, cancer, end-stage renal disease, and infections such as pneumonia. Historically, cardiovascular disease was responsible for 65–75% of deaths in people with diabetes in high-income countries, but its contribution has declined, leading to a relative increase in deaths from non-vascular causes like cancer. For instance, in the UK, the proportion of diabetes-related deaths due to vascular diseases dropped from 44% in 2001 to 24% in 2018, while cancer's share rose from 22% to 28% over the same period. Similar trends have been observed in Australia and the USA. In low-resource settings, acute metabolic emergencies remain a significant cause of death, accounting for 8%, 9.3%, and 11.9% of diabetes-related deaths in Mexico, India, and Asia, respectively. End-stage renal disease also contributes substantially to mortality in people with diabetes, largely due to limited access to dialysis and transplant services in low- and middle-income countries.
Several anti-diabetes drug classes have been associated with either increased or decreased cancer risk, including insulins, thiazolidinediones, incretin-based agents, and metformin. Recent evidence on these associations has largely been reassuring and can be shared with individuals who are currently using or starting these medications as part of their diabetes management.
Living with and managing diabetes can lead to specific anxieties, including fears related to hypoglycemia, complications, and invasive procedures such as insulin injection and blood glucose testing. Various assessment tools have been developed to measure these diabetes-specific anxieties, including the Hypoglycaemia Fear Survey, the Fear of Complications Questionnaire, the Diabetes Fear of Injecting and Self-Testing Questionnaire, and the Measure of Invasiveness and Skipping Self-Monitoring.
People with diabetes who have had a non-cardioembolic ischaemic stroke may benefit from antiplatelet therapy, as post hoc analyses suggest that clopidogrel reduces the combined risk of stroke, myocardial infarction, or death compared to aspirin, and cilostazol reduces the recurrence of stroke, particularly in those with lacunar stroke. However, in the PRoFESS trial, where the prevalence of diabetes was 28%, no difference was found between combination dipyridamole and aspirin therapy versus clopidogrel in preventing recurrent stroke among those with diabetes.
A mutation in islet brain 1 (IB1, MAPK8IP1) has been linked to diabetes in a family, with IB1 being a homologue of JIP-1 involved in modulating apoptosis and acting as a transactivator of the islet glucose transporter GLUT-2. The mutant IB1 was unable to prevent apoptosis in vitro, suggesting that its abnormal function may increase susceptibility of β-cells to apoptotic stimuli, thereby reducing β-cell mass. Given that glucotoxicity and lipotoxicity induce apoptosis and downregulate transcription factors in pancreatic β-cells, inherited or acquired defects in IB1 activity could negatively impact β-cell function.
Epidemiological studies show a consistent association between blood glucose and atherosclerosis, and recent intervention studies demonstrate that reducing glucose can improve cardiovascular disease (CVD) outcomes. In the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up from the Diabetes Control and Complications Trial (DCCT), lowering glucose in people with type 1 diabetes was linked to long-term benefits in CVD complications, evident years after recruitment. Similarly, 10-year follow-up data from the UK Prospective Diabetes Study (UKPDS) on intensive glucose therapy in type 2 diabetes showed long-term beneficial effects on macrovascular outcomes. However, risk reductions for myocardial infarction and death from any cause were observed only with extended post-trial follow-up, suggesting that improved glucose management may lead to greater CVD risk reduction in type 1 diabetes compared to type 2 diabetes, a finding supported by a meta-analysis.
Type 2 diabetes has a complex and variable aetiology and pathogenesis, typically involving disturbances in multiple tissues and organ systems, leading to defects such as insulin resistance and pancreatic β-cell dysfunction. Effective blood glucose management can be approached in various ways, with some treatments directly targeting these underlying defects, while others aim to improve glycaemic indices through safe interventions to reduce the risk of complications. Given that diabetes treatments are often life-long and must coexist with comorbidities, frailty, multiple pharmacotherapies, and lifestyle challenges, it is crucial that new agents have a commendable safety profile, are well tolerated, and compatible with a wide range of other medications. Ideally, these agents should offer durable and additive glucose-lowering effects when used alongside existing treatments, through different but complementary mechanisms, while posing minimal risk of serious hypoglycaemia. Furthermore, agents that can also reduce adiposity and improve other modifiable cardiovascular risk factors such as dyslipidaemia and hypertension are particularly advantageous.
Autoantibodies against minor autoantigens, such as Tetraspanin-7 (gluma38), ICA12/SOX13, VAMP2, NPY, carboxypeptidase H, ICA69, and INS-IGF2, are detected in individuals with newly diagnosed type 1 diabetes and may improve the positive predictive value for the disease, though these autoantigens are typically found in less than 25% of new-onset cases.
Metformin has several advantages in diabetes management, including a low risk of causing hypoglycemia or weight gain, and it is cost-effective. Its glucose-lowering effect is comparable to sulfonylureas, even in elderly patients, and it is effective in both lean and overweight individuals. The typical daily dose is around 1.7 grams. Notably, metformin was the only antidiabetic medication shown to reduce macrovascular events in the UK Prospective Diabetes Study (UKPDS), and it demonstrated lower all-cause mortality and combined diabetes-related endpoints compared to insulin or sulfonylureas in obese patients.
Individuals with fulminant type 1 diabetes typically experience a short duration of hyperglycaemic symptoms, averaging four days, often preceded by common cold-like and gastrointestinal symptoms. Diabetic ketoacidosis (DKA) presents with near-normal HbA1c levels despite very high plasma glucose, indicating acute hyperglycaemia. This condition shows seasonal variation, suggesting a possible viral cause, and is associated with abnormal exocrine pancreatic function, elevated serum pancreatic enzymes (such as lipase, elastase-1, and amylase), absent C-peptide, and minimal detectable autoantibodies against pancreatic beta cell components. Fulminant type 1 diabetes has been predominantly reported in Japan but also in other Asian countries including Korea, the Philippines, and China. Due to the high fatality rate of undiagnosed or untreated DKA, prompt recognition and intensive management are crucial, with many patients requiring long-term insulin therapy.
Hospitalization for newly diagnosed diabetes in children often lasts several days to provide families and caregivers with essential education and training in diabetes management. While insulin infusion and intravenous fluids are necessary for some cases, many hospitalizations could potentially be avoided with safe outpatient alternatives and appropriate reimbursement. These inpatient stays have significant economic and emotional effects on families and the healthcare system, prompting some institutions to adopt alternative diabetes education models. Recent studies suggest that outpatient education can reduce healthcare costs without compromising the quality of care.
OCT scanning can detect pathological lesions in the retina not visible through clinical inspection and is used to quantify retinal oedema in diabetic maculopathy with high depth accuracy, allowing for monitoring treatment effects and differentiating diabetic macular oedema from other causes of retinal swelling. OCT angiography is being investigated for diagnosing diabetic retinopathy by visualizing perfused vessels and identifying areas of capillary occlusion.
When diet and exercise are insufficient to manage maternal hyperglycaemia, insulin is an effective treatment to prevent fetal complications, especially those related to fetal overgrowth. Insulin is tailored to glycaemic targets and is preferred by some international bodies as the mainstay of treatment due to its inability to cross the placenta. The goals of treatment, including the reduction of post-prandial hyperglycaemia, are similar to those for type 1 diabetes, and multiple-daily insulin regimens are frequently used. The starting dose of insulin is 0.1 unit/kg/day, and with expert advice, it can be commenced as an outpatient with active titration. Both twice-daily and multiple-daily insulin injections are reasonable delivery strategies, with neither showing superiority over the other during pregnancy.
Previous foot ulceration and/or amputation are the most important risk factors for developing a foot ulcer in individuals with diabetes, with some studies reporting an annual recurrence rate of up to 50%. Psychosocial and behavioural factors also play a significant role in the development and recurrence of foot ulcers among diabetic patients.
Excess superoxide production in diabetes directly inhibits key endothelial enzymes such as eNOS and prostacyclin synthase, contributing to microvascular complications. In diabetic patients and animals, this oxidative stress reduces eNOS activity by 65% and prostacyclin synthase activity by 95%. Conventional antioxidants are ineffective at continuously neutralizing superoxide, making catalytic antioxidants like SOD/catalase mimetics a more promising treatment approach. These mimetics can prevent enzyme inactivation and normalize the five major pathways involved in hyperglycemic damage. Inhibiting ROS production in diabetic mice using antioxidant enzymes or compound combinations prevents the development of retinopathy, nephropathy, neuropathy, and cardiomyopathy, suggesting that targeting superoxide overproduction may be an effective strategy for preventing diabetic microvascular complications.
Glucocorticoids can worsen hyperglycemia in patients with diabetes and may cause significant increases in blood glucose and insulin concentrations in previously normoglycemic individuals when administered in high doses, equivalent to 30 mg/day or more of prednisolone. Impaired glucose tolerance or diabetes mellitus has been reported in 14–28% of individuals receiving long-term glucocorticoid therapy, with those having a low insulin response to glucose being particularly susceptible. These individuals are also considered to be at higher risk of developing type 2 diabetes in the future compared to the general population. Research using data from the Health Improvement Network by Gulliford et al. indicated that oral glucocorticoid use was linked to up to 2% of new diabetes mellitus cases in a large primary care population from 114 family practices.
Severe hypoglycaemia is associated with cognitive impairment and decline in individuals with diabetes, particularly in older adults. In a study of people with diabetes and a mean age of 75.7 years, those with dementia or cognitive impairment were significantly more likely to have been hospitalized for hypoglycaemia compared to those with normal cognitive function. Another population-based study of individuals with type 2 diabetes found that a self-reported history of severe hypoglycaemia was linked to poorer cognitive performance in tests of verbal fluency, digit symbol testing, letter–number sequencing, and trail making, independent of diabetes duration, vascular risk factors, or complications. The association between severe hypoglycaemia and lower cognitive ability persisted even after adjusting for prior cognitive ability, suggesting a potential direct effect of hypoglycaemia on age-related cognitive decline, with a linear relationship observed between increasing frequency of severe hypoglycaemia and poorer cognitive function in the year prior to testing.
TNF-α is a cytokine produced by immune cells, adipocytes, and muscle tissue, with its expression increasing in adipose and muscle tissues in relation to insulin resistance. In adipose tissue, TNF-α and other proinflammatory cytokines are generated by both adipocytes and macrophages that infiltrate under conditions of obesity and insulin resistance, suggesting a potential role in inducing cellular insulin resistance through autocrine and/or paracrine effects. TNF-α impairs insulin signaling by inducing serine phosphorylation of IRS1, which diminishes its ability to be phosphorylated by the insulin receptor tyrosine kinase, thereby disrupting downstream insulin signal transduction. Several TNF-α-activated pathways, including the stress-induced kinases JNK and IKKβ, are involved in increased serine phosphorylation of IRS-1.
Interstitial glucose monitoring involves implantable or subcutaneous sensors that measure glucose levels using non-enzymatic fluorescence or electrochemical methods, with data transmitted either intermittently for scanning or continuously in real-time to devices such as smartphones or insulin pumps, aiding in the management of diabetes.
Glycemic treatment goals for diabetes include an HbA1c of <7% (<53 mmol/mol) as a general target according to the ADA, with individualization recommended based on patient selection. For certain patients, less tight control or more rigorous normalization down to 6% (42 mmol/mol) HbA1c may be appropriate, provided hypoglycemia is not an issue. The IDF and AACE recommend a general goal of ≤6.5% (48 mmol/mol) HbA1c. All guidelines emphasize the importance of tailoring glycemic targets to individual patient circumstances.
The reduced incretin effect in type 2 diabetes, particularly the diminished post-prandial GLP-1 responses, has led to the exploration of GLP-1 as a therapeutic target due to its glucose-dependent insulinotropic and glucagonostatic properties. In contrast, GIP was initially overlooked as a glucose-lowering agent because of its impaired insulinotropic effect in type 2 diabetes and potential glucagonotropic actions. However, GIP may play a role in fat storage by promoting lipogenesis, adipokine secretion, and weight gain. As a substrate of DPP-4, GIP may contribute to the glucose-lowering effects of DPP-4 inhibitors. Dual or triple hormonal receptor agonists that include GIP receptor stimulation are being developed for type 2 diabetes and other metabolic disorders like obesity and non-alcoholic fatty liver disease. Tirzepatide, a dual GIP/GLP-1 receptor agonist administered weekly via subcutaneous injection, has shown significant reductions in glycated hemoglobin (HbA1c) and body weight in individuals with type 2 diabetes and overweight or obesity during its Phase III clinical trials.
Lifestyle changes including an extremely low-fat diet and low caloric intake help reduce ectopic fat, which in turn reduces insulin resistance and improves glycaemic levels. GLP-1 receptor agonists aid in reducing oral intake by slowing gastric emptying. Roux-en-Y gastric bypass surgery improves glycaemic indices, enhances insulin sensitivity, and promotes weight loss, particularly in familial partial lipodystrophy. Hypertriglyceridaemia unresponsive to fat reduction strategies may require fibrates and high-dose fish oils, while high-dose statins are recommended early due to the high cardiovascular risk associated with diabetes.
A clinical study involving individuals with diabetes demonstrated that intra-arterial administration of bone marrow mononuclear cells (BM-MNCs) led to significant improvements in ankle-brachial index (ABI), wound healing, and blood flow compared to other delivery methods. Additionally, the Intraarterial Progenitor Cell Transplantation study reported that intraarterial BM-MNC therapy improved wound healing and reduced rest pain in people with critical limb ischaemia, even though it did not affect ABI or limb salvage rates. Both intramuscular and intraarterial injections of G-CSF-mobilized peripheral mononuclear cells showed beneficial effects, including an improvement in ABI and increased walking distance in small clinical series involving diabetic patients.
Reimbursement mechanisms such as Pay-for-Performance (P4P) have been explored as a means to improve the quality of diabetes care, with studies indicating both potential benefits and adverse effects. Research by Millett et al. found that P4P led to improvements in intermediate outcomes for patients with diabetes, though these improvements varied across ethnic groups. Implementation of P4P has also been associated with unintended consequences, including a narrow focus on measured elements and the potential avoidance of severely ill patients. Differences in physician perceptions were noted between the USA and UK, with US physicians more likely to report minimal impact, resentment, lack of understanding, loss of autonomy, and reduced job satisfaction. Key design elements influencing effectiveness include whether incentives are directed at individual clinicians, medical groups, or hospitals, and whether they focus on documentation of care processes or actual outcome measures.
Dietary education programmes improve anthropometric measures and glycaemic levels while reducing the need for prescribed medication in individuals with diabetes. Dietician-led diabetes management programmes enhance patients' knowledge of self-management, making them effective for glycaemic control and improving dietary habits, particularly in type 2 diabetes. Registered dieticians play a key role in comprehensive diabetes care across multidisciplinary teams in various healthcare settings, including primary and specialist care. They provide dietary advice to those at risk of diabetes and those newly diagnosed, support individuals with type 1 diabetes in carbohydrate counting, and assist in managing cases where insulin therapy is initiated or intensified. In specialist settings, dieticians contribute to antenatal and postnatal care for women with diabetes, offer pre- and post-operative dietary support for bariatric surgery, and help manage diabetes in individuals with mental health conditions or eating disorders. They also provide complex nutritional care, including enteral feeding, for individuals with diabetes experiencing complications such as gastroparesis, pancreatitis, or those undergoing dialysis.
In individuals with pre-diabetes, increased insulin resistance leads to greater $\beta$-cell workload, which can trigger adaptive responses such as increased insulin and proinsulin secretion without apparent $\beta$-cell failure. This adaptive increase in $\beta$-cell function is often accompanied by an expansion of $\beta$-cell area, potentially through mechanisms such as neogenesis from duct cells or trans-differentiation from $\alpha$ cells, suggesting a form of $\beta$-cell plasticity that may help maintain glucose homeostasis under metabolic stress.
The text describes genetic factors associated with diabetes, particularly highlighting HLA genes and non-HLA genes. The HLA genes, located on chromosome 6p21, include the highest risk genotypes DR3-DQ2 and DR4-DQ8, which have odds ratios of 18.7 when combined and 2.0–11.4 for DR4-DQ8 alone. The DR3-DQ2 haplotype has an odds ratio of 2.5–5.0. Protective haplotypes include DR15-DQ6 with an odds ratio of 0.03–0.2 and DR14-DQ5 with an odds ratio of 0.02. Non-HLA genes such as INS-VNTR on chromosome 11p15, which regulates central tolerance to insulin, have an odds ratio of 2.25. Other genes include PTPN22 on chromosome 1p13 (odds ratio 1.95), IL2RA on chromosome 10p15 (odds ratio 1.70), and several others with lower odds ratios, such as C12orf30 (1.33), ERBB3 (1.25), PTPN2 (1.22), CLEC16A (1.22), CTLA-4 (1.20), and IFH1 (1.15). These genes are associated with susceptibility to diabetes and involve immune regulation and insulin signaling.
Insulin injections can be introduced for people with type 2 diabetes who are no longer managing their blood glucose with diet, lifestyle, and non-insulin medications by starting with one daily injection, typically added to existing therapies like metformin, sulfonylurea, DPP-4 inhibitors, SGLT-2 inhibitors, or GLP-1 RAs rather than replacing them. Guidelines from the UK, Europe, the USA, and the ADA/EASD consensus recommend combining basal insulin with oral therapy as a starting approach. Insulin initiation, whether in hospital or community settings, should occur within a structured program that includes active insulin dose titration, appropriate education, ongoing support via phone, text, or email, glucose monitoring to guide dose adjustments toward agreed targets, dietary understanding, hypoglycemia management, and support from trained healthcare professionals, with structured diabetes self-management education systems showing high effectiveness.
Metformin, gliclazide, dapagliflozin, GLP-1 receptor agonists, and DPP-4 inhibitors are medications used in the management of diabetes. During Ramadan, adjustments to the treatment regimen may include modifying the timing and dosage of oral hypoglycemic agents to align with fasting schedules. For example, metformin and gliclazide doses may be consolidated at Suhoor and Iftar, and dapagliflozin may be continued as part of the treatment plan. Substituting gliclazide with a GLP-1 receptor agonist or DPP-4 inhibitor may offer advantages in certain situations.
Gatifloxacin, a nolone antibiotic, has emerged as an important cause of hyperglycemia.
Some disturbances in the complement system and cytokine responses have been observed in people with diabetes, such as low complement factor 4 levels and decreased cytokine responses after stimulation, though the impact of these findings on the increased susceptibility to infection remains unclear. No consistent defects in adaptive immunity have been identified in individuals with diabetes.
Insulin pump users should carry spare batteries, long-acting insulin, syringes or pens, and the contact details of the pump manufacturer for emergencies. Written documentation of pump settings, including basal rates, bolus ratios, sensitivity factor, blood glucose targets, active insulin time, consumable types, and pump serial number is essential. Some insulin pumps may be affected by X-ray security scanners but can safely pass through metal detectors. Sudden reductions in atmospheric pressure, such as during cabin depressurization, can increase insulin delivery due to bubble formation in the cartridge, potentially causing hypoglycaemia, with severe cases delivering up to 8 additional units. Changes in altitude during normal flight can also slightly alter insulin delivery. Insulin pumps may be mistaken for other electronic devices and are at risk of theft, so travel insurance should cover such incidents.
Biomarker screening using brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) can help assess heart failure risk in individuals with diabetes. In the STOP-HF trial, participants with BNP levels of at least 50 ng/L underwent further cardiac evaluation and specialist referral, leading to a 45% lower odds of developing heart failure or left ventricular dysfunction compared to usual care. Similarly, the PONTIAC trial showed that diabetic individuals with NT-proBNP levels of at least 125 ng/L benefited from intensified treatment, including rapid uptitration of neurohormonal blocking therapies and specialist referral, which reduced the risk of cardiac events by 65%.
Postoperative hyperglycemia is associated with an increased risk of postoperative infections in individuals with diabetes undergoing coronary artery bypass grafting (CABG), although it remains uncertain whether hyperglycemia independently increases infection risk. Some studies show that higher postoperative glucose levels correlate with more infections, while elevated HbA1c does not. Improved glucose control during and around the time of surgery may reduce the likelihood of postoperative infections in diabetic patients undergoing cardiac procedures. A retrospective study involving 1574 CABG patients, 34.6% of whom had diabetes, found no significant increase in mortality or infection rates linked to higher postoperative glucose levels.
SGLT-2 inhibitors lower systolic and diastolic blood pressure by approximately 3–5 mmHg and 2–3 mmHg respectively in individuals with type 2 diabetes without causing hypotension, and they reduce the incidence of new-onset heart failure and the progression of existing heart failure, resulting in about 30% fewer hospitalizations for heart failure, particularly in those with reduced ejection fraction. These cardiovascular benefits appear to be independent of their glucose-lowering and weight-reducing effects, as similar effects have been observed in people without diabetes, and they occur consistently regardless of age, prior cardiovascular disease history, treatments for hypertension and heart failure, or renal function status.
The text indicates that research into the pathogenesis of counter-regulatory failure in diabetes has explored the role of the hypothalamus as the central integrator of sympathoadrenal responses to hypoglycaemia, with potential alterations in hypothalamic function being either primary or secondary to changes in other brain regions. Studies using $[^{15}\mathrm{O}]$ water and positron emission tomography (PET) show that hypoglycaemia activates various interconnected brain regions, including the medial prefrontal cortex, lateral orbitofrontal cortex, thalamus, globus pallidus, and periaqueductal grey region. Additionally, recent antecedent hypoglycaemia reduces sympathoadrenal and symptomatic responses while increasing synaptic activity in the dorsal midline thalamus during subsequent hypoglycaemia, suggesting a cerebral network involving thalamic inhibition of hypothalamic activity in hypoglycaemia-associated counter-regulatory impairment. This hypothesis aligns with findings from studies on ${}^{18}\mathrm{F}$-deoxyglucose uptake patterns in individuals with type 1 diabetes who have impaired awareness of hypoglycaemia.
α-Glucosidase inhibitors are used primarily in the management of type 2 diabetes, particularly for individuals with elevated post-prandial (after-meal) blood glucose levels but only mildly increased fasting glycaemia. These medications can be used either as monotherapy or more commonly as an add-on to other treatments, with the main goal of controlling post-prandial hyperglycaemia.
Children and families should be aware of risk factors related to diabetes so that glucose monitoring and insulin regimens can be adjusted accordingly; hypoglycaemia risk is increased during, immediately after, and up to 24 hours following exercise, and untreated coeliac disease and hypoadrenalism (Addison disease) may also contribute to higher hypoglycaemia risk, warranting screening in cases of recurrent, severe, or unexplained hypoglycaemia.
The prevalence of diabetes in Greece increased from 2.4% in 1974 to 3.1% in 1990, with aging and obesity being associated risk factors for both type 2 diabetes mellitus (T2DM) and impaired glucose tolerance (IGT). In a 2001–2002 survey, the prevalence of T2DM was 7.6% in men and 5.9% in women, and in a follow-up study of individuals without cardiovascular disease at baseline, the 5-year incidence rate of diabetes was 5.5%. In Turkey, the overall prevalence rates of T2DM and IGT were 6% and 9%, respectively, with low occupational activity, family history, and obesity identified as associated risk factors. Adherence to a Mediterranean diet may offer protective effects against diabetes.
Melatonin receptor 1B (MTNR1B) has been associated with both fasting glucose and risk of type 2 diabetes. Melatonin works as a chronobiotic factor, adjusting the timing of the biological clock, and its receptors are present in the pancreas, where it is proposed to contribute to the nocturnal lowering of insulin in humans. The MTNR1B risk genotype is associated with impaired early insulin release in response to both oral and intravenous glucose, and insulin secretion deteriorates over time in carriers of the risk allele.
Liraglutide and glimepiride, when added to metformin, showed similar reductions in HbA1c levels over 26 weeks, each reducing HbA1c by 1.0% (11 mmol/mol) from a baseline mean of 8.4% (68 mmol/mol). Patients treated with liraglutide experienced weight reductions of 2.6 kg and 2.8 kg with daily doses of 1.2 mg and 1.8 mg, respectively, whereas those on glimepiride had a weight gain of 1.0 kg. Mild hypoglycemic events occurred in up to 2.5% of patients receiving metformin and liraglutide.
Common intronic variants of the TCF7L2 gene, which encodes the transcription factor 7-like 2, are strongly associated with type 2 diabetes mellitus (T2DM) risk, showing the largest risk effect among known T2DM susceptibility loci; this association was first identified in the Icelandic population and later replicated across diverse ethnic groups including white Europeans, West Africans, Mexican Americans, Indian, and Japanese populations, with the rs7903146 T allele exhibiting an estimated risk effect of 1.46.
Gene variants such as the G/G variants of the calpain-10 gene (CAPN10) and KCNJ11 are associated with impaired insulin action, and specifically, the G/G variant of SNP-43 of CAPN10 is linked to a reduced insulin response to glucose in individuals.
In individuals with no diabetes, plasma glucose levels are normal, accompanied by appropriate responses of insulin, glucagon, and epinephrine. In type 1 diabetes, there is an absence of the expected decrease in insulin and lack of normal increases in glucagon and epinephrine. Early type 2 diabetes shows decreased insulin levels with increased glucagon and epinephrine, while late type 2 diabetes is characterized by a lack of insulin decrease and attenuated increases in glucagon and epinephrine.
Newly diagnosed individuals with diabetes, particularly those treated with insulin, should refrain from driving until glycemic control and vision stabilize; recurrent daytime hypoglycemia, especially if severe, and impaired awareness of hypoglycemia can affect safety; reduced visual acuity worse than 6/12 on the Snellen chart, severe sensorimotor peripheral neuropathy with loss of proprioception, severe peripheral vascular disease, and lower limb amputation are also relevant considerations.
Screening for diabetic retinopathy involves inspection of the ocular fundus, often supplemented by measuring visual acuity to assess the disease's impact on central vision, and it is recommended to document the fundoscopic findings through photography. This photographic documentation provides an overview of lesions across the fundus, enables review for second opinions, and allows for tracking morphological changes over time. There is ongoing debate about conducting screening without pupil dilatation to improve patient convenience and procedural efficiency, a method supported by the availability of cameras capable of imaging the retina through small pupils. However, this non-mydriatic approach results in lower-quality images of the retinal periphery.
Fetal inheritance of the HNF4A gene variant, whether from the mother or father, significantly increases the risk of macrosomia and neonatal hypoglycaemia, adding over 800g to birth weight and potentially causing obstetric complications, thus early delivery should be considered. In women with HNF4A, maternal glycaemia further contributes to fetal birth weight, making it crucial to avoid sulfonylurea (glibenclamide) treatment from the second trimester onwards to prevent exacerbating this effect.
Infants of women with diabetes are at increased risk of developing obesity, diabetes, and metabolic syndrome later in life, contributing to public health concerns. The Pedersen hypothesis, which originally linked maternal hyperglycaemia to fetal abnormalities, has been expanded to consider other fuels in teratogenesis and is now incorporated into the developmental origins hypothesis. This broader concept suggests that in utero hyperglycaemia can lead to fetal metabolic programming that increases the risk of obesity and diabetes later on. When this metabolic programming occurs in female offspring, it may raise their susceptibility to gestational diabetes mellitus (GDM), potentially creating a transgenerational cycle with significant public health implications.
Type 2 diabetes can present with diabetic ketoacidosis (DKA) alongside insulin insufficiency, but individuals often regain β-cell function quickly after treatment, potentially avoiding long-term insulin therapy. The increasing use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors in treating type 2 diabetes has led to a rise in cases of euglycaemic DKA, where blood glucose levels remain within the range of 4–11 mmol/l (70–200 mg/dL). This condition is more frequent in individuals using concomitant insulin therapy and when medication cessation guidelines, such as not stopping basal insulin during illness or surgical stress, are not followed. Proper management includes staying hydrated, monitoring glucose and ketone levels every 2–3 hours, administering additional insulin if needed, and seeking prompt medical advice. Mortality from DKA is generally less than 1%, though recent UK data from 2017 to 2019 indicate a mortality rate of 3.8%, with rates rising to 10–20% for those over 65 years old, largely due to underlying triggers like infection or trauma.
The treatment of hyperosmolar hyperglycemic (HH) state follows similar guidelines to diabetic ketoacidosis (DKA), focusing on controlled correction of hyperglycemia, hyperosmolality, and water and electrolyte deficits over 24 hours. Patients with HH are generally more sensitive to insulin, and an infusion of 0.1 IU/kg body weight/hour is typically sufficient, although repeated hourly boluses of 0.15 IU/kg body weight (or 10 IU) may also be used. Insulin dosage should be adjusted based on normal daily insulin needs and therapeutic response. Initial rehydration usually involves 1 L of isotonic saline in the first hour, followed by slower rehydration. Hemodynamic performance must be closely monitored, especially as many patients have pre-existing or coexisting cardiac disease, making central venous pressure monitoring helpful. A significant proportion of HH patients are hypernatremic, in which case hypotonic saline can be administered more slowly. Potassium management follows similar principles to DKA, and monitoring in the intensive care unit is often advisable.
Dipeptidyl peptidase 4 inhibitors, such as sitagliptin, saxagliptin, and linagliptin, are linked to an increased risk of bullous pemphigoid, with skin-related adverse effects being more frequent when these medications are used in combination. Sodium-glucose cotransporter type 2 (SGLT-2) inhibitors lower blood glucose by reducing its reabsorption in the proximal tubule, leading to increased urinary glucose excretion, which can result in urogenital infections, including those caused by candida; additional skin-related side effects associated with SGLT-2 inhibitors, like ipragliflozin, include generalized rash, urticaria, and eczema.
Dermal thickening is associated with diabetes, particularly in men with type 2 diabetes and those who are overweight or have persistent hyperglycaemia, with a prevalence ranging from 2.5% to 14%. This condition typically begins insidiously and is asymptomatic, though severe cases can cause neck and back pain. The skin becomes hard, thick, and may be indurated and erythematous, with histological findings of thickened dermis containing large collagen bundles and increased mast cells. Its pathogenesis involves non-enzymatic glycation of collagen, leading to increased crosslinking and reduced degradation, which results in skin thickening. While no specific therapy is highly effective, some responses to ultraviolet light or PUVA therapy have been reported, and strict glycaemic control is advised to slow progression.
Structured education, or re-education, is a core approach for individuals experiencing iatrogenic hypoglycaemia, effectively reducing rates of severe hypoglycaemia, a complication often associated with diabetes management.
Adolescents and emerging adults may differ in their ability to independently manage diabetes self-care due to challenges with executive functioning, such as those seen in attention-deficit/hyperactivity disorder (ADHD), as well as short-term and working memory difficulties. Research has explored how hypoglycaemia and hyperglycaemia may affect cognitive and executive functioning, though findings have been mixed. Impairments in executive functioning can impact diabetes self-care, glycaemic control, and health-related quality of life, particularly in females with type 1 diabetes. To support self-management, individuals may benefit from tools like step-by-step checklists or mobile alarms to remind them of diabetes tasks, especially when blood glucose levels are out of range.
Loci associated with type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome have been identified on chromosomes 2p and 3q27, with the latter region containing the APM1/ACDC gene that encodes adiponectin, an adipokine present in plasma. The C-terminal domain of adiponectin has been shown to protect mice on a high-fat diet from obesity and improve insulin resistance in obese or lipoatrophic mouse models by reducing plasma free fatty acids and promoting lipid oxidation in muscle. Lower plasma levels of adiponectin are observed in obese individuals with diabetes and are linked to reduced insulin sensitivity, suggesting a role for adiponectin in the development of fat-induced metabolic syndrome and T2DM.
Tighter blood pressure control (averaging 144/82 mmHg) over 8 years in patients with type 2 diabetes mellitus (T2DM) led to significant improvements in microvascular complications such as retinopathy and nephropathy, as well as a 44% reduction in stroke risk and a 56% reduction in heart failure risk, compared to less strict control averaging 154/87 mmHg. Myocardial infarction and peripheral vascular disease showed nonsignificant reductions.
Growth hormone increases fasting hepatic glucose output by enhancing hepatic gluconeogenesis and glycogenolysis while decreasing peripheral glucose utilization through inhibition of glycogen synthesis and glucose oxidation, and it also stimulates lipolysis. However, growth hormone increases the production of insulin-like growth factor I (IGF-I), which has insulin-like actions that oppose those of growth hormone on glucose metabolism. The interactions between growth hormone, IGF-I, and insulin in regulating glucose homeostasis are not fully understood, but disruptions in glucose metabolism are common in conditions of growth hormone deficiency or excess. Additionally, insulin-like growth factor-binding protein 1 (IGFBP-1), which has a diurnal variation and is highest overnight when insulin levels are lowest, plays a modifying role in glucose homeostasis.
Acute hypoglycaemic episodes in diabetes are often uncomfortable and unpredictable, accompanied by autonomic arousal and aversive symptoms such as trembling, sweating, lightheadedness, pounding heart, nervousness, and feelings of agitation and worry. These episodes can lead to fear of hypoglycaemia, which is an adaptive psychological reaction aimed at avoiding situations that may trigger recurrence. According to the DAWN2 study, 56% of individuals with diabetes reported worry about hypoglycaemic events, and this fear occurs across age groups, affecting both children and adults. Parents and spouses of individuals with diabetes often experience heightened fear, sometimes more so than the individuals themselves, as they are more acutely aware of the impact, especially during unconscious episodes with little recall. The DAWN2 study also found that 61% of family members of people with diabetes expressed concern about hypoglycaemia.
Plasma concentrations of ET-1 are elevated in individuals with type 2 diabetes and atherosclerosis compared to those without diabetes but with atherosclerosis and healthy individuals. Increased ET-1 levels are associated with diabetes and carotid atherosclerosis, and ET-1 contributes to inflammation by stimulating the production and release of cytokines from monocytes. Additionally, ET-1 enhances the uptake of LDL cholesterol by monocytes, promoting their transformation into foam cells, and cytokines from monocytes-macrophages further stimulate ET-1 production, creating a positive feedback loop that amplifies cytokine production.
Diabetes is a significant risk factor for cardiovascular disease (CVD), with the association between diabetes and heart disease first described over a century ago and later linked to atherosclerosis. Landmark studies, including the Framingham Study, established diabetes as a major CVD risk factor, with a two- to fourfold increase in cardiovascular risk. Some guidelines classify diabetes as a coronary heart disease (CHD) risk equivalent, a concept based on a Finnish cohort showing comparable CHD outcomes, such as myocardial infarction and CHD death, between individuals with type 2 diabetes for more than 10 years and those with established CHD, even after adjusting for other risk factors. The OASIS study further demonstrated that individuals with diabetes but no prior CVD have similar long-term morbidity and mortality as non-diabetic individuals with established CVD following hospitalization for unstable coronary artery disease. However, the validity of this equivalence varies, particularly in older populations, where those with existing CHD have a greater risk than those with diabetes alone. Additionally, individuals with type 1 diabetes also face an increased CVD risk across all ages, despite typically presenting at a younger age.
Long-acting glucagon-like peptide 1 receptor agonists (GLP-1RAs) such as liraglutide, semaglutide, and dulaglutide have demonstrated cardiovascular benefits in individuals with type 2 diabetes and pre-existing atherosclerotic cardiovascular disease. These agents also show benefits in chronic kidney disease (CKD) populations, leading to recommendations for their use in treating type 2 diabetes with diabetic nephropathy when metformin and SGLT-2 inhibitors are insufficient for optimal glucose control. Studies have indicated positive kidney effects as secondary endpoints, primarily through reductions in albuminuria and some potential effects on eGFR. The AWARD7 study supported a kidney benefit with dulaglutide in type 2 diabetes and CKD, while the FLOW study is investigating whether semaglutide offers benefits on hard renal outcomes in addition to cardiovascular advantages.
Necrobiosis lipoidica does not have any proven effective treatment based on double-blind placebo-controlled trials, and spontaneous remission is rare. Optimal glycaemic management typically does not significantly influence the progression of the condition. Individuals with diabetes are advised to avoid smoking and trauma to affected areas to prevent painful and difficult-to-heal ulcers. Various treatments have been reported, but most lack established efficacy. Commonly used therapies include topical steroids, calcineurin inhibitors, and PUVA. For early-stage lesions, topical or intralesional corticosteroids may be beneficial, especially when applied to the edges of the lesions where inflammatory activity extends beyond visible margins. However, once atrophy occurs, it is irreversible, and topical steroids should be used cautiously in chronic cases.
The 16189C variant of mitochondrial DNA is associated with an increased risk of type 2 diabetes mellitus (T2DM) in Asian populations, with studies showing a higher frequency of this variant in Asians compared to Europeans. Additionally, in Chinese subjects, the frequency of this variant is higher in those with metabolic syndrome compared to those without, even after adjusting for age and BMI.
Early identification of gestational diabetes mellitus (GDM) is important as diagnosis after 28 weeks' gestation is associated with a twofold higher risk of fetal abdominal circumference above the 90th centile, which increases further when combined with maternal obesity, ultimately leading to a fourfold increase in the risk of being born large for gestational age (LGA). Fetal growth acceleration and increased fat mass can be detected as early as 20 weeks' gestation. In India, elevated fetal adiposity was observed before GDM diagnosis in women without pre-diabetes or type 2 diabetes in early pregnancy, and their offspring exhibited higher adiposity without elevated birth weight, referred to as the thin–fat phenotype.
Transition for individuals with diabetes involves preparing for self-care and a future change in their diabetes care team, typically from paediatric endocrinologists or diabetologists to adult physicians, and it is distinct from the actual transfer event; poor management of this process can lead to reduced engagement with adult services, lower rates of regular attendance at diabetes medical centres, and increased use of emergency departments and hospitalizations.
Early identification of gestational diabetes mellitus (GDM) may enable timely intervention, though large cohorts and randomized controlled trials (RCTs) in early pregnancy are needed to evaluate various risk factors while excluding women with a high likelihood of pre-existing diabetes, such as those with impaired fasting glucose (6.0–6.9 mmol/l) or elevated HbA1c (6–6.5%). An ongoing RCT using oral glucose tolerance testing (OGTT) before 20 weeks of pregnancy aims to determine if early intervention improves pregnancy outcomes.
Poor metabolic control in diabetes can lead to nutritional deficiencies, which may necessitate multivitamin supplementation.
Retinal microaneurysms in middle-aged adults without diabetes are associated with cognitive decline characterized by psychomotor slowing, suggesting that retinopathy may serve as a marker of cerebral microangiopathy due to the homology between retinal and cerebral microvascular systems. In patients with significant diabetic retinopathy, microangiopathy can lead to cerebral hypoperfusion, potentially disrupting the delivery of glucose and other essential substances to neural tissue, thereby contributing to brain structure and function abnormalities. The frequent association between peripheral neuropathy and brain dysfunction in diabetes may stem from the concurrent appearance of microvascular complications sharing a common origin, with microvascular disease being a primary mechanism underlying neurocognitive dysfunction in young and middle-aged adults.
Lower levels of glycaemia are associated with reduced risk of long-term microvascular complications in both type 1 and type 2 diabetes, as demonstrated by the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study. Learned societies such as the American Diabetes Association and European Association for the Study of Diabetes, along with government bodies like NICE, have established tight glycaemic targets to minimize complications. General practitioners in the UK are financially incentivized to achieve these targets, though there is increasing recognition of the need to individualize glycaemic goals based on factors including life expectancy, duration of diabetes, comorbidity, cardiovascular disease, and available support.
Emphysematous pyelonephritis is an infection that predominantly affects people with diabetes, who account for 90% of cases, and is more common in women. It is a severe necrotizing infection of the renal parenchyma and surrounding areas, which can be focal or diffuse and may extend to the collecting system or perinephric tissues. The presence of gas in these areas is attributed to the fermentation of high concentrations of glucose by gas-forming organisms, impaired renal perfusion, and mixed acid fermentation of glucose, particularly by Enterobacteriaceae, which is considered a major pathway for gas formation.
In diabetes, insulin-producing cells (yellow double-positive cells) may trans-differentiate into alpha cells (yellow to green cells), while beta cells can undergo dedifferentiation into a resting state (red to grey cells), and overstressed beta cells can also trans-differentiate into alpha cells (red to green cell), contributing to the failure of compensatory mechanisms; alpha cells may increase fivefold through neogenesis, potentially enhancing the source of glucagon-like peptide 1 (GLP-1) (white to green cell).
Hyperosmolar hyperglycemia (HH) is a severe complication typically resulting from poorly managed type 2 diabetes mellitus (T2DM) or undiagnosed T2DM, characterized by extreme hyperglycemia exceeding 35–40 mmol/L and serum osmolality above 320 mOsm/kg. It is associated with a high mortality rate, around 15%, and often occurs in vulnerable individuals with concurrent serious conditions. Differentiating HH from diabetic ketoacidosis (DKA) can be challenging due to overlapping features such as ketosis, lactic acidosis, and organ failures, though treatment approaches for both conditions are largely similar.
Gene therapy shows promise in treating diabetic complications, with some approaches in early clinical testing. Herpes virus-mediated nerve growth factor expression has been explored for diabetic cystopathy and peripheral neuropathy. Vascular endothelial growth factor (VEGF) gene therapy has been studied for coronary artery disease, showing potential in promoting vascular formation, while angiopoietin-1 (Ang-1) gene therapy has demonstrated benefits in improving myocardial angiogenesis and reversing diabetes-related myocardial remodeling in animal models. A small clinical trial reported improvement in diabetic peripheral vascular disease following intramuscular VEGF gene delivery. Additionally, non-viral insulin-like growth factor I gene therapy combined with autologous cell transplantation improved wound healing in a preclinical large-animal model of diabetes.
Premixed insulin regimens such as Novomix 30®, Humulin M3®, Humalog Mix 25®, Humalog Mix 50®, Insuman Comb 15®, Insuman Comb 25®, Insuman Comb S®, and Hypurin Porcine 30/70 Mix® are typically administered in two or three daily doses, with specific adjustments recommended for the morning dose prior to admission, such as halving the usual amount, and regular blood glucose monitoring should be conducted.
Developments in β-cell replacement therapies for diabetes include xenotransplantation, such as the transplantation of neonatal pig islets, which has shown a 45% decrease in insulin requirements and a 22.5% decrease in HbA₁c levels at one year post-transplant. Challenges include stronger immune responses compared to human islet cell transplantation, though cellular encapsulation has been used to improve survival of transplanted cells, with documented survival of encapsulated neonatal porcine islets for up to 9.5 years. Concerns about zoonosis, particularly porcine-endogenous retrovirus, remain mostly theoretical as no in vivo transmission has been documented in preclinical or clinical trials. Advances in large-scale isolation of porcine islets are expected to lead to more clinical trials involving xenotransplantation in the near future.
People with diabetes have an increased susceptibility to infections, primarily due to deficiencies in the host innate immune response, which plays a more significant role than changes in adaptive immunity. The innate immune system, acting as the first-line barrier against microorganisms, includes physical barriers like skin and mucous membranes, as well as phagocytes such as neutrophils, macrophages, mast cells, and natural killer cells, along with cytokines and inflammatory mediators. Diabetes affects innate immune responses by impairing functions such as chemotaxis, phagocytosis, and bactericidal activity of neutrophils and monocytes, contributing to the higher prevalence and severity of infections in diabetic individuals.
Following the onset of islet autoimmunity, a prolonged pre-clinical phase exists during which secondary prevention strategies may slow progression to clinical diabetes. Individuals exhibiting multiple autoantibodies along with susceptibility HLA-DR, DQ genotypes are at higher risk of developing the disease. There may be a critical 'point of no return' in the autoimmune destruction of islets, limiting the effectiveness of interventions to earlier stages. Most individuals with persistent islet autoantibodies progress to diabetes within a decade. Prior to overt insulin dependence, a phase of mild asymptomatic hyperglycaemia, detectable via oral glucose tolerance testing or elevated HbA1c levels, may occur months or years earlier. Intervening during this dysglycaemic stage could potentially preserve endogenous insulin secretion and reduce both acute and long-term complications of type 1 diabetes. Even after diagnosis, maintaining or regaining residual insulin secretion may be beneficial, although current immunomodulatory agents used in tertiary prevention pose significant long-term risks.
Thiazolidinediones, a class of medications used in diabetes management, are associated with fluid retention, leading to increased plasma volume, reduced hematocrit, and decreased hemoglobin concentration. These effects make thiazolidinediones contraindicated in patients with heart failure, with varying cardiac exclusion criteria between regions. Clinical monitoring is crucial, especially in high-risk patients and those experiencing initial weight gain. A meta-analysis raised concerns about rosiglitazone increasing the risk of myocardial infarction in the first 6–12 months of treatment, although this finding remains controversial. Despite fluid retention, these drugs typically do not elevate and may slightly lower blood pressure.
Reducing adiposity through weight loss, whether by dietary restriction, increased energy expenditure, very low-calorie diets, or bariatric surgery, improves insulin sensitivity and glycaemic control in individuals with overweight or obesity and type 2 diabetes. Pharmacological agents used for weight loss, such as the intestinal lipase inhibitor orlistat, centrally acting satiety-inducing drugs like phentermine, phentermine–topiramate, bupropion–naltrexone combinations, and the 5HT2c serotonin receptor agonist lorcaserin (now withdrawn), also improve glycaemic indices in individuals with type 2 diabetes, though it remains unclear whether these effects are independent of their weight-reducing properties. GLP-1 receptor agonists and SGLT-2 inhibitors offer combined benefits of lowering blood glucose and reducing body weight, highlighting the importance of addressing both obesity and diabetes in treatment strategies.
People with diabetes and clinical atherosclerotic cardiovascular disease, including stroke or TIA, should be treated with high-intensity statin medication if safe, and those without such events but with LDL cholesterol above 70 mg/dL (1.8 mmol/L) should also receive statin treatment, aiming for a 50% reduction in LDL cholesterol with high-intensity therapy, as recommended by guidelines from the American Heart Association, American College of Cardiology, and the Endocrine Society.
Patients with type 1 diabetes mellitus (T1DM) may misuse insulin as a method of weight control, a behavior known as "self-induced glycosuria," which involves underusing or omitting insulin. This practice, more commonly observed in weight-conscious individuals—especially females—leads to rapid but often unsustainable weight loss primarily due to acute dehydration. It is associated with impaired glycemic control and likely increases the risk of both microvascular and macrovascular complications if continued. Additionally, individuals engaging in this behavior are at higher risk of hospital admission due to ketoacidosis.
Management of type 1 and type 2 diabetes in children is similar to that in adults and involves education for children and their families on insulin therapy and dosage adjustment, blood glucose monitoring, and recognizing and managing hypoglycaemia, hyperglycaemia, and ketosis. The impact of diet, physical activity, and intercurrent illness on blood glucose levels is also addressed. An individualized approach should consider the child's age, maturity, emotional well-being, and life goals. As energy requirements change with age, growth rates must be monitored, and meal plans should be reevaluated at least annually.
Many older teenagers and young adults with diabetes experience gaps in care during the transition to adult providers, leading to deterioration in glycaemic control, increased risk of acute complications, and the possible emergence of chronic complications; this transition can be further complicated by ambivalence from both patients and long-term paediatric providers who may struggle with transferring care due to concerns about how well patients will adapt to new models of adult care. Coordinated efforts between paediatric and adult providers are necessary to facilitate this transition for patients, families, and healthcare teams.
Financing for healthcare in low- and middle-income countries (LMICs) is insufficient, particularly for non-communicable diseases (NCDs) like diabetes, with only 2% of development assistance for health allocated to NCDs despite their significant contribution to mortality. A large portion of healthcare costs in LMICs are paid out-of-pocket by individuals, in contrast to high-income countries, and diabetes care often lacks dedicated funding, unlike treatments for conditions such as HIV/AIDS which may be provided for free. National programs addressing NCDs and diabetes in LMICs also face severe budget constraints, as exemplified by the minimal funding allocated to NCD departments in countries like Mozambique and Peru.
Genetic variation in the organic cation transporter 1 (OCT1), which is involved in the hepatic uptake of metformin, a commonly prescribed biguanide for diabetes, has been shown to influence the drug's therapeutic effect and patient response. This indicates that individual differences in OCT1 genetics may play a role in how effectively metformin works in treating diabetes.
MODY (Maturity-Onset Diabetes of the Young) is a form of diabetes that can be identified through genetic testing, particularly in individuals with specific clinical features. Genetic testing for MODY is informed by factors such as body mass index (BMI), the presence of autoantibodies like glutamic acid decarboxylase (GAD) and islet antigen 2 (IA-2), and measurements of glycated haemoglobin ($\mathsf{HbA}_{1c}$). These markers help distinguish MODY from other types of diabetes and guide the selection of appropriate genetic tests.
Supervised aerobic and combined aerobic/resistance exercise training are associated with greater reductions in $\mathrm{HbA_{1c}}$ in individuals with type 2 diabetes, particularly when the baseline $\mathrm{HbA_{1c}}$ is higher. Each additional set of aerobic exercise per week contributes to a $0.4\%$ $(4\mathrm{mmol / mol})$ decrease in $\mathrm{HbA_{1c}}$. However, no significant association between exercise variables and $\mathrm{HbA_{1c}}$ reduction is observed with supervised resistance training alone.
Sulfonylureas are effective as monotherapy in patients with type 2 diabetes mellitus (T2DM) who are not adequately controlled by lifestyle measures alone, reducing fasting plasma glucose by approximately 2–4 mmol/L and lowering HbA1c by 1–2% (11–22 mmol/mol). Their glucose-lowering effect is immediate and particularly beneficial in the short term, though efficacy depends on sufficient β-cell function, which declines progressively in T2DM. As β-cell function deteriorates, the durability of sulfonylurea efficacy diminishes, necessitating dose escalation over time. Secondary sulfonylurea failure, characterized by rapid deterioration in glycemic control, occurs in about 5–10% of patients annually, primarily due to advancing β-cell failure. Patients with greater β-cell reserve at initiation tend to have a better and longer response, although hypoglycemia is a notable risk, while those with severely compromised β-cell function respond less effectively.
New formulations of GLP-1 receptor agonists, including a once-weekly depot formulation of exenatide, long-acting analogs, slow-release versions, and alternative administration routes such as transdermal, buccal, and inhaled, are under clinical evaluation. Hybrid peptides like DAPD, which acts as both a GLP-1 receptor agonist and a glucagon receptor antagonist, are being studied to improve glucose-lowering effectiveness. Non-peptide GLP-1 receptor agonists, such as Boc5, are also being investigated to eliminate the need for injections, as they bind to GLP-1 receptors on islet β-cells and enhance glucose-dependent insulin secretion.
Skin thickness in individuals with diabetes correlates with the duration of the disease and the presence of complications such as neuropathy and microangiopathy. Diabetic hand syndrome and diabetic scleroderma are specific complications that may arise from advanced skin thickening, with the combination of thick, tight waxy skin and limited joint mobility referred to as cheiroparthropathy, which affects up to a fifth of people with type 1 diabetes. While topical emollients can help manage skin dryness, there is no effective treatment for skin thickening, though rigorous glycaemic management may slow its progression.
Glycated hemoglobin (HbA₁c) and blood glucose are key measures used to assess glycemia, with HbA₁c reflecting overall glucose control over the previous 6–8 weeks and blood glucose indicating day-to-day control and response to treatment. HbA₁c has less within-person variation and is linked to long-term disease outcomes, making it valuable for evaluating therapeutic needs and responses, while blood glucose measurements can be more variable except when fasting. Urinary glucose may also be used to identify poor glycemic control in individuals not aiming for intensive glucose management.
The regulation of insulin secretion involves multiple factors, including nutrients, islet products, neurotransmitters, gastrointestinal hormones, adipokines, and stress conditions. Elevated levels of glucose, amino acids, and fatty acids increase insulin secretion, while low glucose decreases it. Among islet products, glucagon, adenine nucleotides, and divalent cations enhance insulin release, whereas somatostatin, ghrelin, and PYY reduce it. Neurotransmitters such as acetylcholine through parasympathetic stimulation, norepinephrine via sympathetic α-receptors, VIP, PACAP, and GRP stimulate insulin secretion, while norepinephrine via sympathetic β receptors, dopamine, NPY, and galin inhibit it. Gastrointestinal hormones like cholecystokinin, GIP, and GLP-1 promote insulin secretion, but somatostatin and ghrelin suppress it. Adipokines such as adiponectin increase insulin secretion, whereas leptin and resistin decrease it. Stress conditions including exercise, hypoxia, hypothermia, surgery, and severe burns can also decrease insulin secretion.
The number of women with diabetes during pregnancy is rising, largely due to the increasing prevalence of type 2 diabetes and obesity among women of reproductive age. Diabetes in pregnancy increases the risk of perinatal mortality and morbidity, including stillbirths and congenital malformations, which occur at rates three to five times higher than in non-diabetic pregnancies. During pregnancy, maternal insulin resistance helps direct glucose to the fetus, but women with pre-gestational diabetes may not produce enough insulin, requiring increased insulin therapy. Women without prior diabetes may develop glucose intolerance during pregnancy if their insulin reserves are inadequate. Poor glycemic control during early pregnancy can lead to malformations as glucose has a teratogenic effect on the developing embryo. Maternal diabetes also affects fetal pancreatic islets and beta-cell development, potentially increasing the child's risk of diabetes later in life. Fetal hyperinsulinemia due to maternal hyperglycemia leads to accelerated fetal growth, increasing the risk of hypoxia, acidosis, stillbirth, and neonatal hypoglycemia. Effective maternal diabetes management reduces risks of malformations, fetal overgrowth, stillbirth, and neonatal complications, as well as the long-term risks of obesity and diabetes for the child. Women with existing diabetes complications such as retinopathy or nephropathy may experience worsening during pregnancy, though these effects are typically limited to those with pre-existing significant disease and are usually self-limiting.
Diabetes-related concepts include impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), which are prediabetic states. Insulin-dependent diabetes mellitus (IDDM) refers to type 1 diabetes, where insulin production is deficient. Insulin autoantibody (IAA) and islet cell antibody (ICA) are markers associated with autoimmune diabetes. Glycogen synthesis is influenced by GSK (glycogen synthase kinase), which plays a role in glucose metabolism. The International Diabetes Federation (IDF) provides guidelines and standards for diabetes care. Hyperosmolar hyperglycemic syndrome (HSS) and hyperosmolar non-ketotic coma (HONK) are severe complications of diabetes characterized by extreme hyperglycemia. Insulinoma-associated antigen 2 (IA-2) is a protein involved in the autoimmune response in type 1 diabetes. Islet amyloid polypeptide (IAPP) is associated with beta-cell dysfunction in type 2 diabetes. The homeostasis model assessment (HOMA) is used to quantify insulin resistance and beta-cell function. Internet-based glucose monitoring systems (IBGMS) support diabetes management through remote glucose tracking.
Transplant recipients often experience glucose intolerance and develop type 2 diabetes, influenced by factors such as the use of corticosteroids and immunosuppressant agents like cyclosporine and tacrolimus. While it was previously believed that cyclosporine is less likely to impair glucose homeostasis compared to tacrolimus, this notion has been challenged. The development of glucose intolerance in these patients is associated with alterations in insulin sensitivity and impaired β-cell function, with recent evidence suggesting that defective insulin secretion is the primary pathological defect. The potential advantages of cyclosporine over tacrolimus in managing transplant recipients with preexisting type 2 diabetes remain controversial.
Cotton wool spots may indicate an aggravation of disturbances in blood flow and metabolism, which can be associated with diabetes.
Delayed gastric emptying in diabetic mice is associated with macrophage-based immune dysregulation, specifically linked to oxidative stress and the depletion of anti-inflammatory resident M2 macrophages expressing HO-1. In people with gastroparesis, similar patterns are observed, including loss of anti-inflammatory macrophages and increased expression of pro-inflammatory macrophage-related genes. Diabetic gastroparesis is also associated with abnormalities in enteric neural control, involving disorders of pacemaker cells such as interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor α (PDGFRα) fibroblast-like cells, as well as changes in nitrergic neurons and CD206-positive macrophages.
Insulin is released from $\beta$ cells through exocytosis, a process where secretory granules fuse with the plasma membrane, releasing insulin into the interstitial space. This mechanism involves the SNARE complex, a group of proteins that facilitate granule docking at the plasma membrane. The fusion and subsequent insulin release occur only when intracellular calcium levels are elevated, a condition detected by calcium-binding proteins called synaptotagmins. Secretory granules are spread throughout the $\beta$-cell cytoplasm, and their transport to the plasma membrane is likely regulated separately from the final release process. A ready pool of docked granules enables a swift initial release of insulin in response to glucose stimulation, characterized by a brief, high-rate exocytotic phase.
Insulin treatment is associated with substantial weight gain, leading to unfavorable changes in lipid levels and blood pressure, similar to those observed in the insulin resistance syndrome. In the UK Prospective Diabetes Study (UKPDS), insulin therapy resulted in a mean weight gain of approximately 7 kg over 12 years in newly diagnosed individuals with type 2 diabetes mellitus (T2DM). Additionally, sulfonylureas, which stimulate insulin secretion, are known to cause weight gain, with glibenclamide treatment in the UKPDS leading to an average weight gain of about 5 kg.
At diagnosis of diabetes mellitus, during each consultation if metabolic control is insufficient or vascular risk factors are not well controlled, every year as a routine, at the initiation of insulin therapy, and when special nutritional problems arise, medical evaluations and interventions related to diabetes management are indicated.
The future of diabetes care is expected to face significant challenges due to rising incidence rates, leading to more complications and higher healthcare costs. The global prevalence of diabetes is projected to increase from 6.6% in 2010 to 7.8% by 2030, with the number of individuals affected rising from 285 million to 435 million. In the USA, one in three babies born is predicted to develop diabetes during their lifetime, emphasizing the urgency for preventive measures. Low and middle-income countries are anticipated to experience a sharp rise in diabetes cases. Healthcare costs related to diabetes already exceed $174 billion annually in the USA, with global costs being even higher, and these figures are expected to grow. As a result, improved care models and intensified prevention efforts will be essential to manage the increasing burden of diabetes.
Eruptive xanthomas are skin lesions that can occur in association with hyperlipidemia, which is often seen in individuals with poorly controlled diabetes, particularly diabetes mellitus type 2, and may present as small, yellowish papules on areas such as the buttocks and knees.
SGLT-2 inhibitors are used in the management of diabetes, acting by reversibly inhibiting SGLT-2 at low nmol/l concentrations, which blocks the glucose reabsorption site in the kidneys for several minutes. These medications are administered as once-daily tablets with rapid absorption and high bioavailability. They are predominantly protein-bound in plasma and primarily metabolized via glucuronidation by uridine diphosphoglucuronosyltransferases into inactive metabolites. SGLT-2 inhibitors exhibit minimal interaction with P450 enzymes, resulting in few clinically significant drug interactions.
Integration of care ensures continuity of care, which is a guiding principle for diabetes care in low- and middle-income countries (LMICs), aiming to maintain health over the life course by avoiding exposures to diabetes risk factors at different ages through measures such as proper maternal nutrition, breastfeeding, access to food, and proper living conditions during childhood, adolescence, and adulthood, representing the public health role of the health system, while a parallel continuum of care focuses on access to comprehensive services and interventions that address the health needs and well-being of individuals from the identification of a health condition until recovery of a functional state, ensuring optimal treatment within the health system.
For people with hypertension and type 2 diabetes, the optimal blood pressure goal remains uncertain, as studies show no significant difference in cardiovascular outcomes between targets below 120 mmHg and 140 mmHg, though lower targets may reduce stroke risk. Blood pressure lowering improves mortality and clinical outcomes in those with baseline blood pressure of 140 mmHg or higher, but may be harmful if baseline is lower. In younger individuals with shorter diabetes duration, fewer comorbidities, and higher risk for stroke and renal events, a target range of 130–140/80–90 mmHg may be appropriate, with European guidelines recommending below 130 mmHg for those younger than 65 years.
Simple policy changes can improve diabetes care by addressing cost and supply chain issues through prescriptions valid for several months but dispensed monthly, and by improving continuity of care through linking rotating junior doctors with more permanent staff so that patients see someone familiar, particularly helpful for managing complex diabetic problems such as insulin allergy or psychosocial challenges like poor family support.
The incidence of hypoglycaemia in insulin-treated type 2 diabetes is approximately one-third of that in type 1 diabetes, with rates of any and severe hypoglycaemia being ~1600 and 35 episodes per 100 patient-years respectively, compared to ~4300 and 115 episodes in type 1 diabetes. Population-based studies show the incidence of severe hypoglycaemia requiring emergency treatment in insulin-treated type 2 diabetes is ~40% to 100% of that in type 1 diabetes. The Hypoglycaemia Awareness Tool study found hypoglycaemia rates to be three times higher than population-based estimates when using self-reported data over six months. Despite lower individual risk, most episodes of iatrogenic hypoglycaemia occur in type 2 diabetes due to its ~20-fold higher prevalence and the eventual need for insulin treatment in most cases.
Hypoglycaemia and hypokalaemia are common complications during the management of diabetic ketoacidosis (DKA), with hypoglycaemia occurring in approximately 10–30% of individuals with type 1 diabetes, often several hours after starting intravenous insulin infusion. The main causes of hypoglycaemia during DKA management include delayed initiation of glucose-containing fluids or failure to reduce the insulin infusion rate when blood glucose reaches 14 mmol/l (250 mg/dl). Frequent glucose monitoring is crucial as early warning symptoms like sweating, anxiety, hunger, or tachycardia may be absent or masked by the stress of DKA. Acute kidney injury is also a common complication of DKA due to hypovolaemia from osmotic diuresis leading to pre-renal failure, while cerebral injury, though rare in adults, occurs in about 1% of children with DKA.
Certain anti-diabetes medications require careful consideration in individuals at elevated risk for heart failure or those who have heart failure, although the overall response to most heart failure therapies is not affected by diabetes status and the management of both HFrEF and HFpEF remains similar for people with or without diabetes.
Practical monitoring of diabetes management became feasible in the late 1970s with the introduction of test strips for measuring blood glucose in fingerprick samples, allowing most people with diabetes to monitor at home. The discovery of haemoglobin A1c by Samuel Rahbar led to glycated haemoglobin (HbA1c) assays, which provided an objective measure of overall glucose levels. These advancements enabled the North American Diabetes Control and Complications Trial (DCCT), which in 1993 demonstrated that optimal glycaemic management prevents and delays microvascular complications in type 1 diabetes. For type 2 diabetes, the UK Prospective Diabetes Study (UKPDS) showed in 1998 that improved glycaemic levels benefit microvascular complications and emphasized the importance of treating hypertension. By the late 1990s, it was established that lowering glucose levels, high blood pressure, or cholesterol separately could reduce the frequency of heart disease and death.
Cushing syndrome can lead to hyperglycaemia and diabetes through mechanisms involving elevated levels of non-esterified fatty acids (NEFA) and increased expression of phosphoenolpyruvate carboxykinase (PEPCK), which contribute to insulin resistance and impaired glucose metabolism.
The secretion of insulin is a complex process involving both nutrient initiators and non-nutrient potentiators, with the overall insulin output depending on the interaction between these factors at the level of individual beta cells, the synchronization of secretory activity within beta cells of individual islets, and the coordination of secretion across the many islets in the human pancreas. Understanding these mechanisms is important in the context of diabetes, as inappropriate insulin secretion can lead to harmful hypoglycemia.
Cardiovascular outcomes trials in type 2 diabetes have evaluated the composite endpoint of MACE and recruited individuals with increased cardiovascular risk, including those with a history of atherosclerotic disease or multiple cardiovascular risk factors. DPP-4 inhibitors and insulin glargine have shown neutral effects on cardiovascular outcomes, while insulin degludec was non-inferior to insulin glargine in this regard. GLP-1RAs and SGLT-2 inhibitors have demonstrated favorable effects on MACE and mortality, with both drug classes also showing benefits in kidney outcomes; SGLT-2 inhibitors further improved heart failure endpoints. The effects of SGLT-2 inhibitors have been studied in dedicated trials involving individuals with chronic kidney disease or heart failure regardless of diabetes status. Current guidance recommends selecting pharmacological treatments for type 2 diabetes based on atherosclerotic cardiovascular risk profile and presence of chronic kidney disease, heart failure, or obesity-related morbidities.
Adjusting alarm thresholds for glucose sensors involves setting initial thresholds and optimizing them over time based on continuous glucose monitoring data, with specific consideration for individuals with hypoglycaemia unawareness or a history of severe hypoglycaemic reactions, for whom the low glucose alarm threshold should be set at or above 4.5 mmol/l (80 mg/dl) to prioritize reducing hypoglycaemia, taking into account the physiological lag between blood and interstitial glucose levels depending on the device used.
Older people with diabetes benefit from statin therapy, as shown by a post hoc analysis of the Heart Protection Study, which found a 25% risk reduction in cardiovascular events among participants with diabetes aged 40–80 years. The PROSPER study, involving individuals aged 70–82 years with 10.5% having diabetes, demonstrated a 15% reduction in cardiovascular endpoints in those receiving statin therapy, whether for primary or secondary prevention. A meta-analysis of 14 trials involving 18,686 people with diabetes showed a 20% relative risk reduction in major adverse vascular outcomes with statin use in both older (≥65 years) and younger (<65 years) individuals, supporting the effectiveness of statin therapy for primary and secondary prevention in older adults with diabetes up to age 80.
Hyperglycaemia and weight loss are recognized as symptoms of pancreatic adenocarcinoma by diabetes healthcare professionals, along with glucose derangements associated with functional pancreatic neuroendocrine tumours and in individuals who have undergone pancreatectomy. The management of glucocorticoid-induced hyperglycaemia in individuals receiving chemotherapy is a common aspect of diabetes care. Diabetes management often worsens following a cancer diagnosis, potentially due to the psychological impact of the cancer diagnosis on the individual.
Sulfonylureas may accumulate in renal failure, leading to an increased risk of hypoglycemia and toxicity, so insulin or sulfonylureas not cleared through the kidneys, such as glicludone or gliclazide, should be used instead. Metformin accumulates in renal failure, increasing the risk of lactic acidosis, and should therefore be avoided. ACE inhibitors or ARBs can cause an initial rise in plasma creatinine and pose a risk of hyperkalemia, requiring cautious use and appropriate monitoring of renal function. NSAIDs or COX-2 inhibitors may further compromise renal function and should be avoided if possible. Radiocontrast media can reduce renal function, so adequate hydration before the procedure is recommended. β-Adrenoceptor antagonists can accentuate hypoglycemia in patients with diabetes.
Diabetes is commonly comorbid with heart failure and is associated with an increased risk of adverse outcomes, including higher rates of New York Heart Association class III or IV symptoms, reduced six-minute walk distance, and a 46% higher risk of unfavorable quality of life based on the Kansas City Cardiomyopathy Questionnaire. Diabetes is a strong predictor of hospitalization after heart failure diagnosis, and it increases the risk of all-cause, cardiovascular, and heart failure-related hospitalizations and death. Compared to those without diabetes, individuals with diabetes have a 28% higher risk of death after accounting for cardiovascular risk factors. Among heart failure subtypes, diabetes is associated with a higher risk of cardiovascular death or heart failure hospitalization in those with HFpEF compared to HFrEF, with hazard ratios of 2.0 and 1.60 respectively, although the excess risk of death is similar between HFrEF and HFpEF.
Diabetes prevalence varies across regions in Pakistan, with higher rates observed in rural Sindh Province at 16% in men and 12% in women. A more recent study indicates urban and rural male prevalence rates of 10–11%, with urban women showing similar rates and rural women lower at 5.9%. However, IGT rates in females were twice those in males. In urban areas across Pakistan, diabetes prevalence was 6.0% in men and 3.5% in women, with an estimated 22% of the urban population having some degree of glucose intolerance. WHO projections based on the National Diabetes Survey indicate a significant increase in T2DM cases in Pakistan from 4.3 million in 1995 to 14.5 million by 2025. In rural Bangladesh, diabetes prevalence is lower at 2.1%, but IGT prevalence is higher at 13%, despite a relatively low mean BMI of 20.4 kg/m².
Aggressive blood pressure lowering to a systolic target of less than 120 mmHg in individuals with type 2 diabetes did not reduce mortality or ischaemic heart disease but decreased stroke events by 47%, though it was associated with more arrhythmic events, hypokalaemia, and hypotension, making it unsuitable for general recommendation. In patients with diabetes and established ischaemic heart disease, overly intense blood pressure lowering increased mortality risk, with those having systolic blood pressure below 110 mmHg showing significantly higher mortality compared to those between 125 and 130 mmHg. The VADT study found that lowering diastolic blood pressure to less than 70 mmHg increased cardiovascular event risk, indicating that extremely low blood pressure targets are not advisable for people with diabetes at high cardiovascular risk, especially those with established coronary artery disease.
Repaglinide is ideally taken 15–30 minutes before a meal, with therapy introduced at a low dose (e.g., 0.5 mg), and glycemic control should be monitored during dose titration every 2 weeks up to a maximum of 4 mg before each main meal; the corresponding dose should be omitted if a meal is not consumed, and with appropriate caution and monitoring, repaglinide can be administered to patients with moderate renal impairment where certain other antidiabetic agents like sulfonylureas and metformin are contraindicated.
Pharmacologic therapy that interrupts the renin-angiotensin system (RAS) may provide special benefits in reducing cardiovascular disease (CVD) in people with diabetes. In a post hoc subgroup analysis of the Captopril Prevention Project (CAPP) study, patients with diabetes treated with captopril had significantly better outcomes compared to those on conventional therapy with beta-blockers and diuretics, particularly in terms of the primary endpoint, myocardial infarction (MI), all cardiac events, and total mortality. The beneficial effects of ACE inhibitor therapy were most pronounced in patients at highest risk, such as those with elevated fasting glucose or higher blood pressure. In contrast, the UKPDS found comparable CVD benefits in patients with type 2 diabetes mellitus (T2DM) treated with either captopril or atenolol, which may reflect the lower CVD risk among the newly diagnosed patients studied in that trial.
Weight management is increasingly relevant for individuals with type 1 diabetes due to rising rates of overweight and obesity, which can co-occur with insulin resistance and contribute to hyperglycaemia. However, there is limited evidence that body weight or intentional weight loss significantly affects glycaemic control in type 1 diabetes. In both type 1 and type 2 diabetes, distinguishing between intentional and unintentional weight loss is important, as unintended weight loss may indicate poor medical management, medication omission, or inadequate dosing, all of which can lead to hyperglycaemia.
Loss-of-function mutations in the GCK gene cause a form of diabetes that presents in the neonatal period and requires insulin treatment, with over 200 such mutations identified, while gain-of-function mutations in the same gene lead to congenital hyperinsulinism.
Islet transplantation may lead to improvement or stabilization of diabetic retinopathy in approximately 80% of patients over 3 years, but a subset of patients (18.4% in one cohort) may experience complications such as vitreous hemorrhage or require laser photocoagulation, indicating the need for ongoing ophthalmologic monitoring.
Long-term complications of diabetes, such as retinopathy, neuropathy, and nephropathy, can have a significant impact on an individual's health and are a major concern for people with diabetes. These complications may be perceived as a sign of failure in self-management by individuals, families, healthcare providers, and others, leading to psychological distress, changes in self-perception, and feelings of self-blame and guilt. Research indicates a bidirectional relationship between depression and diabetes complications, with depression being a stronger predictor of complications than the reverse. Baseline depression is associated with an increased risk of both macrovascular (hazard ratio 1.38) and microvascular complications (hazard ratio 1.33), while having diabetes complications is linked to a higher risk of developing depressive disorder (hazard ratio 1.14).
Metrics such as the low glucose index (LGI), high glucose index (HGI), and average daily risk range (ADRR) are used to assess glucose variability in diabetes management, with LGI reflecting hypoglycaemic excursions, HGI reflecting hyperglycaemic excursions and correlating with $\mathrm{HbA_{1c}}$, and ADRR capturing overall glucose variability including both hypo- and hyperglycaemic risks; additional measures like the lability index and mean absolute glucose change (MAGE) are applied in hospital settings to evaluate outcomes such as islet transplantation effects or mortality risk in intensive care.
The onset of diabetes during adulthood can lead to adjustment disorders within several months of diagnosis, affecting both the patient and family members. In a German study, newly diagnosed adult patients with type 1 diabetes mellitus (T1DM) had a higher rate of major depressive episodes compared to a national reference group, particularly among women (9.3% vs. 3.2%), though no significant difference was found for men or other psychiatric disorders. This cross-sectional data does not clarify if the depression is chronic or a transient adjustment disorder. In contrast, studies on adults with type 2 diabetes mellitus (T2DM) show minimal psychological distress in the first year after diagnosis, with over 50% reporting no emotional reaction and feeling capable of coping. Negative emotional reactions were noted in 26% of cases, often linked to lower social support. Another larger study found little psychological reaction in 824 newly diagnosed T2DM patients, with women showing higher depressive symptoms than men (16.1% vs. 8.2%), but these rates were similar to general population norms. Increased depressive symptoms in T2DM patients were associated with greater medical comorbidities, particularly among those using both lipid-lowering and antihypertensive medications.
Coronary heart disease and limb amputation rates vary significantly across different regions, with ischaemic heart disease and lower-extremity amputations being relatively rare in Hong Kong and Tokyo, while stroke incidence is notably high, especially in Hong Kong. Indigenous American populations in Arizona and Oklahoma also show high stroke rates, along with a significant occurrence of myocardial infarction, particularly among men. The highest rates of ischaemic heart disease are found in European centres, especially among women in Warsaw, while renal failure and proteinuria are most prevalent among Indigenous Americans and in Hong Kong.
Early-onset non-autoimmune diabetes mellitus is a feature of the syndrome known as DIDMOAD, which includes diabetes insipidus, optic atrophy, and deafness. Variants in the  $WFS1$  gene, such as the non-synonymous SNP R611H, are associated with an altered risk of adult type 2 diabetes mellitus (T2DM), with a minor allele frequency of approximately 40% and an odds ratio of around 0.92. These genetic variants account for 9% of the population attributable fraction and may explain 0.3% of the excess familial risk in T2DM. The  $WFS1$  gene, which encodes wolframin, plays a critical role in the endoplasmic reticulum stress response in insulin-producing pancreatic β-cells, further contributing to the development of common T2DM.
Individuals with diabetes are up to four times more likely to develop cardiovascular disease, and those with impaired glucose tolerance also face an elevated risk compared to individuals with normoglycaemia. Nutritional recommendations for diabetes focus on glucose management and reducing the risk of cardiovascular disease and its complications. The strength of these recommendations is based on the type and quality of published studies and expert committee statements. While meta-analyses of large, well-controlled trials with long follow-up periods are considered the gold standard for evidence-based guidelines, surrogate endpoints such as glycaemia, body composition, lipoprotein profile, blood pressure, insulin sensitivity, and renal function are often used to assess the impact of dietary modifications on glycaemic levels and the risk of acute and chronic complications of diabetes.
Some herbal, traditional, and folk remedies contain compounds with mild glucose-lowering effects, though certain preparations have led to severe hypoglycemia due to the presence of undeclared sulfonylureas.
Increased understanding of the pathogenesis of type 1 diabetes has led to improved approaches for specific prevention, with current promising therapies focusing on effector and regulatory T cells, and combination therapies potentially offering greater effectiveness by targeting both the immune system and the $\beta$ cell. Advancements in biomarker screening are essential to determine likely responders and non-responders to specific treatments, ultimately contributing to better management, prevention, and possible reversal of type 1 diabetes.
Brain- islet connections involving both the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) play a role in the regulation of insulin secretion and glucose homeostasis.
Management of diabetes in children involves careful monitoring of blood glucose levels, appropriate insulin therapy, and individualized treatment plans to maintain glycemic control while minimizing the risk of hypoglycemia. Education of the child and caregivers regarding diet, physical activity, and insulin administration is essential. Regular follow-up and adjustment of therapy are necessary to address growth, developmental changes, and varying insulin requirements.
A 5% weight loss did not affect oral glucose tolerance or other measures of glycaemia but improved organ-specific insulin sensitivity in adipose tissue, liver, and skeletal muscle. Insulin-mediated suppression of hepatic glucose production and adipose tissue lipolytic activity were maximal after 5% weight loss, while insulin-stimulated muscle glucose uptake increased further with greater weight loss of 11-16%. Greater weight loss beyond 5% further improved β cell function, intrahepatic triglyceride content, and adipose tissue expression of genes involved in cholesterol flux, lipid synthesis, extracellular matrix remodelling, and oxidative stress. The Cuban economic collapse from 1991 to 1995 provided real-world evidence for the impact of energy restriction on weight loss and diabetes, with a population-wide average weight loss of 5.5 kg associated with a 53% fall in diabetes incidence at the lowest point.
Increased vascular superoxide production in diabetes is associated with atherosclerosis and is mediated by elevated NAD(P)H oxidase (Nox) activity, particularly through upregulated Nox subunits such as p47phox, gp91phox, and rac-1. This heightened local vascular reactive oxygen species (ROS) generation is further evidenced by increased nitrotyrosine staining in diabetic plaques. Interventions that reduce vascular superoxide production may offer therapeutic benefit in this context.
Insulin sensitivity increases immediately after childbirth, returning to normal within 1–2 weeks. Insulin infusion should be reduced by approximately 50% once the umbilical cord is cut, with regular monitoring of capillary blood glucose and administration of intravenous fluids until the mother resumes normal eating. This process requires close supervision by the diabetes care team and adjustment of insulin as needed. Women should consume a small snack before breastfeeding to prevent hypoglycemia, and may require higher insulin doses during the day due to increased caloric intake, while needing less at night because glucose is redirected into breast milk. Long-acting insulin should be reduced during breastfeeding. Maintaining normal maternal glucose levels is important to avoid elevated milk glucose and maternal hypoglycemia, which can be managed through regular snacking and careful insulin adjustments supported by diabetes specialists.
In diabetes, dysregulation of lipolysis in adipose tissue can contribute to metabolic disturbances, as insulin's antilipolytic action is impaired, leading to excessive release of free fatty acids and elevated levels of glycerol, which may exacerbate insulin resistance and disrupt glucose homeostasis.
Several behavioural and psychological interventions have been developed to improve engagement in self-care among people with diabetes, differing from traditional group therapy programmes by using multiple sessions to target specific self-care behaviours and the associated psychological factors that may influence them.
Current glucose-lowering therapies act at various sites to manage blood glucose levels, with different classes targeting specific mechanisms such as inhibiting DPP-4, enhancing GLP-1 activity, modulating PPAR, or blocking SGLT-2, though not all are approved for treating type 2 diabetes in every region.
Acute complications of diabetes should be assessed through history, with ongoing education provided to prevent recurrence. Adolescents and young adults with type 1 diabetes are at risk for psychiatric disorders such as depression and eating disorders, which can worsen during the transition to adulthood, and diabetes care teams should actively identify and address these issues. Substance use, including alcohol, tobacco, and illicit drugs, can increase the likelihood of diabetes complications like diabetic ketoacidosis. Chronic vascular complications, including retinopathy, nephropathy, neuropathy, and cardiovascular disease, may begin in childhood and progress into young adulthood, with higher risk for those who develop diabetes before or during puberty compared to after puberty. Various organizations provide guidelines for screening these complications.
Yellow nails, particularly in the distal hallux, are frequently observed in patients with diabetes and may serve as an early sign of the condition. The discoloration typically begins as yellowish or brownish in the distal part of the hallux nail plate and later progresses to a canary yellow color, potentially affecting both toe and finger nails. Although yellow nails can occur in onychomycosis, psoriasis, and in the elderly, in diabetes they appear to be a distinct marker unrelated to these other causes. Studies have shown that patients with diabetes exhibit high levels of furosine lysine in finger nails, which is another marker of non-enzymatic glycosylation.
Thickening of skin, tendons, and tendon sheaths has been observed in individuals with limited joint mobility, and histological examination reveals altered mucopolysaccharide distribution, elastin, and collagen, along with reduced vascular lumen. Non-enzymatic glycation and collagen accumulation are involved in the development of these changes. Disordered glycosaminoglycan metabolism is also present, with increased hyaluronan expression in the epidermis and decreased expression in the dermis and basement membrane in those with severe limited joint mobility, particularly in people with diabetes. Additionally, increased urinary glycosaminoglycan excretion occurs in individuals with this condition. Reduced levels of circulating insulin-like growth factor I (IGF-I) are linked to limited joint mobility, suggesting involvement of the growth hormone (GH)-IGF axis in its pathogenesis. Microvascular abnormalities, including impaired palmar microvascular flow in response to thermal challenge, also contribute to the disease process.
People with diabetes are at risk of macrovascular and microvascular complications even at blood pressure levels below standard hypertension thresholds, necessitating lower treatment targets such as below 130/80 mmHg for those younger than 65 years, but not lower than 120/70 mmHg, and between 130-140 mmHg systolic for older individuals. Hypertension, defined by WHO criteria as >140/90 mmHg, is up to twice as common in people with diabetes compared to the general population. In white Europeans, 10-30% of those with type 1 diabetes and 60-80% with newly diagnosed type 2 diabetes have hypertension. Racial and ethnic differences exist in hypertension prevalence, with lower rates observed among Pima and Mexican Americans. Impaired glucose tolerance is also linked to hypertension in 20-40% of cases, likely due to shared mechanisms within the metabolic syndrome.
Effective weight management delivered in primary care can lead to sustained remission of type 2 diabetes, as shown in the Diabetes Remission Clinical Trial (DiRECT). The trial included individuals aged 20–65 years with non-insulin-treated type 2 diabetes diagnosed within six years and a BMI of 27–45 kg/m². Participants received an intervention involving withdrawal of anti-diabetes and antihypertensive drugs, followed by a total diet replacement (825–853 kcal/day for 3–5 months), stepped food reintroduction (2–8 weeks), and structured support for long-term weight loss maintenance. At one year, 24% of the intervention group achieved weight loss ≥15 kg, and none in the control group achieved this. Diabetes remission, defined as HbA1c less than 6.5% (<48 mmol/mol) after at least two months off all anti-diabetes medications, was observed in the intervention group.
A target capillary plasma glucose of 3.9–7.2 mmol/L is recommended based on outcome studies like UKPDS and DCCT, where HbA1c was shown to predict complications. Most patients with T2DM treated with long-acting insulin continue oral glucose-lowering medication. Recommended monitoring schedules aim to reduce HbA1c to within target levels, although their intensity has not been evaluated in broader or more primary care populations. Fasting blood glucose testing twice a week allows weekly or biweekly titration of long-acting insulin for tight control, while 4- or 7-point glucose profiles every 3–4 weeks may help identify patterns needing intervention, such as hypoglycemia or elevated postprandial glucose, which might necessitate short-acting insulin before meals.
Glycaemic memory refers to the long-term effects of prior glycaemic status on the development of diabetic complications, where chronic hyperglycaemia in early stages of diabetes can accelerate complications later even if blood glucose levels improve. Evidence from the DCCT/EDIC trial in type 1 diabetes, and the Steno-2 and UKPDS trials in type 2 diabetes, supports the idea that higher levels of hyperglycaemia are linked to greater complication risks. However, the VADT study in type 2 diabetes, which compared intensive and standard glucose management after prolonged exposure to hyperglycaemia (12–15 years), did not show significant cardiovascular benefits from intensive treatment.
Taspoglutide, a modified human GLP-1 receptor agonist resistant to DPP-4 degradation with a prolonged release profile suitable for once-weekly administration, reduces HbA1c levels by 1.4–1.5% (15–16 mmol/mol) after 8 weeks of treatment at doses of 10 and 20 mg, enabling approximately 80% of patients to reach an HbA1c goal of 7.0% (53 mmol/mol) from a baseline mean of 7.9% (63 mmol/mol), and also leads to a weight reduction of about 2.1–2.8 kg over the same period.
Patients with diabetes have a higher risk of developing trigger finger, with a lifetime risk of 10% compared to 2.6% in the general population. The risk is influenced by patient age, duration of diabetes, and the presence of microvascular complications. Trigger finger associated with diabetes typically results in worse outcomes, including reduced response to corticosteroid injections and increased need for surgery. Type 1 diabetes mellitus (T1DM) is linked to a higher disease prevalence, more affected digits, greater surgical requirements, and a higher recurrence risk.
For patients who are unable to cooperate but can swallow, hypoglycemia can be managed by administering 1.5–2 tubes of GlucoGel™ between the teeth and gums, or 1mg of glucagon intramuscularly if GlucoGel is ineffective. Blood glucose levels should be monitored after 15 minutes, and if still below 4 mmol/L, GlucoGel can be repeated up to three times. If hypoglycemia persists despite this, an IV infusion of 10% glucose at 100 mL per hour may be necessary. Once blood glucose rises above 4 mmol/L and the patient has recovered, a long-acting carbohydrate snack should be provided.
Islet cells regulate insulin secretion through multiple communication mechanisms, including gap junctions, cell surface adhesion molecules such as E-cadherin and ephrins, and intra-islet paracrine and autocrine effects involving hormones like insulin, glucagon, and somatostatin, as well as neurotransmitters, adenine nucleotides, and gaseous signals such as nitric oxide and carbon monoxide. These interactions are essential for coordinating hormone secretion in response to physiological conditions.
Thiazide diuretics used at low dosages lower blood pressure effectively and are suitable for use in patients with diabetes, while certain drugs require special consideration in patients with diabetic complications. Metformin and several sulfonylureas are cleared through the kidney, making them contraindicated in advanced nephropathy and unsuitable for co-administration with nephrotoxic drugs. Non-selective β-adrenoceptor antagonists inhibit insulin secretion, impair glucose tolerance, and reduce awareness of hypoglycemia, thereby delaying recovery to normoglycemia; these adverse effects are much less pronounced with cardioselective β-adrenoceptor antagonists. Alcohol can provoke, prolong, or exacerbate hypoglycemia by inhibiting hepatic gluconeogenesis, and hypoglycemia can also be complicated by overdosage with acetaminophen or aspirin, which blocks hepatic glucose output and stimulates peripheral glucose uptake.
In the context of diabetes, glucagon-driven hepatic glucose production involves glycogenolysis and gluconeogenesis, with their contributions varying over time during fasting. Glycogenolysis accounts for about 50% of liver glucose output in the postabsorptive state but drops to less than 10% after 36 hours of fasting. Acute increases in glucagon action primarily stimulate glycogenolysis, while gluconeogenesis activation depends on the availability of precursors like lactate, alanine, and glycerol. The delivery of these precursors to the liver is not directly controlled by glucagon and requires prolonged fasting to lower plasma insulin and promote lipolysis and proteolysis. During extended starvation, gluconeogenesis is further regulated by precursor supply to preserve protein stores.
Gestational diabetes mellitus (GDM) prevalence varies significantly across different regions, with rates ranging from 9.3% in Israel to 25.5% in the US, and some centers reporting rates as high as 40%. The adoption of new diagnostic thresholds has led to a 2–3-fold increase in GDM prevalence in many countries, raising concerns about the appropriateness and validity of these higher rates. Observational studies indicate that treating GDM defined by IADPSG criteria, which result in higher prevalence, does not significantly improve outcomes compared to using older criteria that identify fewer cases.
Telehealth interventions are increasingly used in pregnancies complicated by gestational diabetes mellitus (GDM), though current studies have involved highly selected populations, and challenges remain regarding technology usability, data reliability, and their role in clinical decision-making, despite ongoing technological advancements offering potential benefits.
Combination oral contraceptives have been historically linked to metabolic abnormalities such as glucose intolerance, with concerns about their oestrogen component contributing to overt diabetes. Research has explored whether COCs affect glucose metabolism through alterations in insulin sensitivity and secretion, but current evidence does not support a significant impact on glucose homeostasis or the development of diabetes. A recent analysis found that women with gestational diabetes were nearly 1.5 times more likely to have used hormonal contraception before conception, suggesting a potential association. However, a Cochrane review analysing 31 trials found no significant differences in carbohydrate metabolism across different COC preparations, based on measures such as fasting and post-prandial glucose, insulin levels, glucose area-under-the-curve, and HbA1c. The metabolic risk of oral contraceptives in women with obesity remains unclear due to study design limitations.
Type 1 diabetes mellitus (T1DM) has been studied in relation to enterovirus infections, with some research suggesting a possible association. Certain studies have found an increased risk of childhood-onset T1DM linked to maternal enterovirus infections during pregnancy, though findings are inconsistent. Prospective studies from Finland using serum enterovirus antibodies and RNA as markers have reported a connection between enterovirus and elevated risk of islet autoimmunity and T1DM, but other similar studies have not confirmed this association. An immunohistochemical study detected enterovirus capsid protein VP1 in the β-cells of multiple islets from individuals with recent-onset T1DM in 44 out of 72 cases, with very few positive controls, supporting earlier smaller studies. However, these findings require further confirmation using in situ hybridization to detect enterovirus RNA in a larger sample set. Additionally, while enterovirus infections have become less frequent due to improved hygiene, the incidence of T1DM in children has increased, leading to the hypothesis that reduced protection from maternal enterovirus antibodies may contribute to this trend, though direct evidence remains lacking.
Many men with diabetes will be taking medication known to cause erectile dysfunction (ED), and experience has shown that changing the treatment in an attempt to improve sexual function rarely works, potentially causing delays and frustration for the patient; therefore, such changes are not advisable unless there is a strong temporal relationship between starting treatment and the onset of ED.
Insulin injections can be introduced for individuals with type 2 diabetes mellitus (T2DM) who are no longer managing their blood glucose effectively with diet, lifestyle changes, and oral therapy alone, typically starting with one injection per day as an add-on to existing oral therapies rather than a replacement. Studies show that once-daily basal insulin can be combined with metformin, sulfonylureas, or pioglitazone, and may also be used alongside dual or triple oral therapy regimens. Guidelines from the UK, Europe, and the USA support the use of basal insulin in combination with oral therapies for initiating insulin treatment in T2DM patients. However, newer agents like DPP-4 inhibitors and GLP-1 receptor agonists currently lack approval for use with insulin therapy in T2DM, although ongoing trials may influence future licensing.
Chinese people with type 2 diabetes and chronic HBV infection are more likely to develop end-stage kidney disease compared to those without HBV infection, with an increased hazard ratio of 4.5. Additionally, individuals with HBV infection tend to experience an earlier onset of diabetes and have a higher frequency of diabetic retinopathy than those without HBV infection, although cardiovascular complications do not appear to be affected.
The text describes various GLP-1 receptor agonists used in the treatment of diabetes, including Liraglutide (Victoza), a GLP-1 analog linked to palmitoyl fatty acid with a half-life of 12–13 hours administered once daily subcutaneously; Exenatide-LAR, a long-acting release exendin given once weekly subcutaneously; Albiglutide (Syncria), a complex of alimeric GLP-1 bound to albumin administered once weekly subcutaneously; LY548806, a DPP-4 resistant GLP-1 analog; LY315902, a GLP-1 analog linked to a fatty acid; Taspoglutide (BIM-51077, R1583), a long-acting GLP-1 analog given once weekly subcutaneously; CJC-1131, a GLP-1 analog linked to a chemical complex; and Lixisenatide (ZP10A, AVE0010), a GLP-1 analog.
DPP-4 inhibitors are a class of medications developed for therapeutic use, with the first compounds tested in the late 1990s but lacking sufficient specificity for clinical application. More specific DPP-4 inhibitors were later developed, leading to the introduction of sitagliptin in 2007 and vildagliptin in 2008 in several countries. Saxagliptin, another DPP-4 inhibitor, was introduced in 2009, and additional inhibitors in this class are currently under development.
Individuals with severe insulin-resistant diabetes are more likely to carry the risk allele of the PNPLA3 rs738409 polymorphism, which is associated with impaired TAG hydrolysis and higher adipose tissue insulin resistance, suggesting a role of PNPLA3 in adipose tissue function. Gene-environment interactions may predispose even lean individuals to hepatic insulin resistance, NAFLD, and type 2 diabetes, although there are exceptions such as Chanarin-Dorfman syndrome, where ectopic lipid deposition occurs without insulin resistance due to a mutation in ABHD5 leading to CGI-58 deficiency, preventing DAGs from promoting PKCε translocation and inhibiting insulin signaling in the liver.
Antibiotic-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are an increasing concern in diabetic foot clinics, often arising as opportunistic colonizers following inappropriate long-term use of broad-spectrum antibiotics. When MRSA is suspected as the infecting organism in diabetic foot infections, newer agents like linezolid offer effective treatment options, available both parenterally and orally. Additionally, larval therapy has been suggested as a potential method for eradicating MRSA in contaminated diabetic foot wounds.
Type 1 diabetes is an autoimmune disease that shares common or overlapping aetiology and pathophysiological mechanisms with other autoimmune conditions such as Addison disease and autoimmune thyroid disease, necessitating consideration of new autoimmune pathology in affected individuals. Screening for hyperthyroidism or hypothyroidism using serum thyroid-stimulating hormone (TSH) measurement is recommended annually in people with type 1 diabetes. The presence of Addison disease in individuals with type 1 diabetes can significantly increase insulin sensitivity, leading to unexpected hypoglycaemia even with reduced insulin doses. Rare conditions that resemble type 1 diabetes may present with associated endocrinopathies, including autoimmune polyglandular syndromes and POEMS syndrome. Monogenic causes of diabetes can also affect other endocrine organs, as seen in conditions like haemochromatosis (associated with primary hypogonadism), Wolfram syndrome (linked to diabetes insipidus), and Kearns-Sayre syndrome (involving hypoparathyroidism, hypogonadism, and hypopituitarism).
Time in range for blood glucose levels is defined as 3.5 to 7.8 mmol/l (63 to 140 mg/dl) with a goal of maintaining levels within this range more than 70% of the time.
Sleep disturbance in people with type 1 diabetes and type 2 diabetes can negatively impact efforts at optimal diabetes self-management, potentially through several putative mechanisms, although formal tests of mediation in prospective cohort studies are lacking. Addressing sleep disturbance as part of the clinical management of diabetes may be beneficial.
A phase II clinical study evaluated the use of a TGF-β antibody in individuals with type 1 diabetes and diabetic nephropathy, showing a minor effect on the rise in serum creatinine. Pirfenidone, which blocks TGF-β promoter activity, was tested in individuals with type 1 and type 2 diabetes and kidney disease who were already on renin-angiotensin system blockade, demonstrating a beneficial effect on estimated glomerular filtration rate (eGFR) compared to placebo, though with a high dropout rate among those treated. Preclinical studies have indicated positive effects on kidney variables by blocking the CTGF axis, and a clinical trial using a human monoclonal antibody to CTGF (FG-3019) in people with diabetic nephropathy showed that the treatment was generally well tolerated and reduced urinary albumin excretion.
DPP-4 inhibitors are a class of medications used in the management of diabetes, and their effects on pancreatic cancer have been studied. However, a Cochrane review found that the quality of evidence from 13 studies comparing DPP-4 inhibitors with placebo was too low to determine whether these medications have any impact on pancreatic cancer.
When blood glucose levels fall below 3.9 mmol/l (70 mg/dl), interventions to prevent further decline are advised, with the required glucose amount varying by individual, situation, and insulin treatment. In children, 0.3 g/kg of rapidly acting carbohydrate-containing preparations can effectively treat hypoglycaemia, raising median blood glucose by 1–1.3 mmol/l (90–113 mg/dl) within 10 minutes and by 2.0–2.1 mmol/l (180–190 mg/dl) within 15 minutes without causing rebound hyperglycaemia at the next meal. Children using insulin pump therapy may require a smaller glucose dose along with temporary suspension of insulin delivery.
The prevalence of diabetes in Greece increased from 2.4% in 1974 to 3.1% in 1990, driven by an aging population and rising obesity. Type 2 diabetes prevalence was higher in men (7.6%) than in women (5.9%) in a 2001–2002 survey, and a follow-up study found a 5.5% incidence rate of diabetes over five years among those initially free of cardiovascular disease. In Turkey, the prevalence of type 2 diabetes was 6% with an additional 9% having impaired glucose tolerance. Risk factors identified include low occupational activity, family history, and obesity, while adherence to a Mediterranean diet may offer protective effects against diabetes.
Subcutaneous injection of exogenous insulin does not replicate the natural delivery of endogenous insulin from the pancreas to the liver via the portal circulation, resulting in lower hepatic exposure. To address this, insulin analogues have been developed with large carrier molecules like polyethylene glycol, albumin, or thyroid-binding protein, which allow greater access to liver cells compared to muscle cells due to differences in capillary structure. Research continues to improve the hepato-selectivity of insulin formulations.
Some glucose-lowering agents used for diabetes management also demonstrate efficacy and safety in treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), indicating a potential dual benefit for patients with diabetes and concurrent liver conditions.
SGLT-2 inhibitors reduce the risk of end-stage kidney disease and provide cardiorenal protection in people with diabetes. These drugs stabilize kidney function and slow the progression of albuminuria, potentially by activating tubuloglomerular feedback, which lowers intraglomerular pressure and prevents hyperfiltration. Starting SGLT-2 inhibitors may cause a temporary decline in eGFR that stabilizes over time, a pattern similar to that seen with renin-angiotensin system blockade. Renal function should be assessed before initiating SGLT-2 inhibitors and monitored at least annually. Dose adjustments are required for canagliflozin and empagliflozin in patients with moderate renal impairment (eGFR < 60 ml/min/1.73 m²).
In two large cohorts of children with established type 1 diabetes, on average 4–7 per 100 developed diabetic ketoacidosis (DKA) every year, with nearly 60% of DKA episodes occurring in 5% of children who experienced recurrent events. Recurrent DKA was associated with insulin omission, suboptimal metabolic management, intercurrent gastroenteritis with dehydration, psychiatric and eating disorders, difficult family or social circumstances, limited access to medical care, and the use of insulin pump therapy. Recurrent DKA was more common in peripubertal or adolescent girls.
Metformin has been shown to reduce the risk of diabetes development in several clinical trials, including the DPP (2002) with a relative risk (RR) of 0.69, CDPS (2001) with an RR of 0.23, and IDPP-1 (2006) with an RR of 0.74. Thiazolidinediones such as troglitazone and rosiglitazone also demonstrate risk reduction, with RRs of 0.45 and 0.40 respectively in the TRIPOD (2002) and DREAM (2006) trials. The α-glucosidase inhibitor acarbose reduced diabetes risk with an RR of 0.75 in the STOP-NIDDM trial (2002). Insulin glargine demonstrated a reduced risk with an RR of 0.72 in the ORIGIN trial, with a mean dose of 0.4 units/kg/d.
Type 2 diabetes is characterized by reduced insulin sensitivity and defective insulin secretion, differing from type 1 diabetes where pancreatic β cells stop producing insulin altogether. While type 2 diabetes was historically associated with middle or older age, the rise in childhood obesity has significantly increased the number of young people diagnosed with the condition. High prevalence rates of young-onset type 2 diabetes are observed in countries like China and the USA, with 520 and 212 cases per 100,000 people respectively. In the USA and UK, certain racial and ethnic groups, including Black, Hispanic, Asian/Pacific Islander, and Native American populations, show higher incidence rates. Young individuals with type 2 diabetes face a greater risk of severe complications such as diabetic kidney disease, retinopathy, and peripheral neuropathy compared to those with type 1 diabetes. Additionally, β-cell function declines more rapidly in young people with type 2 diabetes, at an estimated rate of 20–35% annually, compared to older individuals with the same condition.
For individuals with type 1 diabetes mellitus (T1DM), factors such as older age, presence of biomedical complications, being female, lower physical activity, and lower income are associated with poorer health-related quality of life, with even a single complication having a measurable impact that worsens as the number of complications increases. Chronic hyperglycemia, indicated by higher HbA1c levels, correlates with poorer general health independent of complications, and recurrent hypoglycemia negatively affects mental, social, and physical health. Similar factors, including diabetes-related complications, demographic characteristics like being female, lower education, and reduced physical activity, also predict poorer health-related quality of life in older adults with type 2 diabetes mellitus (T2DM), although the relationship between metabolic control and quality of life remains inconclusive across studies.
Unemployment and reduced employment among individuals with diabetes have been observed in some studies, with factors such as disability from diabetic complications, depressive illness, and poor glycemic control contributing to work-related difficulties. While some surveys found no significant difference in unemployment rates between people with diabetes and the general population, others indicated that diabetes-related health issues, including intercurrent illness and early retirement, limited employment opportunities. Adolescents with diabetes are more likely to experience job loss or difficulties with shift work compared to their non-diabetic peers. In North America, workers with diabetes, particularly those with insulin-treated diabetes and poor glycemic control (HbA1c > 10%, 86 mmol/mol), show higher sickness absence rates and lower employment income, often due to diabetes-related disabilities. Improved glycemic control is associated with fewer absences and better work performance.
Seasonal variation in the diagnosis of type 1 diabetes shows a peak in cases during autumn and winter with fewer diagnoses in spring or summer, a pattern observed consistently in both hemispheres though with some variation in exact timing between countries, age groups, sexes, and periods. The seasonal variation appears more pronounced in individuals diagnosed at ages 10–14 years compared to younger children, and this fluctuation may be influenced by viral or other periodic factors affecting the timing of disease onset in susceptible individuals, considering the long and variable pre-clinical period of type 1 diabetes.
Epidemiological data suggest that circulating endotoxin is associated with an increased risk of type 2 diabetes. Studies have shown that adults with impaired fasting glucose and those with overt type 2 diabetes have higher plasma LPS concentrations compared to healthy controls. A large analysis of the FINRISK97 cohort found that individuals with type 2 diabetes had higher baseline circulating endotoxin levels, which were also predictive of those who developed type 2 diabetes over a 10-year follow-up period. Another prospective study using total 16s rDNA concentration as a marker of intestinal permeability found that higher baseline concentrations were linked to an increased risk of developing type 2 diabetes after nine years.
Sorbitol accumulation in nerve cells and sheath, along with myoinositol depletion, contributes to the development of diabetic neuropathy, while microangiopathy is a complication of diabetes that affects small blood vessels, leading to reduced blood flow and tissue damage.
Metformin is associated with gastrointestinal adverse effects such as abdominal discomfort and diarrhea, which are often transient and can be managed by taking the drug with meals and slowly titrating the dose. Some patients experience symptom remission upon dose reduction, though approximately 10% cannot tolerate the drug at any dose. A rare but serious adverse event linked to metformin is lactic acidosis, occurring at an estimated rate of 0.03 cases per 1000 patient-years, with about half of these cases being fatal. The background incidence of lactic acidosis in patients with type 2 diabetes mellitus (T2DM) is not well established, and some cases previously attributed to metformin may have been caused by other factors.
HbA₁c, initially recognized as an indicator of chronic hyperglycaemia, is now used to monitor glycaemic control, screen for and diagnose diabetes and pre-diabetes, and predict micro- and macrovascular complications. The test results are traceable to the Diabetes Control and Complications Trial (DCCT) values expressed as a percentage and can also be reported using International Federation of Clinical Chemistry (IFCC) standardized units (mmol/mol). HbA₁c offers several advantages over blood glucose measurements, though it has some limitations, especially in middle- and low-income countries, and healthcare providers should be aware of these when interpreting results.
Bolus advisors in modern insulin pumps recommend bolus doses based on target glucose values, insulin sensitivity factor, predicted carbohydrate intake, insulin-to-carbohydrate ratio, and current glucose levels, while accounting for insulin on board from prior doses. These tools help individuals with diabetes, particularly those on intensive insulin therapy, overcome challenges related to poor numeracy skills, which are common and linked to suboptimal glycemic management. Studies show that manual bolus dose calculations by people with type 1 diabetes are often incorrect, and bolus advisors can improve accuracy. Clinical trials have demonstrated that using bolus calculators can lead to greater reductions in HbA1c levels compared to mental calculations, though some studies show reductions in glucose variability and postprandial glycemic excursions without significant HbA1c changes. Users also report increased treatment satisfaction, confidence in dosage accuracy, and reduced fear of hypoglycemia when using bolus advisors.
Phosphorylation of IRS1 at serine 307 (pS307IRS1) is associated with insulin resistance and is influenced by factors such as free fatty acids, insulin, and pathways involving PI3K, AKT, mTORC1, and S6K1. In obese mice, activation of JNK1 or mTORC1 can promote pS307IRS1 and other phosphorylation sites. Genetic modification studies show that replacing S307IRS1 with alanine leads to increased fasting insulin and glucose levels, reduced PI3K binding to IRS1, and worsened glucose tolerance during a high-fat diet. Evidence suggests that pS307IRS1 and other phospho-serine/threonine modifications may help mitigate the negative effects of compensatory hyperinsulinemia to preserve insulin sensitivity in mice.
Advances in insulin delivery and glucose monitoring technologies have improved the management of type 1 diabetes. Insulin pen technology has evolved since 1985, with modern 'smart' pens capable of recording insulin dose and timing, and integrating with blood glucose monitoring and continuous glucose monitoring (CGM) systems. New insulin pumps are smaller, more user-friendly, and offer features like temporary basal rates, advanced bolus options, and integration with CGM. While there is conflicting evidence on whether continuous subcutaneous insulin infusion (CSII) is better than multiple daily injections for glycaemic control and hypoglycaemia reduction, individuals with elevated HbA1c or frequent hypoglycaemia benefit most from pump therapy. Data support a positive impact of CSII on quality of life. Tubeless patch pumps are now available and may offer advantages over traditional tubed pumps, although comparative data are limited. Common adverse effects of insulin pumps are related to infusion set issues. Intraperitoneal pumps serve as an alternative when subcutaneous insulin delivery is ineffective. Glucose-responsive smart insulin systems are under development and show promise for future diabetes care.
HbA₁c levels are used to assess glycemic control in patients with diabetes, with a target of 7% recommended by the American Diabetes Association (ADA). Despite increased use of multiple antidiabetic agents between 1999-2002, nearly half of patients still had HbA₁c levels above the ADA-recommended target, and 20% had levels greater than 9% (>75 mmol/mol). Although there was a non-significant reduction in the proportion of patients with HbA₁c > 9%, the overall mean HbA₁c did not significantly change between the survey periods due to an increase in patients with HbA₁c levels between 6-8% (64-86 mmol/mol).
In individuals without diabetes, a higher plasma glucose cutoff value is used to account for the relative inaccuracy of glucose monitors at low concentrations, which can lead to higher frequencies of hypoglycemia and a greater proportion of asymptomatic episodes compared to using lower cutoff values.
Diabetes may be independently associated with many different types of cancer, although recent large reviews suggest this perception is changing. Two major reviews have evaluated the evidence: one by Tsilidis et al. based on 27 meta-analyses from 474 individual studies, and another by Ling et al. based on 151 cohorts encompassing over 32 million people and 1.1 million cancer cases. These reviews applied novel methods to address confounding and biases common in earlier studies. Tsilidis et al. assessed between-study heterogeneity, small study effects, and excess significance, and reported 95% prediction intervals alongside confidence intervals. Ling et al. conducted a bias analysis for unmeasured confounding, estimating the proportion of studies with meaningful effect sizes based on a pre-specified relative risk threshold.
Close collaboration between psychotherapists and diabetes teams is important to avoid conflicting messages and to enable joint care management using a stepwise approach that integrates both diabetes and eating disorder care. Dietary and refeeding plans should be coordinated with diabetes therapy, as some individuals with type 1 diabetes and eating disorders (T1DE) may prefer lower-carbohydrate diets (around 150g of carbohydrates per day), requiring access to hypoglycaemia treatment carbohydrates and careful consideration of hypoglycaemia risk, especially in those who purge.
Several clinical trials have aimed to prevent type 1 diabetes mellitus (T1DM) by either stopping islet autoimmunity, slowing the autoimmune destruction of beta cells, or preserving remaining beta-cell secretory function before clinical diagnosis. Intervention strategies focus on halting beta-cell destruction and maintaining beta-cell function after clinical diagnosis. These approaches are often based on findings from animal models like the NOD mouse and BB rat, although differences between these models and humans may limit the direct applicability of results. Factors such as intervention duration, disease stage at enrollment, drug dosage, and safety profiles also impact outcomes, contributing to the limited success seen so far in preventing or intervening in T1DM, due to its complex etiopathogenesis.
Blood glucose levels should be monitored before, during, and after exercise, and children should consume carbohydrates prior to physical activity, with the amount based on pre-exercise blood sugar levels and the duration and intensity of the exercise. For short-duration activities, sports drinks containing simple sugars are recommended as they provide optimal absorption and help prevent hypoglycemia for 30 to 60 minutes. For longer-duration activities, solid foods with carbohydrates are preferred due to their slower digestion.
GLP-1RAs carry a low risk of severe hypoglycaemia because their insulin-stimulatory effects occur only when plasma glucose levels exceed 4 mmol/l (72 mg/dl). When used as monotherapy or combined with other agents that have a low hypoglycaemic risk, such as metformin, GLP-1RAs rarely cause hypoglycaemia. However, when combined with hypoglycaemic agents like sulfonylureas or insulin, the incidence of non-severe hypoglycaemia increases significantly, affecting up to one-third of participants depending on trial duration, study population, and dosage. In clinical trials combining GLP-1RAs with insulin, symptomatic hypoglycaemic events occurred in approximately 25% of individuals, with a slightly higher occurrence observed with short-acting compared to continuous-acting GLP-1RAs.
Chronic painful diabetic peripheral neuropathy (DPN) affects up to 26% of patients with diabetes, and individuals with macrovascular disease are particularly prone to neuropathic pain. Among survivors of myocardial infarction, the prevalence of neuropathic pain was higher in those with diabetes (21.0%) compared to those with impaired glucose tolerance (IGT, 14.8%), impaired fasting glucose (IFG, 5.7%), and normal glucose tolerance (NGT, 3.7%). Key risk factors for DPN and neuropathic pain include age, obesity, and low physical activity, with peripheral arterial disease being a significant comorbidity, underscoring the importance of cardiovascular risk factors in the development of DPN.
Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy, leading to the development of several therapeutic approaches targeting the underlying mechanisms rather than symptomatic pain relief. These include aldose reductase inhibitors, antioxidants like α-linolenic acid, essential fatty acids, ACE inhibitors, prostacyclin analogs, prostaglandin derivatives, NGF, PKCβ inhibitors, C-peptide, vascular endothelial growth factor, and benfotiamine. These treatments may be effective even under conditions of persistent hyperglycemia, which is expected to remain common in most people with diabetes. Research into low-dose combination therapies indicates potential for enhanced efficacy through drug interactions, and while trial quality has improved, long-term success in slowing neuropathy progression remains limited. Some newer agents have shown promise in early trials, and it is hypothesized that interventions targeting the pathogenesis of diabetic neuropathy may be more effective as preventive rather than interventional strategies.
The text includes several medical knowledge points related to diabetes, such as DEA (diabetic ketoacidosis), a serious complication of diabetes characterized by high blood ketone levels and metabolic acidosis. It also references the DPP (dipeptidyl peptidase) enzyme, which plays a role in glucose metabolism and is a target for diabetes treatment. Additionally, the text mentions CSII (continuous subcutaneous insulin infusion), a method of insulin delivery used in diabetes management. GAD (glutamine acid decarboxylase) is noted, an enzyme relevant in the context of autoimmune diabetes as it is a common autoantigen in type 1 diabetes. The term DAWN (Diabetes Attitudes, Wishes, and Needs study) refers to a research initiative aimed at understanding psychosocial aspects of diabetes care. Lastly, the DECT (Diabetes Control and Complications Trial) is referenced as a landmark study demonstrating the benefits of intensive glucose control in reducing diabetes complications.
When blood glucose levels are ≥15 mmol/L before exercise, the presence of ketones should be checked; if ketones are present, exercise is not recommended and supplemental insulin may be needed, such as 1 unit to reduce glucose by 2–3 mmol/L. Exercise should be delayed until ketones are absent and blood glucose is below 15 mmol/L. If ketones are absent but blood glucose remains ≥15 mmol/L, decisions about exercise should consider the timing of the last meal and quick-acting insulin dose. If a meal was consumed within the last 1–2 hours, exercise can proceed with close blood glucose monitoring. However, if the last meal was ≥2 hours ago, 30% of the usual correction insulin dose should be administered.
Hepatic expression of IRF3 decreases in animals with diet-induced and genetic obesity, and adenoviral-mediated liver-specific overexpression of IRF3 or IRF9 improves glucose and lipid homeostasis while attenuating systemic and hepatic inflammation in diet-induced diabetic and ob/ob mice, suggesting a potential role for IRF proteins in gene therapy approaches for type 2 diabetes.
Genetic variations in the CAPN10 gene, including specific SNPs such as SNP-43, SNP-44, and SNP-63, define a high-risk haplotype associated with type 2 diabetes mellitus (T2DM), particularly in certain ethnic groups. Although this association is less clear in populations like French Caucasians due to the rarity of the high-risk haplotype, pooled and meta-analyses suggest that genetic variation in CAPN10 influences T2DM risk in Europeans. CAPN10 was the first diabetes gene identified through a genome-wide scan and has been linked to T2DM as well as insulin action, insulin secretion, adipocyte biology, and microvascular functions, though the specific SNPs, haplotypes, and phenotypes involved may vary between ethnic groups. Evidence indicates that calpain-10 plays a role in insulin resistance and related intermediate phenotypes, potentially facilitating GLUT-4 translocation and cytoskeletal reorganization. Additionally, calpain-10 is important in pancreatic β-cells, where it may influence fuel sensing, insulin exocytosis at the mitochondria and plasma membrane, and β-cell apoptosis.
Patients with diabetes may experience numbness, which requires regular self-examination of the feet, including the use of a small mirror to inspect the sole, in order to detect hidden foot lesions early and prevent complications such as infection, osteomyelitis, and gangrene.
Periungual telangiectasia, characterized by erythema around the nail bed due to dilated proximal nailfold capillaries, is a marker of functional microangiopathy and can occur in up to 49% of individuals with diabetes. In diabetic patients, this condition presents with isolated homogenous engorgement of venular limbs, differing morphologically from the mega-capillaries or irregularly enlarged loops seen in connective tissue diseases. Capillary changes in those with recently diagnosed diabetes differ from those with long-standing disease, and in advanced cases with prolonged poor control, small hemorrhages or vascular occlusions leading to localized non-perfusion may occur. Nailfold capillaries are considered reflective of the general microcirculatory status and are used in studies examining functional changes in diabetic microangiopathy.
Diabetes prevalence varies across regions and populations, with higher rates observed in certain areas. In rural Sindh province in northern Pakistan, diabetes affects 16% of men and 12% of women, while more recent data indicate urban and rural prevalence rates of 10–11% among men and urban women, with lower rates in rural women (5%). Impaired glucose tolerance is more common in women, occurring at twice the rate seen in men. Across all four provinces of Pakistan, diabetes prevalence in urban areas is 6.0% in men and 3.5% in women, with an estimated 22% of the urban population having some degree of glucose intolerance. In rural Bangladesh, an older study reported a diabetes prevalence of 2.1% with a much higher rate of impaired glucose tolerance at 13%, despite a relatively low mean BMI of 20.4 kg/m². A more recent large study using fasting glucose criteria found a diabetes prevalence of 9.7% among over 7000 adults.
Hypoglycaemia incidence is higher in older individuals, with 11% of people in primary care reporting at least one episode in a 12-month period, and older people (≥70 years) experiencing more episodes compared to those under 60 years (12.8% vs 9.0%, p < 0.01). Older adults also report more symptomatic episodes without needing help (9.2% vs 5.6%) and more episodes requiring medical assistance (0.7% vs 0.1%). In care homes, hypoglycaemia incidence can reach up to 41.9% over a year, with a median of 2 episodes per person per year, attributed to higher comorbidities.
In adolescents with type 1 diabetes, emotion-focused coping styles such as behavioural and mental disengagement or aggressive coping are associated with suboptimal glycaemic levels and reduced diabetes-specific quality of life, whereas active coping strategies, which involve directly addressing the source of psychological distress, are linked to better glycaemic control. A meta-analysis of 21 studies has also found that approach coping is associated with better overall psychological adjustment and improved glycaemia.
Gliptins, which are DPP-4 inhibitors, have the potential to influence various physiological systems due to the presence of multiple natural substrates for DPP-4 such as bradykinin, enkephalins, neuropeptide Y, and several chemokines. However, no significant immune-related adverse effects have been observed with DPP-4 inhibitors in animals or humans despite DPP-4 being the CD26 T-cell activation antigen. Selectivity of DPP-4 inhibition is important as inhibition of related enzymes like DPP-8 and DPP-9 has led to blood dyscrasias and skin lesions in some species, though not in clinical practice. Monitoring for skin lesions is still recommended.
Steroid use, particularly glucocorticoids, can lead to elevated blood glucose levels, a condition known as steroid-induced hyperglycaemia, which may worsen existing diabetes or result in new-onset diabetes, termed steroid-induced diabetes. This increase in glucose levels may require temporary additional glycaemic management, especially with higher-dose or longer-duration steroid use, as it can cause significant symptomatic hyperglycaemia and potentially lead to acute complications. The hyperglycaemia may resolve after discontinuation of steroids, but management during treatment is important to mitigate risks.
Nausea and vomiting associated with gastroparesis may impair glycaemic management and often cause hypoglycaemia, possibly due to insufficient delivery of food into the small bowel to match the effects of exogenous insulin.
Treatments with increased hypoglycaemic risk, such as sulfonylureas or intensive insulin regimens, should be avoided in individuals where hypoglycaemia can be life threatening. Agent-specific adverse events, such as gastrointestinal issues with metformin or GLP-1RAs, can limit medication use in some people. Pharmacological treatment for older people with diabetes and frailty requires special attention, as GLP-1RAs and SGLT-2 inhibitors may not be feasible due to practical concerns, susceptibility to side effects like falls from volume depletion, or issues with availability and affordability. Diabetes and its management costs disproportionately affect ethnic minorities and low-income populations, highlighting the importance of addressing social determinants of health to ensure equitable and affordable care for all individuals with type 2 diabetes.
Islet cell transplantation is a potential approach for treating diabetes, particularly in individuals requiring lifelong immunosuppression. Certain immunosuppressants have been found to influence autoantibody recurrence and immune responses post-transplant. For instance, ATG and tacrolimus or MMF may increase the risk of autoantibody recurrence compared to daclizumab, sirolimus, or cyclosporine A. The role of regulatory T cells (Tregs) is significant in immunological tolerance and autoimmune diseases, and different immunosuppressants elicit varying Treg responses. Alemtuzumab and ATG combined with daclizumab have been associated with increased Treg percentages and higher Treg-to-effector T-cell ratios, while sirolimus and MMF favor Treg activity more than tacrolimus and cyclosporine A. These findings suggest potential for developing Treg-centric immunosuppressive strategies to improve outcomes in islet cell transplantation for diabetes.
Insulin therapy is commonly used initially after diabetes diagnosis, but most individuals with KCNJ11 and ABCC8 variants can transition to sulfonylurea therapy, often with significant improvements in glycaemic control. Around 90% of those with KCNJ11 variants can stop insulin use, and HbA1c levels typically improve, showing a mean reduction from 65 to 46 mmol/mol (8.1% to 6.4%) within 12 weeks. Glibenclamide, a non-selective and widely available sulfonylurea, has been commonly used in this context.
The prevalence of type 2 diabetes has increased significantly over time in various regions, with data showing a rise from less than 1% in 1985 to 3% in men and 5% in women among the Indigenous Mapuche in rural Chile by 2001. Urban communities exhibit higher prevalence rates, such as 14% in Mexico City in 1994, compared to the national range of 5–10%. Surveys in Brazil and Colombia during the early 1990s found age-adjusted prevalence rates of approximately 7%, with a later study in Brazil reporting a self-reported diabetes rate of 10.1%. A systematic review and meta-analysis revealed a substantial increase in diabetes prevalence from 7.4% in the 1980s to 15.7% in the 2010s. Abdominal obesity, a potential contributing factor, was found to affect more than 80% of women in these populations.
Neurocognitive abnormalities can appear early in the course of diabetes, with developmental delays observed within 2–3 years of diagnosis, particularly in children diagnosed before age 4. These delays are evident in lower improvements over time on cognitive tests such as the Wechsler Vocabulary and Block Design subtests compared to children diagnosed later or healthy peers. After 6 years, children with diabetes perform worse overall on measures of intelligence, attention, processing speed, long-term memory, and executive function, with those having an earlier onset showing greater deficits in attention and executive skills. By 12 years post-diagnosis, these cognitive differences persist into young adulthood, with lower verbal and full-scale IQ scores, indicating a true loss in cognitive efficiency rather than just a developmental delay. Additional studies confirm a gradual decline in IQ scores as the duration of diabetes increases.
Prolonged hyperglycemia in diabetes leads to activation of monocytes and macrophages, increasing cytokine production such as interleukin 1β and IL-6, which in turn activates protein kinase C and nuclear factor κB, resulting in higher levels of reactive oxygen species. Glucose autooxidation also contributes to reactive oxygen species formation and oxidized low density lipoprotein, which is taken up by scavenger receptors on macrophages, promoting atherogenesis. In the hyperglycemic environment, advanced glycation end-products form and modify albumin, inhibiting cholesterol efflux to high density lipoprotein. These processes collectively contribute to lipid profile changes, cellular lipid accumulation, foam cell formation, and protein modifications that alter cellular structure and function.
Metformin, a first-line drug for type 2 diabetes, exerts its anti-diabetes effects in part through the induction of growth and differentiation factor-15 (GDF-15), a potent endogenous inhibitor of feeding. GDF-15 is secreted by various cell types in response to cellular stress and acts centrally via its receptor GFRAL, which is expressed by neurons in the area postrema and nucleus of the solitary tract. Although metformin-induced increases in circulating GDF-15 levels are modest, studies in mice show that the anti-diabetes effect of metformin is abolished by GFRAL deletion, indicating a critical role for GDF-15 signaling in the brain. These findings highlight the importance of the brain in glucose homeostasis and diabetes pathogenesis, suggesting that targeting the brain may improve diabetes management.
Exercise improves HbA1c and blood pressure, which are key risk factors for diabetic microvascular complications, suggesting that regular exercise may offer protection against such complications. Impaired exercise capacity is linked to diabetic nephropathy and retinopathy. Some cohort studies indicate that regular physical activity is associated with reduced progression and development of diabetic kidney disease, and the Look Ahead study found that individuals in an intervention group involving diet, exercise, and weight loss were less likely to develop retinopathy or neuropathy. However, the Japan Diabetes Complications Study found no difference in the incidence of retinopathy or nephropathy between those receiving lifestyle interventions (diet and exercise) and those receiving usual care over eight years, and no randomized controlled trials have specifically examined the effect of exercise alone on microvascular risk in people with type 2 diabetes.
Pregnancy may be the first time asymptomatic forms of monogenetic diabetes, such as maturity-onset diabetes of the young (MODY), are diagnosed, especially when caused by a mutation in the glucokinase gene. Although the prevalence of this form of MODY may be less than 2% in the general antenatal population, screening selected women can increase the likelihood of detecting a glucokinase gene mutation to around 80% in a white population. Certain clinical features may suggest MODY.
Globally, it is estimated that 463.0 million people had diabetes in 2019, with projections indicating an increase to 578.4 million in 2030 and 700.2 million in 2045, driven largely by ageing populations, lack of physical activity, and unhealthy nutrition due to rapid urbanization, particularly in low- and middle-income countries (LMICs). In 2019, people with type 2 diabetes in LMICs represented 33% of global cases, and 30% of the estimated 1.1 million children and adolescents (aged 0–19 years) with type 1 diabetes lived in these regions. The countries experiencing the greatest rise in diabetes prevalence are also those with the least prepared health systems to manage the disease.
In individuals with diabetes, reducing blood pressure below currently recommended targets (130/80 mmHg for normal or moderately increased albuminuria and 125/75 mmHg for severely increased albuminuria) can reduce the risk of kidney events by 21%, primarily by lowering the risk of developing moderately or severely elevated albuminuria. However, achieving a systolic blood pressure below 120–130 mmHg is associated with increased mortality and end-stage kidney disease, indicating that extremely tight blood pressure control should be avoided.
Intraperitoneal insulin delivery, such as through implantable pumps or a port, mimics natural insulin secretion by directing insulin into the portal circulation rather than the systemic circulation, offering potential benefits like faster absorption and more physiological carbohydrate and lipid metabolism while avoiding peripheral hyperinsulinaemia. Clinical studies have explored its advantages, with some showing improvements in glycated haemoglobin (HbA₁c) and quality of life for individuals with type 1 diabetes. Despite these potential benefits, this method is not widely used, though ongoing research continues to investigate its role in developing an artificial β cell.
Some drugs are relatively or absolutely contraindicated in the presence of certain diabetic complications; examples include oral contraceptives or hormone replacement therapies in women with diabetes and severe vascular disease, the antiplatelet agents abciximab and cilostazol, and growth hormone in patients with proliferative retinopathy, as well as propranolol by injection in patients prone to hypoglycemia.
High insulin levels following intrahepatic transplantation may lead to steatotic changes in hepatocytes, which have been observed through imaging and confirmed by biopsy in some cases, though it remains uncertain whether these changes result in long-term complications.
Infections involving the foot, soft tissues, skin, nails, and urinary tract are particularly important in people with diabetes, often being present at diagnosis or serving as the initial presenting feature that leads to the suspicion of diabetes. Physicians in primary care must maintain a high level of awareness regarding the relationship between diabetes and these infections. Although foot and skin infections are discussed in more detail elsewhere in the textbook, they remain a critical concern in the context of diabetes management.
Women with diabetes have an increased risk of neural tube defects in their offspring, which necessitates a higher folic acid intake of 5 mg/day. To effectively reduce this risk, folic acid supplementation should be initiated up to 12 weeks' gestation, although in cases of unplanned pregnancies, which account for 50% in the UK, supplementation should start immediately upon recognition of pregnancy.
Thiazolidinediones, when added to a sulfonylurea regimen, may cause hypoglycemia after several weeks, and self-monitoring of blood glucose can help determine when sulfonylurea dosage should be reduced; rosiglitazone is suggested to be initiated at half the maximal dose when combined with a sulfonylurea. Postmenopausal women taking thiazolidinediones may have an increased risk of bone fractures, particularly at distal sites, with a possible slight increase in risk also seen in men, warranting bone density evaluation in high-risk individuals. Although PPAR-γ stimulation in colonic cells has shown conflicting effects on tumor risk in animal and cell studies, thiazolidinediones are contraindicated in familial polyposis coli on theoretical grounds.
Optimal diabetes care has been shown to improve clinical outcomes, particularly in type 1 diabetes mellitus (T1DM), as demonstrated in the Diabetes and Complications Clinical Trial (DCCT), where intensive treatment resulted in a 2% (22 mmol/mol) lower HbA1c level compared to conventional treatment (7.2% vs 9.1%, or 55 vs 76 mmol/mol). After the DCCT, in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, glycemic control deteriorated when intensively treated patients returned to usual care, while conventionally treated patients improved, leading both groups to converge at an HbA1c level of 8% (64 mmol/mol). Despite this convergence, those previously treated intensively maintained over 50% risk reduction in all diabetes-associated complications, including cardiovascular events.
Elevated glucagon levels are observed in many individuals with diabetes, particularly during diabetic ketoacidosis, suggesting a role for glucagon in the pathogenesis of diabetes. Early research indicated that both insulin and glucagon, the two main islet hormones, contribute to diabetes development, a hypothesis supported by studies using somatostatin to inhibit glucagon secretion. Although interest in glucagon's role declined over decades as focus shifted to insulin resistance and beta-cell dysfunction, recent advancements have renewed attention on glucagon physiology, especially with the development of new glucose-lowering drugs that suppress glucagon activity.
SGLT-2 inhibitors, also called gliflozins, are a recent addition to the therapeutic armamentarium for type 2 diabetes, acting by increasing urinary glucose excretion and thereby lowering plasma glucose levels through an insulin-independent mechanism that does not increase the risk of hypoglycaemia. Their glycaemic efficacy is relatively modest and limited by any decline in renal function, but they also offer additional benefits including weight loss and modest blood pressure reduction due to osmotic diuresis. Four SGLT-2 inhibitors—canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin—have been approved for use in Europe and the USA.
Low or high blood sugar symptoms may be hard to recognize in a dying individual, which can complicate the management of diabetes in end-of-life care.
In a basal-bolus insulin regimen involving three injections of short-acting insulin and one or more injections of long-acting insulin, at least four glucose monitoring time-points are required daily: pre-breakfast, pre-lunch, pre-dinner, and before bedtime. Testing one hour after meals may help adjust pre-meal short-acting insulin more accurately, though this is less convenient. Frequent glucose testing helps identify times when blood glucose levels are outside the target range, allowing adjustments to insulin doses. For individuals with consistent routines and minimal variation in food intake and activity, monitoring can be done less frequently, such as with a daily fasting test and four-point sampling on one or two days per week or additional tests on different days to assess patterns over time. Once the long-acting insulin dose is established, paired bedtime and fasting glucose readings are necessary.
Telecare systems have been developed to support glucose control in patients with diabetes, including those with type 1 diabetes mellitus (T1DM) and gestational diabetes. These systems provide periodic advice, continuous support, frequent encouragement, problem assessment, and individualized education on diet, exercise, and drug modification, effectively reducing HbA1c levels. In some systems, glucose analysis software assists nurses in interpreting patient data and delivering feedback, particularly when glycemic control deviates from desired targets. Specialized telecare systems have also been designed for women with gestational diabetes.
Critically ill surgical patients should have blood glucose levels maintained as close to $6.1\mathrm{mmol / L}$ as possible and generally $< 7.8\mathrm{mmol / L}$ using an intravenous insulin protocol, while targets for non-surgical critically ill patients are less well defined but may also benefit from maintaining levels $< 7.8\mathrm{mmol / L}$, though concerns about hypoglycemia raise safety considerations for these glycemic goals.
Meglitinide analogues, such as repaglinide and nateglinide, are glucose-lowering agents that stimulate insulin secretion similarly to sulfonylureas but with a rapid and short-lived effect, making them suitable for administration with meals to promote prandial insulin release. These agents help restore the first-phase glucose-induced insulin response lost in type 2 diabetes, specifically targeting post-prandial hyperglycaemia to potentially reduce vascular risk and inter-prandial hypoglycaemia. Although their main action occurs during and after meals, they also have some effect on reducing fasting hyperglycaemia, particularly repaglinide.
In people with type 1 diabetes using insulin pump therapy, a randomized study comparing steel and Teflon infusion sets showed no difference in function over seven days, but Teflon sets had a 15% initial failure rate due to kinking. By seven days, both types of infusion sets had a 64% failure rate, primarily due to hyperglycaemia and pain. An in vivo study in swine found no significant difference in inflammatory response between steel and Teflon cannulas, which is relevant because inflammation can affect bolus shape and tubing pressure during continuous insulin delivery.
Achieving consistently low HbA₁c levels below the target range is challenging without substantial personal and national healthcare resources and is difficult outside of clinical trials. In the DCCT study, intensively treated adolescents had a mean HbA₁c of 65 mmol/mol (8.1%), while adults achieved a lower mean of 54 mmol/mol (7.1%). Older, well-educated DCCT participants with good access to advanced diabetes technology maintained HbA₁c levels between 62–66 mmol/mol (7.8–8.2%) over 12 years in the EDIC study.
Colesevelam has been shown to produce modest reductions in HbA₁c levels of approximately 0.5% (5 mmol/mol) when used as an add-on therapy to metformin, sulfonylurea, or insulin in patients with type 2 diabetes. It does not affect body weight, carries a low risk of hypoglycaemia, and is associated with a reduction in LDL cholesterol, consistent with its use in treating hypercholesterolemia.
Type 2 diabetes mellitus (T2DM) is more prevalent among Polynesians, including Maoris and Pacific Islanders, compared to Caucasians in New Zealand, accounting for 95% of diabetes cases in Polynesians versus 89% in Caucasians. Polynesians are typically diagnosed 5–10 years earlier than Caucasians and exhibit a four- to eightfold higher prevalence of diabetic nephropathy. High prevalence rates of 37–75% have been reported for unemployed males, highlighting the influence of socioeconomic factors. According to the 2006–2007 New Zealand Health Survey, adult prevalence rates for diabetes among those over 30 years were 4.3% for Europeans, 5.8% for Maoris, 6.5% for Asians, and 10.0% for Pacific Islanders.
Nocturnal hypoglycemia, often asymptomatic, should be suspected if morning blood glucose is low or if episodes of confusion, nightmares, or seizures occur during the night, or if there is impaired thinking, altered mood, or headaches upon awakening. It can be confirmed with nighttime blood glucose monitoring and may be prevented by including more protein and fat in the bedtime snack, though care must be taken to avoid causing high overnight blood glucose levels.
RAS inhibitors should be offered to all individuals with type 1 diabetes and albuminuria regardless of blood pressure, with the dose titrated up to the maximum recommended or tolerated to maximize the antiproteinuric effect. If blood pressure remains above 125/75 mmHg on the maximum dose of RAS inhibitors, antihypertensive therapy should be intensified. Lower blood pressure reduces the rate of decline of GFR from 10 to 12 ml/min/year untreated to less than 5 ml/min/year, and regression from severely to moderately increased albuminuria can be achieved, with the fall in GFR reduced to less than 1 ml/min/year. The choice of agent should be made individually as no specific add-on agent has been shown to be superior in type 1 diabetes, and often multiple agents are needed in CKD stage 3 and beyond.
The insulin receptor shares structural similarities with the insulin-like growth factor 1 receptor and other growth factor and cytokine receptors, all of which have an extracellular ligand-binding domain that activates an intracellular tyrosine kinase domain. The mammalian insulin-like signaling system includes insulin, IGF-1, and IGF-2, all of which can bind and activate cell-surface insulin receptors. The insulin receptor exists in two isoforms due to alternative splicing involving exon 11 of the insulin receptor gene; isoform A, which lacks 12 amino acids near the COOH-terminus of the α-subunit, has high affinity for IGF-2 and predominates during fetal development, promoting growth, while isoform B, containing those amino acids, predominates postnatally and is mainly activated by insulin. Evidence suggests that dysregulated expression favoring the fetal isoform pattern in adult tissues may lead to insulin resistance.
Retinopathy can progress during pregnancy, particularly in women with type 1 diabetes, though progression to proliferative retinopathy is uncommon unless more advanced retinopathy is present at the start of pregnancy. In a study of 169 pregnancies among women with type 1 diabetes, only 2.2% progressed to proliferative retinopathy requiring laser therapy, and this occurred mainly in those with more advanced retinopathy or a longer duration of diabetes. Laser treatment prior to pregnancy offers protection against proliferative changes during pregnancy, and hypertension may influence the progression of retinopathy.
Many children diagnosed with diabetes do not require intravenous fluids or insulin infusion, yet hospitalization is common, though potentially avoidable with safe outpatient alternatives and proper reimbursement. The presence of outpatient care centers has reduced hospitalization rates at diagnosis from 88% in 1978–1982 to 46% in 1998–2001, while the proportion of hospitalizations due to diabetic ketoacidosis (DKA) increased from 44% to 63% during the same periods.
Hyperglycemia can be caused by infections, myocardial infarction, inadequate hypoglycemic treatment, or the use of diabetogenic drugs such as thiazide diuretics and glucocorticoids, which can also precipitate diabetic ketoacidosis (DKA). Thiazide diuretics and furosemide are particularly associated with hyperosmolar hyperglycemic state. In some cases, a specific cause of DKA cannot be identified. Residents of care homes are at higher risk of hyperosmolar hyperglycemic state, which has significant mortality.
Several approaches have been used to intervene in diabetes-associated complications, including aldose reductase inhibitors and PKC isoform inhibitors, particularly PKC β, with most evidence supporting their role in microvascular complications. Inhibitors of glucose-induced ROS formation, such as benfotiamine, have been studied in clinical trials with mixed results. AGE inhibitors and RAGE antagonism have also been explored, mainly in diabetic nephropathy. Alagebrium, a cross-link breaker, has shown benefits in reducing arterial stiffness in hypertensive patients and improving left ventricular function. Direct antagonists of RAGE and human chimeric sRAGE are under early clinical investigation, though not yet in relation to macrovascular disease.
Self-monitoring of blood glucose (SMBG) has been shown to contribute to improved motivation and lifestyle adjustments in diabetes management. A recent trial demonstrated that using SMBG to adjust oral glucose-lowering medication resulted in a small but significant improvement in glycemic control compared to usual care. Research is ongoing to determine the long-term benefits of SMBG versus more frequent HbA1c measurements in guiding the titration of glucose-lowering therapy.
In proliferative diabetic retinopathy, treatment involves applying laser therapy outside the macular area to the retinal periphery, aiming to reduce the release of growth factors that stimulate neovascularization by eliminating ischaemic and hypoxic retinal tissue; this treatment typically requires 2000-3000 applications delivered in multiple sessions to achieve the desired clinical outcome, and while visual prognosis is influenced by age and pre-treatment visual acuity, it is not affected by the number of laser applications needed to control the disease.
Hyperglycemia in elderly patients can occur secondary to acute illness, diabetogenic therapy, or other stress-inducing disorders, and can be distinguished from diabetes by a normal $\mathrm{HbA_{1c}}$ level. In cases of diagnostic uncertainty, an oral glucose tolerance test (OGTT) is recommended, though challenges such as difficulty obtaining a true fasted sample or patient reluctance due to the test's duration and inconvenience may arise. Retesting after resolution of the acute condition may be necessary to avoid a false diabetes diagnosis.
Insulin pump therapy can be continued during short periods of starvation, typically less than one missed meal, with the person remaining on their basal insulin rate until they resume normal eating and drinking, though regular blood glucose monitoring is required. In cases of prolonged starvation, the insulin pump should be stopped and replaced with a variable rate intravenous insulin infusion (VRIII). Post- or perioperative hypotension or significant use of inotropes may impair subcutaneous insulin absorption due to reduced peripheral skin perfusion, which may necessitate VRIII use, especially if the individual cannot self-manage their insulin. Once the person is eating and drinking normally, the insulin pump should be resumed, and the VRIII discontinued 30 minutes after the first mealtime bolus.
Studies have investigated the effects of continuous subcutaneous insulin infusion (CSII) on long-term complications in individuals with type 1 diabetes. One study found that despite equivalent glycaemic levels between CSII and multiple daily injection (MDI) groups, CSII was associated with lower rates of retinopathy and peripheral nerve abnormalities. Another study confirmed a reduced risk of retinopathy with CSII even when HbA1c levels were similar between groups. Additionally, a study on microalbuminuric nephropathy showed that CSII users had significantly lower albumin excretion rates at two- and three-year follow-ups compared to MDI users, though this finding was influenced by slightly improved glycaemic control in the CSII group at follow-up, with HbA1c levels of 8.1% (65 mmol/mol) versus 8.4% (68 mmol/mol) in the MDI group.
Type 2 diabetes is characterized by a 60% reduction in insulin-stimulated muscle glycogen synthesis, which is the primary defect underlying insulin resistance. Following mixed meals, individuals with type 2 diabetes show a ~30% lower increase in muscle glycogen synthesis compared to insulin-sensitive individuals, despite having double the serum insulin levels. Studies using combined ¹³C/³¹P NMR spectroscopy reveal that during hyperinsulinemia, there are reduced increases in intramyocellular glucose and glucose-6-phosphate concentrations in skeletal muscle of people with type 2 diabetes, indicating impaired insulin-stimulated glucose transport. This transport defect is mainly attributed to issues with glucose transporter 4 (GLUT4), with upstream defects in the insulin signaling cascade leading to impaired GLUT4 translocation being identified as a key mechanism contributing to insulin resistance in type 2 diabetes and related conditions such as obesity or in insulin-resistant first-degree relatives of those with type 2 diabetes.
Nicotinic acid (niacin) is an effective treatment for dyslipidemia in patients with diabetes and does not interfere with antidiabetic therapy, offering an alternative to fibrates or statins for those who cannot tolerate them. However, it may cause hyperglycemia and flushing, though a slow-release formulation is available to reduce the latter side effect. Acipimox, an analog of nicotinic acid, does not cause hyperglycemia.
Acquired factors such as hyperglycemia and elevated plasma free fatty acids contribute to the development of type 2 diabetes mellitus (T2DM) through mechanisms known as glucotoxicity and lipotoxicity, which impair β-cell function. Additionally, alterations in incretins like GLP-1 and GIP, along with malnutrition during fetal and early life stages, may affect β-cell programming related to glucose sensing, apoptosis, regeneration, and the capacity to compensate for insulin resistance. Recent research highlights the role of endoplasmic reticulum stress-induced apoptosis and the impact of interleukin-1β on β-cell function and life cycle in the progression of T2DM.
α-Glucosidase inhibitors are contraindicated in individuals with chronic intestinal disease, and high doses of acarbose may elevate liver enzyme levels, necessitating periodic monitoring of transaminase concentrations in patients on the maximum dosage (200 mg three times daily), with the expectation that elevated liver enzymes will resolve upon dose reduction, or otherwise prompting investigation into alternative causes of liver dysfunction.
Insulin is used in various clinical scenarios to provide flexibility in managing rapidly changing glycemic needs, particularly in critical care settings such as acute coronary syndromes, postoperative periods following heart surgery, and in patients who are "nil by mouth." It is essential in managing type 1 diabetes and plays a key role in general preoperative, intraoperative, and postoperative care, as well as in organ transplantation and stroke. Insulin is also crucial in managing hyperglycemia during high-dose corticosteroid therapy, labor and delivery, and other acute illnesses where prompt glycemic control is important for recovery, including the prevention or treatment of infections. Additionally, insulin is central to treating diabetes emergencies such as diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome.
In the Diabetes Control and Complications Trial (DCCT), a fall in HbA1c of ≥35 mmol/mol (3.2%) during pregnancy was associated with some deterioration in retinopathy, whereas a fall of ≤17 mmol/mol (1.6%) showed no overall change in retinopathy; however, the benefits of improved glycaemia to the fetus outweigh any maternal risk, and women with no or minimal retinopathy at baseline are at minimal risk.
Treatment of diabetes and its complications is costly, with significant portions of healthcare budgets allocated to diabetes-related illnesses. The WHO estimated that in 2006, between 2.5% and 15% of healthcare budgets in both developing and developed regions were spent on such illnesses, while the IDF estimated that 7–13% of annual healthcare expenditure went toward treating diabetic complications. In eight European countries, the total direct annual costs of diabetes were estimated at €29 billion, averaging €2,834 per patient yearly. In the USA, diabetes is associated with an annual direct medical expenditure of $91.8 billion, with a per capita cost of $13,243 for individuals with diabetes.
Increased emotional eating is associated with poor sleep quality and fatigue in adults with type 2 diabetes, and unhealthy diets along with low physical activity are linked to sleep disturbance, suggesting a reciprocal relationship between sleep and health behaviors in people with diabetes. Higher levels of weekly physical activity have been associated with a lower risk of sleep disturbances assessed by polysomnography, though the bidirectional and potential reciprocal associations between sleep and diabetes self-management behaviors remain understudied.
Calcium-channel blockers can impair glucose metabolism, with some cases of clinically significant hyperglycemia reported, particularly at excessive doses. Verapamil, a type of calcium-channel blocker, inhibits glucose-stimulated insulin release by blocking calcium uptake into pancreatic β-cells and also interferes with sulfonylurea and glucagon-induced insulin secretion. Hyperglycemia and metabolic acidosis can occur in verapamil poisoning, likely due to a combination of impaired insulin release, insulin resistance, reduced insulin-mediated glucose clearance, and increased catecholamine activity. Serum glucose levels have been shown to correlate with the severity of calcium-channel blocker intoxication.
In cases of diagnostic uncertainty, a standard 75g oral glucose tolerance test (OGTT) can be used for targeted screening in the post-acute setting, and studies in individuals with myocardial infarction and no prior diabetes diagnosis show a good correlation between OGTT results taken pre-discharge and six weeks post-discharge, with 49% concordance in glucose classification between the two tests.
Islet cell transplantation does not significantly worsen nerve conduction velocities compared to intensive insulin therapy, with some studies showing improvement over time. One study found reduced expression of advanced glycation end products and their receptors in nerves and perineural vessels in individuals undergoing islet-after-kidney transplantation compared to kidney transplantation alone. A study of 21 individuals undergoing islet-after-kidney transplantation showed stable motor function and improved sensory measurements at five years post-transplant. Approximately 30% of individuals undergoing islet cell transplantation have peripheral neuropathy, and about 20% have autonomic neuropathy before transplantation, though evidence on how islet cell transplantation affects autonomic neuropathy is limited.
Adrenaline is more potent than noradrenaline in producing hyperglycaemia due to its higher affinity for β₂-receptors, which may influence glucose metabolism.
Women with type 1 diabetes mellitus (T1DM) and pre-existing kidney complications, such as macroalbuminuria or proteinuria (defined as ACR > 30 mg/mmol or urinary albumin concentration > 200 mg/L), are at increased risk of accelerated renal function decline during pregnancy, and the risk of adverse maternal and fetal outcomes rises with greater proteinuria and reduced kidney function. In a prospective study of 203 women with T1DM, the incidence of pre-eclampsia increased with the severity of kidney involvement, occurring in 6% of those without microalbuminuria, 42% with microalbuminuria, and 64% of those with proteinuria.
Treatment with angiotensin-converting enzyme (ACE) inhibitors in microalbuminuric patients with type 1 diabetes mellitus (T1DM) reduces the odds of progression to persistent proteinuria by an odds ratio of 0.35 and increases the odds of regression to normal urinary albumin excretion (UAE) by an odds ratio of 3.07 compared to placebo. After two years of treatment, ACE inhibition leads to a mean reduction in UAE of 50.5%, with the greatest reduction observed in patients with the highest baseline UAE, though the treatment effect plateaus over time, indicating a delay rather than prevention of disease progression.
Improved sensors and evolving consensus on interpreting continuous glucose monitoring (CGM) have led to its acceptance as a valid clinical measure of blood glucose and as an endpoint in clinical trials.
Pregnant women with type 1 diabetes using standard insulin delivery methods spend only around 12 hours per day with near-normal glucose levels, achieving 50% time in target range during pregnancy. They spend approximately 10 hours per day above the NICE recommended glucose target range of 3.9–7.8 mmol/l, with 40% of the time too high, and around 2 hours per day below target, with 10% of the time too low. Despite frequent antenatal clinic visits, maternal hyperglycaemia improves only slightly by the third trimester.
Methylglyoxal, a highly reactive dicarbonyl, is 20,000 times more reactive with proteins than glucose and its formation may correlate better with glucose fluctuations in diabetes, potentially explaining why post-prandial glucose concentrations are independent risk factors for cardiovascular disease. Impaired glucose metabolism and type 2 diabetes are associated with higher plasma methylglyoxal levels, and methylglyoxal-derived advanced glycation end products (AGEs) are linked to an increased risk of cardiovascular events in people with type 2 diabetes. Experimental studies show that oral administration of methylglyoxal to non-diabetic animals leads to accelerated atherosclerosis similar to that seen in diabetic animals, along with upregulation of vascular inflammatory markers.
Insulin excess, whether relative or absolute, can result from excessive, ill-timed, or inappropriate insulin or insulin secretagogue doses, reduced exogenous glucose delivery, increased glucose utilization, decreased endogenous glucose production, heightened insulin sensitivity, or reduced insulin clearance. Hypoglycemia-associated autonomic failure can occur due to absolute endogenous insulin deficiency and is influenced by a history of severe hypoglycemia, hypoglycemia unawareness, recent low blood sugar episodes, prior exercise, and sleep. Aggressive glycemic control, characterized by lower HbA1c levels and glycemic goals, also contributes to the risk of hypoglycemia.
Thiazolidinediones can be used as monotherapy in both non-obese and obese patients with type 2 diabetes mellitus (T2DM) when lifestyle modifications do not provide adequate glycemic control. They are often utilized when metformin is inappropriate or not tolerated, or when an insulin secretagogue is less favored. These drugs are also used in combination with other antidiabetic medications, especially metformin, to achieve better glycemic control. Due to their slow onset of action, substituting a thiazolidinedione for a sulfonylurea or metformin may lead to a temporary worsening of glycemic control. Combining a thiazolidinedione with insulin can improve glycemic control and reduce insulin dosages, particularly in obese patients, though this combination requires caution as it increases the risk of peripheral edema.
Common nucleotide variants within or near genes associated with monogenic diabetes, such as GCK, HNF4A, HNF1B/TCF2 in maturity-onset diabetes of the young (MODY), and WFS1 in Wolfram syndrome, may contribute to type 2 diabetes mellitus (T2DM) with modest risk effects.
The incidence of diabetes in HIV-infected individuals was found to be 4.4 cases per 1000 person-years during a study with 27,798 person-years of follow-up. Factors associated with an increased incidence rate ratio included male sex, older age, obesity, and Afro-American or Asian ethnicity. A weaker but still significant association was observed with CDC disease stage C. Strong associations were noted with treatment regimens involving nucleoside reverse-transcriptase inhibitors (NRTI), NRTI plus protease inhibitors (PI), and NRTI + PI + non-nucleoside reverse-transcriptase inhibitors (NNRTI), but not with NRTI + NNRTI regimens.
Infants and toddlers with diabetes who have vomited more than twice or have multiple loose stools may need to be referred to an emergency department for evaluation and intravenous fluids, while those with milder symptoms can be given oral fluid therapy at home using small amounts of cold fluids every 5 minutes, and most children with vomiting can be successfully rehydrated orally with persistent gentle encouragement from parents.
Islet cell transplantation, a treatment approach for diabetes, carries two major complications: bleeding and portal thrombosis. The incidence of bleeding is approximately 7%, with risk factors including high-dose heparin (>45 IU/kg) and the number of infusions. The use of haemostatic agents or coils to obliterate the percutaneous tract can significantly reduce the risk of major bleeding, allowing for safer systemic anticoagulation with intravenous heparin. Anticoagulation helps mitigate the instant blood-mediated inflammatory response and reduces the likelihood of portal vein thrombosis, which occurs in 3–10% of cases, typically as a partial thrombosis. Risk factors for portal thrombosis include portal pressure during infusion exceeding 22–25 mmHg, a large packed-cell volume (>5.5 ml or 0.25 ml/kg), and thrombophilic disorders; therefore, these conditions should be avoided.
Elevated triglycerides in diabetes result from complex mechanisms, with defects in insulin action and hyperglycemia contributing to changes in plasma lipoproteins. Some suggest diabetes should be termed "lipidus" rather than "mellitus" due to the significant role of lipid abnormalities. In type 2 diabetes, obesity and insulin-resistant metabolic disturbances can lead to lipid abnormalities independent of hyperglycemia. The interplay between lipid and carbohydrate metabolism supports a "lipocentric" view of insulin resistance and type 2 diabetes pathogenesis. Fatty acids are central to insulin sensitivity, obesity, and type 2 diabetes, with the main disturbance in lipoprotein metabolism involving triglyceride-rich lipoproteins due to issues in chylomicron synthesis and clearance.
Islet transplantation can benefit patients with difficult diabetes by freeing them from frequent hypoglycemia or glycemic lability, although the procedure carries acute risks such as bleeding and portal vein thrombosis, as well as long-term risks of sepsis and neoplasms; the decision to proceed is best made by informed patients facing daily challenges with diabetes control, as it remains uncertain whether the achieved glycemic control will prevent long-term complications.
A phase 2 clinical trial evaluated the effectiveness of the TNF-α receptor blocker golimumab in children and young adults aged 6–21 years with newly diagnosed type 1 diabetes, administering it subcutaneously over 52 weeks based on weight with induction and maintenance doses. The study found that golimumab significantly improved the 4-hour C-peptide AUC compared to placebo, indicating better preservation of beta-cell function. Additionally, a higher percentage of the golimumab group (43%) achieved partial remission, defined as an insulin dose-adjusted HbA1c < 9% (75 mmol/mol), compared to the placebo group (7%), though no significant difference in HbA1c change from baseline was observed between groups after 52 weeks.
Rituximab and abatacept have shown significant effects in interventions for new-onset type 1 diabetes, particularly in paediatric populations, suggesting that studies limited to adults might have produced negative results, potentially overlooking benefits in children. Data from cadaveric pancreata reveal heterogeneity in insulitis among type 1 diabetes cases and highlight a discrepancy between β-cell mass and endogenous C-peptide production, as insulin-producing β cells may persist even in individuals with undetectable C-peptide levels and long-standing disease. Research also indicates distinct endotypes in individuals with recent-onset type 1 diabetes, reflecting varied pathobiologies, and suggests that different interactions between the immune system and β cells can lead to various disease outcomes, ranging from benign islet autoimmunity to progression to type 1 diabetes, depending on β-cell vulnerability.
HHS (Hyperosmolar Hyperglycemic State) is a complication related to diabetes, and reducing its risk involves improved education on awareness and risk factors, as well as ensuring access to fluids and glucose monitoring, particularly in the presence of known precipitating factors.
Amputation is a significant and costly health issue among people with diabetes, particularly the elderly, often resulting from foot ulceration, which precedes about 70% of lower-extremity amputations. Risk factors include peripheral vascular disease, sensorimotor and autonomic neuropathy, limited joint mobility, and high foot pressures. Peripheral sensorimotor neuropathy, present in approximately 25% of patients with type 2 diabetes over 80 years old, contributes to numbness, neurogenic pain, gait disturbances, and foot injuries, with symptoms often worsening at night. Visual loss further exacerbates the risk of injury, and even minor foot trauma in those with severe neuropathy can lead to Charcot arthropathy, typically in individuals who have had diabetes for at least 10 years, many of whom are elderly. The 3-year survival rate after lower-extremity amputation is around 50%, with hospitalization lasting an average of 42 days and costing over €10,000 per admission, especially when amputation levels are higher or age increases.
The processes that correct hypoglycaemia involve a sequence of hormonal responses conceptualized as lines of defence. The first defence is a decrease in insulin secretion from pancreatic islet β-cells as plasma glucose drops below 4.7 mmol/l, promoting glucose production and reducing glucose utilization by tissues like muscle. The second defence is increased glucagon secretion from α-cells when glucose falls below 3.9 mmol/l, stimulating glucose release through glycogenesis and glycogenolysis, which is facilitated by reduced intra-islet insulin and other β-cell secretory products. A secondary mechanism for glucagon secretion involves activation of the autonomic nervous system. The third defence is epinephrine secretion from the adrenal medulla as glucose levels fall further, promoting glucose release via gluconeogenesis and glycogenolysis while inhibiting insulin secretion and peripheral glucose use. Epinephrine becomes critical when glucagon is deficient, while norepinephrine also responds to hypoglycaemia but plays a less prominent role in glucose regulation.
Inhibition of fatty acid oxidation can lower glucose concentrations in diabetic animals by reducing hepatic gluconeogenesis and increasing glucose utilization in skeletal muscle, primarily through the use of CPT-1 inhibitors such as oxirane carboxylates (e.g., etomoxir) and alkylglycidates (e.g., methyl palmitoxirate), although these agents carry a risk of hypoglycemia; similar hypoglycemic concerns have been observed with agents targeting intramitochondrial enzymes involved in fatty acid oxidation.
α-glucosidase inhibitors, such as acarbose, pioglitazone, and voglibose, reduce the absorption of carbohydrates from the small intestine, leading to a modest decrease in HbA1c and helping to manage postprandial hyperglycaemia. These drugs work by preventing the breakdown of complex carbohydrates into glucose, which can result in gastrointestinal side effects like flatulence and diarrhoea due to undigested carbohydrates reaching the colon. They are contraindicated in individuals with chronic intestinal diseases or conditions that may worsen from increased gas formation. Hypoglycaemia in patients using these agents can only be effectively treated with glucose ingestion. Acarbose, the most commonly used and studied drug in this class, has been shown to increase the reversion of impaired glucose tolerance (IGT) to normal glucose tolerance and reduce the relative risk of cardiovascular events by 49% in the STOP-NIDDM trial. However, the ACE trial found no reduction in major cardiovascular events among people with coronary heart disease and IGT, although progression to diabetes was reduced.
Low-resource urban settings are associated with elevated type 2 diabetes risk for both African Americans and white Americans, with racial disparities in type 2 diabetes prevalence being small or non-existent in these environments. White Americans in low-resource settings have a higher prevalence of type 2 diabetes compared to white Americans nationally, while African Americans in such settings have a slightly lower prevalence than African Americans nationally.
GCK MODY is characterized by mild hyperglycaemia without typical symptoms of diabetes, with post-meal glucose values only slightly elevated and a small increase in blood glucose observed during oral glucose tolerance tests, often leading to near-normal HbA1c levels and a low risk of complications. HbA1c values above 60 mmol/mol (7.6%) may suggest an alternative diagnosis, such as type 1 or type 2 diabetes, especially if there is marked worsening of glycaemia. Microvascular and macrovascular complications are not typically observed, even with mild hyperglycaemia persisting for up to 50 years. GCK MODY is inherited in an autosomal dominant manner, and while most individuals have an affected parent, the condition may go unnoticed due to its asymptomatic nature, leading to an apparent lack of family history. Testing may reveal that one parent has mildly raised fasting plasma glucose despite appearing unaffected.
Women with pre-gestational diabetes who are not using an insulin pump typically require multiple daily injections (MDI) consisting of short-acting human insulin or quick-acting analog insulin before meals and intermediate-acting human insulin or long-acting insulin analog at bedtime. Studies have shown that MDI regimens provide better glycemic control and result in less neonatal hypoglycemia compared to twice daily mixed insulin. Both US and UK guidelines recommend MDI regimens for managing pre-gestational diabetes.
Exenatide, when added to a thiazolidinedione alone or with metformin, provides a glycemic benefit in patients with type 2 diabetes, resulting in approximately a 1% (11 mmol/mol) reduction in HbA1c from a baseline of 7.9% (63 mmol/mol) over 16 weeks compared to placebo. It also leads to a decline in fasting glucose levels by about 30 mg/dL (1.7 mmol/L), along with greater weight loss of 1.5 kg in the exenatide group. However, nausea is more common with exenatide, occurring in 40% of patients versus 15% in the placebo group, and is associated with a higher dropout rate.
CSII reduces the frequency of mild, moderate, and severe hypoglycaemic events in individuals with type 1 diabetes. Real-world evidence shows that among more than 300 adult CSII users, the percentage of individuals experiencing more than five mild or moderate hypoglycaemic events per week dropped from 29% to 12%, and the frequency of severe hypoglycaemic episodes decreased from 0.6 to 0.3 per year, with these benefits sustained over a mean follow-up of 4.3 years. Similar reductions in hypoglycaemia have been observed in children, adolescents, and adults with type 1 diabetes in other retrospective observational studies. Individuals with a higher baseline burden of hypoglycaemia tend to benefit the most from CSII therapy.
Poor pre-conception glycemic control is strongly associated with an increased risk of congenital malformations in diabetic pregnancies, although such complications occur in only a minority of cases. Achieving optimal glycemic control before conception is crucial for improving pregnancy outcomes, and women should be advised to continue contraception until glycemic targets are met. Exaggerating the risk of malformations may discourage some women from engaging in pre-pregnancy care.
Standard diabetes-prevention interventions, including the Diabetes Prevention Program (DPP), have shown suboptimal effectiveness among African American women, with cultural relevance identified as a key contributing factor. Despite being evidence-based and largely successful in other populations, the DPP has struggled to motivate behavior change and promote weight loss in this group, with two out of every three African American women experiencing significantly less mean weight loss compared to their white American counterparts. These outcomes highlight the influence of unique social and environmental factors that contribute to weight gain or hinder weight loss in this population.
Microvascular complications of diabetes arise from prolonged hyperglycemia, which damages cells unable to regulate glucose uptake, leading to intracellular hyperglycemia. This condition harms tissues through five key mechanisms: increased polyol pathway activity, formation of advanced glycation end-products (AGEs), heightened expression of AGE receptors and their ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. A central driver of these mechanisms is increased mitochondrial production of oxygen free radicals, which can lead to persistent tissue damage even after glycemic control improves, a phenomenon known as "hyperglycemic memory." Genetic variations in the superoxide dismutase 1 gene are associated with differing susceptibility to these complications. Hyperglycemia also impairs the body's response to ischemia by reducing hypoxia-inducible factor 1 activity, and hypertension exacerbates microvascular damage by increasing intracellular glucose through upregulation of glucose transporter 1. Potential therapies targeting these mechanisms include transketolase activators, poly(ADP-ribose) polymerase inhibitors, and catalytic antioxidants.
Most focal and multifocal neuropathies occur in long-term patients with diabetes, particularly those of middle age or older, and while they are often accompanied by pain, the outlook is generally for partial or complete recovery.
Moderate intake of sucrose (10–15% of total energy) or other added sugars can be included in the diet of people with diabetes without worsening glycaemic levels or insulin sensitivity; however, exceeding energy requirements should be avoided. A randomized controlled trial showed no difference in insulin resistance after six weeks of 25% versus 10% of energy from sucrose in healthy individuals, but consuming 11 servings per day of a sucrose-containing beverage increases hepatic lipid deposition compared to isocaloric alternatives like milk, water, or aspartame-sweetened beverages. While there is no definitive evidence that sucrose directly influences cardiovascular disease risk, overall evidence supports limiting or avoiding sucrose as a prudent dietary strategy. Recommendations for sucrose intake in people with or at risk of diabetes align with those for the general population, emphasizing the limitation of energy-dense, nutrient-depleted sucrose.
Vascular disease plays a significant role in the development of diabetic foot complications such as infection, ulceration, and gangrene, and is commonly observed in individuals with diabetes. This condition can manifest as premature, extensive, and severe macrovascular disease, even occurring in atypical locations. Vascular insufficiency leads to tissue ischemia, which promotes the growth of microaerophilic and anaerobic bacteria while reducing the oxygen-dependent bactericidal functions of leukocytes. Antioxidant systems involved in fighting infections may also be impaired due to microvascular disease and the metabolic disturbances of diabetes itself. Hyperglycemia and acidemia further predispose individuals to these effects, though normalization of pH and blood glucose levels can significantly reverse them. Additionally, diabetes-related vascular disease can hinder the local inflammatory response and reduce the effectiveness of antibiotic penetration into tissues.
Prandial insulin releasers bind to the benzamido site on the sulfonylurea receptor SUR1 in the plasma membrane of pancreatic beta cells, a site distinct from the sulfonylurea site, yet both lead to closure of the K+ATP channel and stimulate insulin secretion. While there is no additive therapeutic benefit between the two types of agonists, differences in their binding affinities and duration of action allow for potential combination therapy with a meglitinide and a sulfonylurea to accommodate unusual meal patterns in diabetes management.
Reactive gliosis in the mediobasal hypothalamus contributes to diet-induced obesity in mice, and this response is associated with insulin resistance in humans even when accounting for body weight differences. Microglial mitochondrial dynamics play a role in this gliosis, influencing abnormal POMC neuron responses to hyperglycaemia in mice. Understanding the role of reactive gliosis in the development of human obesity and type 2 diabetes is a key scientific priority.
Children with diabetes exhibit various changes in the central nervous system, including slowed neural activity, which is characterized by increased delta and theta wave activity, reduced alpha peak frequency in frontal regions, and decreased alpha, beta, and gamma fast wave activity in posterior temporal areas. Abnormal electroencephalogram (EEG) patterns are more common in individuals with diabetes, with 26% showing abnormalities compared to 7% of healthy controls. Earlier onset of diabetes and episodes of severe hypoglycemia are associated with a higher likelihood of EEG abnormalities. Neural slowing, as indicated by increased latencies in auditory and visual evoked potentials, becomes more evident after two or more years of diabetes duration, while those with less than two years typically show normal latencies.
Diuretics suitable for use in diabetic hypertension include furosemide, bendroflumethiazide (≤ 2.5 mg/day), hydrochlorothiazide, spironolactone, and indapamide, with low dosages recommended, sometimes in combination with potassium supplements or potassium-sparing drugs like amiloride. If diuretics are ineffective, they should be combined with another first-line drug such as an ACE inhibitor or an angiotensin II-receptor antagonist rather than being increased in dosage. Spironolactone should not be combined with an ACE inhibitor due to the increased risk of hyperkalemia, and furosemide is particularly useful in patients with renal impairment (serum creatinine > 150 μmol/L) or edema.
Thiazolidinediones (TZDs) such as rosiglitazone and pioglitazone are associated with unclear cardiovascular effects in diabetes management. Rosiglitazone showed no increased risk of major adverse cardiovascular events (MACE) in large trials like ACCORD and VADT. Pioglitazone, studied in the PROactive trial, demonstrated favorable effects on secondary cardiovascular outcomes including myocardial infarction, death, and stroke without increasing mortality or MACE in 2600 treated patients. However, the overall cardiovascular impact of TZDs remains an unresolved question requiring further research.
The Steno-2 study demonstrates that protocol-driven multifaceted care using a multidisciplinary approach in type 2 diabetes mellitus (T2DM) leads to significant improvements in metabolic control and reductions in diabetes-related complications. Intensive treatment involving behavior modification, smoking cessation, aggressive control of glycemia, blood pressure, lipids, and microalbuminuria, along with the use of an ACE inhibitor and aspirin, resulted in greater reductions in HbA1c, BP, serum cholesterol, triglycerides, and albuminuria compared to usual care. This intensive approach was associated with a 53% reduction in cardiovascular morbidity and mortality, 71% reduction in nephropathy, 58% reduction in retinopathy, and 63% reduction in autonomic neuropathy. Over 13.3 years, patients receiving intensive treatment had lower all-cause mortality, cardiovascular mortality, and fewer cardiovascular events compared to those receiving conventional care.
Sibutramine, a selective serotonin and noradrenaline reuptake inhibitor, enhances satiety and slightly increases thermogenesis, leading to an average weight loss of 5.1 kg in obese patients with type 2 diabetes mellitus (T2DM), along with improvements in glycemic and lipid measures; however, due to its activation of the sympathetic nervous system, it should not be used in patients with diabetes who have poorly controlled hypertension or coronary artery disease.
Retinal hemorrhages in mild non-proliferative diabetic retinopathy (NPDR) typically appear as small dot hemorrhages or flame-shaped hemorrhages, which may be difficult to distinguish from microaneurysms and are often referred to as HMa. Exudates, also known as hard exudates, are another characteristic feature of mild NPDR. Cotton wool spots may be present in mild NPDR or background diabetic retinopathy, although they are not reliable indicators of increasing retinal ischemia and are frequently associated with hypertension. A single venous loop is classified as a feature of mild NPDR according to the ETDRS system, but it rarely occurs in isolation without other signs of retinal ischemia and is not considered a feature of background diabetic retinopathy in the English Screening definition.
Diet and lifestyle interventions are commonly used to promote weight loss in individuals with obesity and type 2 diabetes to reduce glycaemic levels, inflammatory markers, and cardiovascular risk factors. Weight loss through diet or exercise-based interventions has been shown to improve glycaemic levels and cardiovascular risk factors such as lipids and blood pressure. The Look AHEAD trial demonstrated that an intensive lifestyle modification program led to clinically significant weight loss and improvements in glycated haemoglobin (HbA1c) and cardiovascular risk factors, excluding low-density lipoproteins (LDL). However, the trial was stopped early due to futility as it did not reduce the primary endpoint of cardiovascular events. A post hoc analysis revealed that individuals who lost >10% of their body weight in the first year experienced a 21% reduction in the risk of fatal and non-fatal cardiovascular events.
Increased serum potassium is commonly observed in hyperosmolar hyperglycemic state (HHS) due to similar pathophysiological mechanisms as in diabetic ketoacidosis (DKA), with a comparable estimated serum potassium deficit of 3–5 mmol/l per body weight, leading to similar principles of potassium replacement. Potassium replacement should be initiated if serum potassium is below 5.5 mmol/l. According to UK guidelines, fixed-rate intravenous insulin infusion at 0.05 units/kg/h should only be started when glucose levels no longer decrease with fluid replacement or if the patient presents with ketonaemia indicating hypoinsulinaemia. The target glucose range during treatment is 10–15 mmol/l, which may require administration of intravenous 5–10% glucose, akin to DKA management. The necessity for continued insulin or alternative diabetes therapy is reassessed when the patient regains adequate consciousness and can maintain sufficient oral intake.
Sleep apnoea is associated with insulin resistance and impaired glucose tolerance, potentially contributing to the development of type 2 diabetes through mechanisms such as hypoxia and sleep fragmentation. Research suggests that sleep apnoea increases the risk of type 2 diabetes independently of obesity, as studies adjusting for BMI or body fat percentage still show a persistent risk, and one study found sleep apnoea to be a risk factor for diabetes in both obese and non-obese individuals. Further investigation is needed to understand how variations in BMI influence the relationship between sleep apnoea and type 2 diabetes.
Hypoglycemia, particularly severe episodes, has been studied for its potential impact on cognitive function and brain structure. Research has shown mixed results, with some studies indicating a link between repeated hypoglycemia and cognitive changes, such as slower performance on cognitive tests and lower scores on certain intelligence scale subtests, but without a decline in accuracy or impairment in learning and memory. This is unexpected given the known association between memory and the hippocampus, a brain region susceptible to damage from severe hypoglycemia in both animal and human studies. However, the effects of moderately severe hypoglycemia on brain structure remain uncertain.
Capillary blood glucose testing is recommended for pregnant women at various times including fasting, pre-meals, one hour post-meals, and at bedtime, with the aim of achieving specific glycaemic targets. Achieving these targets can be challenging, as evidenced by data showing that only 13-15% of pregnant women with type 1 diabetes had an HbA1c level below 48 mmol/mol in early pregnancy, increasing to 35% in late pregnancy. Women with HbA1c levels above 48 mmol/mol after 24 weeks of pregnancy experienced higher rates of preterm delivery, large for gestational age (LGA) infants, and neonatal intensive care unit (NICU) admissions, exceeding 50%, compared to 30% in women with HbA1c levels below 48 mmol/mol after 24 weeks.
Sleep problems are common complications associated with both type 1 and type 2 diabetes, influencing poor outcomes in affected individuals. While most research has concentrated on sleep issues in type 2 diabetes, some studies suggest a significant role of sleep in type 1 diabetes as well, though high-quality clinical and observational evidence remains limited.
This mutation is found in individuals with type 1 diabetes and type 2 diabetes presentations, characterized by maternal inheritance and deafness, with a prevalence of 1–3% in Chinese individuals with diabetes having either ketotic or non-ketotic presentation; other point mutations linked to increased diabetes risk involve sites at 3316, 3394, and 14577, along with deletion and rearrangement in mitochondrial DNA.
Diabetes, traditionally considered incurable, may be curable in certain circumstances. Advances in understanding have increased the number of cases where diabetes can be resolved. Hemochromatosis, though a rare cause of diabetes, is treatable. Hyperglycemia caused by the use of thiazide diuretics and beta-blockers may improve with alternative medications. Cushing syndrome can present with curable diabetes, and in cases of steroid-induced diabetes, the condition often resolves or becomes easier to manage once steroid treatment ends. Type 2 diabetes mellitus (T2DM) can be cured through substantial and sustained weight loss combined with increased physical activity, although this requires significant behavioral changes. Bariatric surgery has been shown to result in dramatic and long-term remission of T2DM when performed early in the course of the disease.
Type 2 diabetes is more common among Polynesians, including Māoris and Pacific Islanders, in New Zealand compared to white New Zealanders, accounting for 95% of diabetes cases in Polynesians and 89% in white New Zealanders. Polynesians are typically diagnosed 5–10 years earlier than white New Zealanders and have a four- to eightfold higher prevalence of diabetic nephropathy. Prevalence rates of diabetic nephropathy among unemployed men are strikingly high at 37–75%, highlighting the influence of socioeconomic status. According to the 2006–2007 New Zealand Health Survey, the prevalence of diabetes in adults over 30 years old was 4.3% for white New Zealanders, 5.8% for Māoris, 6.5% for Asians, and 10.0% for Pacific Islanders.
Glucocorticoids affect glucose metabolism through several mechanisms that contribute to insulin resistance and elevated blood glucose levels. They impair β-cell function, particularly in the short term, and interfere with insulin-mediated glucose uptake by disrupting components of the insulin signaling pathway such as glycogen synthase kinase-3, glycogen synthase, and GLUT4 translocation. Additionally, glucocorticoids influence fat metabolism by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) in adipose tissue while increasing its activity in the liver. This shift promotes the release of free fatty acids into the bloodstream, which further impairs glucose utilization and exacerbates insulin resistance, particularly in skeletal muscle.
Tertiary interventions in diabetes research involve testing less safe agents over short periods on individuals who have already developed clinical diabetes, with drugs typically evaluated first in animal studies and then in small pilot studies to assess administration routes and safety. Intervention trials often use C-peptides as a primary outcome measure to evaluate $\beta$-cell function and preservation, and some trials explore combination therapies involving drugs with different mechanisms of action, particularly in pubertal patients with new-onset type 1 diabetes mellitus (T1DM), where two drugs are commonly tested together.
Systemic administration of adenoviral vectors encoding GLP-1 improves insulin sensitivity by restoring insulin signaling in peripheral tissues and reducing hepatic gluconeogenesis in diabetic obese ob/ob mice. Insulin resistance in type 2 diabetes can also be attenuated through systemic AAV-mediated gene transfer of kallikrein, a serine protease that converts kininogen to bradykinin, enhancing insulin sensitivity and stimulating glucose uptake in vivo. AAV-mediated local gene transfer of hexokinase II (HK-II) to white or brown adipose tissue increases glucose uptake in adipocytes, offering a potential strategy for improving insulin sensitivity in type 2 diabetes. Intra-WAT administration of AAV vectors encoding perilipin A lowers blood glucose and free fatty acid levels while modifying the respiratory exchange ratio, suggesting increased glucose utilization as an energy source.
The Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial evaluated the safety of the DPP-4 inhibitor vildagliptin in 254 individuals with heart failure with reduced ejection fraction (HFrEF) and diabetes, finding that vildagliptin appeared safe regarding its effects on left ventricular ejection fraction, as a similar increase was observed in both vildagliptin and placebo groups. However, individuals receiving vildagliptin experienced an increase in left ventricular end-diastolic volume, which is associated with higher mortality risk, and a trend toward increased death compared to placebo, indicating the need for further research on the safety of this medication in people with HFrEF.
GIP (glucose-dependent insulinotropic polypeptide) is secreted by enteroendocrine K cells in response to glucose and lipid ingestion and acts on GIP receptors located on pancreatic islet cells, adipose tissue, and the hypothalamus, contributing to reduced appetite and energy intake, which can influence insulin secretion and diabetes management.
Cystic fibrosis diabetes is associated with chronic microvascular complications, although macrovascular disease is rare. The primary impact of cystic fibrosis diabetes is on lung function and mortality, with studies showing increased mortality rates in affected individuals even after accounting for other risk factors. Declines in health often begin two to six years before a diabetes diagnosis, marked by reductions in weight, body mass index, and lung function markers. The adverse effects of worsening glycaemia on clinical status are not fully understood but are believed to involve multiple factors, including the loss of insulin's anabolic effects and elevated airway glucose levels that may encourage bacterial growth.
Individuals with HNF1A or HNF4A maturity-onset diabetes of the young (MODY) often present with symptomatic diabetes during adolescence or young adulthood and are frequently misdiagnosed as having type 1 diabetes. Genetic testing using targeted next-generation sequencing is recommended for young adults with apparent type 1 diabetes who are antibody negative to GAD and IA2 at diagnosis and have a family history of diabetes. HNF4A MODY should be considered in cases with increased birth weight or neonatal hypoglycaemia. A non-fasting random C-peptide level greater than 200 pmol/l, measured 3–5 years after diagnosis, indicates non-insulin dependence and increases the likelihood of a positive genetic test result.
Rapid referral to a joint antenatal diabetes clinic is important for managing diabetes during pregnancy, with blood glucose targets aimed at achieving excellent glycaemic control to reduce risks. Cessation of potentially teratogenic medications is recommended, along with folic acid supplementation, either 5mg/d as per NICE and ES or 0.6mg/d as per ADA guidelines. HbA1c measurement is used to assess the risk of fetal abnormalities, and diabetes-related complications should be detected, monitored, and managed appropriately. Accurate pregnancy dating and ultrasound are utilized for detecting fetal abnormalities, while determining the optimal time and mode of delivery is part of the management plan. Additionally, a specific management plan for blood glucose levels is necessary post-delivery.
Low carbohydrate or low fat calorie-restricted diets may be effective for weight loss in the short term (up to 1 year), and metabolic characteristics suggest that the most appropriate carbohydrate intake for individuals includes vegetables, legumes, fruits, wholegrain foods, and naturally occurring foods rich in fiber.
The destruction of β-cells, a key event in type 1 diabetes mellitus (T1DM), may be initiated by an environmental factor such as a virus, leading to the activation of dendritic cells that present islet autoantigens to CD4+ T lymphocytes in pancreatic draining lymph nodes, which in turn activate CD8+ T lymphocytes specific for islet autoantigens, resulting in β-cell destruction and triggering a cycle of further autoantigen presentation known as epitope spreading, while CD4+CD25+ regulatory T lymphocytes, which express FOXp3 from the X chromosome, may inhibit the activation of islet autoantigen-specific CD4+ T lymphocytes and play a role in the development of peripheral tolerance in T1DM.
Metformin carries a risk of accumulation and lactic acidosis, particularly when eGFR is below 45 ml/min/1.73 m², and should be discontinued when eGFR falls below 30. Sulfonylureas, including glibenclamide, gliclazide, and tolbutamide, are mainly excreted by the kidneys and may require dose reduction. Meglitinides are approximately 10% renally excreted and are generally considered safe. Thiazolidinediones are primarily metabolized by the liver but can cause fluid retention, limiting their use. Dipeptidyl peptidase 4 inhibitors may require dose adjustments depending on the specific agent. Glucagon-like peptide 1 receptor agonists have limited data for use when eGFR is below 15 ml/min/1.73 m². Sodium-glucose cotransporter 2 inhibitors offer kidney and heart protection down to an eGFR of 25 but become less effective at reducing glucose when eGFR is below 45. Insulin is excreted by the kidneys and may necessitate dose reduction or switching to shorter-acting forms in cases of renal impairment.
Pancreatic autoantibodies, including glutamic acid decarboxylase (GAD), islet antigen 2 (IA2), and zinc transporter 8 (ZnT8) antibodies, are positive in approximately 90% of people with type 1 diabetes around the time of diagnosis, compared to only 1% in those with MODY. However, a negative test does not exclude type 1 diabetes, particularly as antibody positivity may diminish over time. Testing for pancreatic autoantibodies in individuals treated with insulin can help exclude MODY if positive. Preserved C-peptide secretion in long-standing type 1 diabetes may indicate the need for MODY testing, although 8% of people with long-term type 1 diabetes have stimulated C-peptide levels above 200 pmol/l. Non-invasive urinary C-peptide to creatinine ratios aid in differentiating MODY from type 1 diabetes without requiring blood samples. In children, the absence of all pancreatic autoantibodies and modest hyperglycemia, defined as glycated hemoglobin (HbA1c) below 58 mmol/mol (<7.5%) at diagnosis, are distinguishing features of MODY and should prompt genetic testing. Antibody testing is valuable in excluding MODY when positive.
The genetic susceptibility to type 1 diabetes mellitus (T1DM) is strongly associated with loci in the major histocompatibility complex (MHC) on the short arm of chromosome 6, particularly involving the HLA genes, which account for nearly 50% of the familial risk of T1DM. Specific HLA class II alleles, such as DR and DQ, are often found in linkage disequilibrium and contribute to the disease association, with the HLA connection typically described based on an individual's haplotype or genotype.
Diabetes modifies the association between systolic blood pressure and cardiovascular disease, with blood pressure management showing a smaller relative risk reduction in cardiovascular disease for people with diabetes compared to those without. Intensive blood pressure management has a reduced effect on lowering heart failure risk in people with diabetes, though the interaction is not significant. In the ACCORD trial, intensive blood pressure control targeting systolic blood pressure below 120 mmHg did not reduce the risk of atherosclerotic cardiovascular disease or heart failure in people with diabetes and elevated cardiovascular risk. However, a meta-analysis found that intensive blood pressure lowering in people with diabetes was linked to a lower risk of all-cause death, myocardial infarction, and stroke, but not heart failure. The American Diabetes Association (ADA) recommends a blood pressure target of less than 140/90 mmHg for individuals with diabetes and a 10-year atherosclerotic cardiovascular disease risk below 15%, and a stricter target of less than 130/90 mmHg for those with a history of cardiovascular disease or a 10-year risk of at least 15%.
HbA₁c values are converted to new units using a numerical relationship known as "Kilpatrick's rule," where for an HbA₁c of 70/0, subtracting 2 twice gives 53 mmol/mol. For non-integer values, formulas or reference tables are needed. Current HbA₁c targets of 6.5% and 7.5% correspond to 48 mmol/mol and 59 mmol/mol, respectively, in the new units.
Exenatide, when added to metformin, leads to significant improvements in glycemic control in patients with type 2 diabetes, as evidenced by reductions in HbA1c levels. In a 30-week study, exenatide at doses of 10 μg and 5 μg resulted in HbA1c reductions of -0.78% and -0.4%, respectively, compared to a negligible change of +0.08% with placebo. Exenatide also induced dose-dependent weight loss, with patients losing an average of 2.8 kg and 1.6 kg in the 10 μg and 5 μg groups, respectively. Gastrointestinal side effects such as nausea, vomiting, and diarrhea were more common with exenatide, particularly at the higher dose, though these effects tended to diminish over time.
Longitudinal studies of newborns at increased genetic risk for type 1 diabetes, either due to having a first-degree relative with the condition or based on cord blood HLA typing, have shown that some infants develop their first islet autoantibody within the first year of life. The first autoantibody to appear is typically either insulin autoantibody (IAA) or glutamic acid decarboxylase autoantibody (GADA), rather than IA-2A or ZnT8A, and the presence of two or more autoantibodies may be missed if blood sampling intervals are longer than three months. There is a strong association between HLA-DR4-DQ8 and the development of IAA as the first autoantibody, while GADA as the first autoantibody is linked to HLA-DR3-DQ2, particularly in homozygous form. These findings suggest that the primary role of HLA may be in determining which autoantibody appears first rather than directly causing type 1 diabetes itself, indicating that HLA's contribution to disease development may involve triggering islet autoimmunity independently of beta-cell loss, dysglycaemia, or clinical diabetes.
The intake of food-derived advanced glycation end products (AGEs) accelerates renal changes in diabetes, while a low-AGE diet offers protection against kidney damage. Elevated RAGE glomerular podocyte staining has been observed in animal models of both type 1 and type 2 diabetes compared to non-diabetic animals. Diabetic transgenic mice overexpressing human RAGE exhibit kidney and glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and impaired kidney function. Clinical studies show that AGEs are elevated in both type 1 and type 2 diabetes; however, at these concentrations, AGEs are not the primary ligand for RAGE. Instead, several pro-inflammatory protein ligands such as members of the S100 calgranulin family and high-mobility group box 1 (HMGB1), which are increased by hyperglycaemia, activate RAGE at low concentrations. The binding of these ligands to RAGE leads to cooperative interaction with the innate immune system signaling molecule toll-like receptor 4 (TLR-4).
GLP-1 administration has been shown to reduce appetite and food intake in clinical studies involving individuals with and without diabetes, and this effect is believed to occur through activation of GLP-1 receptors in the brain, particularly in the circumventricular organs. Although GLP-1 receptor activation is not essential for body weight regulation under normal physiological conditions, as evidenced by normal weight in GLP-1R knockout mice, it plays a significant role in the weight-lowering effects of GLP-1 receptor agonists used in pharmaceutical treatments.
GLP-1 concentrations enhance suppression of glucagon secretion, and due to their glucose-dependent effects, carry a low risk of causing significant hypoglycemia. DPP-4 inhibitors increase GLP-1 levels, but typically not enough to produce notable satiety, slow gastric emptying, or cause nausea, with minimal impact on body weight.
In type 2 diabetes mellitus (T2DM), glycogen synthesis is impaired due to reduced activity of glycogen synthase, an enzyme deactivated by phosphorylation from GSK3, a serine/threonine kinase. Insulin normally inactivates GSK3 through the PI3K-Akt pathway to promote glycogen synthesis, but in insulin-resistant diabetic states, GSK3 expression and activity are increased, contributing to the impairment of this process.
People with type 1 diabetes typically present early and require continuous insulin treatment, often showing autoimmune markers such as antibodies to glutamic acid decarboxylase (GAD). Other types of diabetes can present similarly to type 1 diabetes with ketoacidosis, including fulminant type 1 diabetes following viral infections or immune checkpoint inhibitor-induced diabetes. Atypical forms of diabetes may have varied causes, such as maturity-onset diabetes of the young (MODY) and other monogenic diabetes forms resulting from mutations in mitochondria, amylin, or pathways involved in pancreatic β-cell biology. Some individuals may develop ketosis-prone diabetes that later transitions to a clinical course resembling type 2 diabetes after improvement in glucotoxicity and partial recovery of pancreatic β-cell function. Accurate diagnosis of these conditions is essential due to differences in clinical progression, prognosis, and management.
Elevated HbA₁c in the periconceptual period and first trimester increases the risk of pre-eclampsia, perinatal or neonatal death, and congenital malformations, while high HbA₁c levels in the second and third trimesters are associated with pre-eclampsia, preterm delivery, large-for-gestational-age infants, and neonatal intensive care unit admission, with increased risk occurring at HbA₁c levels above 48 mmol/mol.
Group therapy programs for diabetes focus initially on providing participants with medical information about diabetes and later allow for discussions of personal concerns, including coping with diabetes-associated problems, guilt over complications, and fears about loss of independence. While anecdotal reports suggest participants may feel happier or better adjusted after group therapy, with benefits such as interpersonal learning and catharsis being highlighted, formal clinical trials in children and adults with diabetes have not shown strong evidence of improved mood or metabolic control, and the quality of research in this area is considered methodologically weak.
Hyperglycaemia and insulin resistance can be induced by second-generation antipsychotics (SGAs), with the mechanism likely being multifactorial. While SGA-induced weight gain, particularly with olanzapine and clozapine, contributes to hyperglycaemia, studies show that some SGAs cause insulin resistance independent of body weight and food intake. Animal studies suggest that SGAs may directly impair insulin secretion through antagonism of α-1-adrenergic, muscarinic (M3), and serotonergic (5HT2) receptors.
Causes of death directly attributed to diabetes include ketoacidosis, severe hypoglycaemia, and hyperosmolar hyperglycaemic state, though these account for a minority of diabetes-related deaths. In high-income countries, premature mortality in people with diabetes is mainly due to a higher prevalence of cardiovascular disease, especially heart failure, which is responsible for 75% of all deaths and linked to a 10-year reduction in life expectancy. Chronic kidney disease and cancer are also common causes of death, with individuals with type 2 diabetes having an increased risk of certain cancers, as both conditions share risk factors such as ageing, obesity, physical inactivity, high-fat–high-sugar diets, alcohol, and smoking.
A CDE, or Certified Diabetes Educator, is a health professional in North America with specialized knowledge and experience in diabetes management, and the role is not limited to nursing. CDEs must hold a relevant health-related degree and complete extensive training. They, along with DISNs (Diabetes Specialist Nurses) in the UK, provide education and support to individuals with diabetes, promoting self-management to achieve personalized behavioral and treatment goals that improve health outcomes. These professionals collaborate with community members such as social workers, case managers, and home care coordinators to ensure a smooth transition from hospital to home care. DSNs and CDEs also contribute to ongoing staff training and may have prescribing responsibilities. Beyond clinical duties, they are often involved in educating medical and nursing staff. However, according to the 2019 NaDIA report, a significant number of UK hospitals lack DISNs, and even fewer provide inpatient dietetic or podiatry support for diabetes care.
Oral glucose-lowering drugs each have distinct strengths and side effect profiles, and strategies can be used to improve their tolerability in diabetes management. For instance, adjusting the timing of metformin relative to meals or using long-acting formulations can help reduce gastrointestinal side effects. When side effects interfere with treatment, medications should be switched to support better adherence. Additionally, patients should be informed about the risk of hypoglycaemia associated with sulfonylureas.
Drivers with diabetes generally do not have higher accident rates compared to those without diabetes, although newly diagnosed individuals, especially those on insulin, should refrain from driving until their glycaemic levels and vision stabilize. Factors that may increase driving risk in people with diabetes include recurrent daytime hypoglycaemia, particularly if severe, impaired awareness of hypoglycaemia, reduced visual acuity below 6/12 on the Snellen chart (which can be affected by the use of mydriatics during eye exams), severe sensorimotor peripheral neuropathy especially with loss of proprioception, severe peripheral vascular disease, and lower-limb amputation. Regulatory measures and voluntary cessation of driving by individuals with advancing diabetes-related complications have also contributed to lowering accident rates.
GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic polypeptide), and oxyntomodulin are involved in glucose regulation and have been used as foundational structures in the development of dual and triple co-agonist hybrid peptides for potential diabetes treatment, with modifications aimed at enhancing agonism at other relevant peptide receptors.
Oxymetholone and danazol, which are synthetic steroid derivatives with androgenic properties, can impair glucose tolerance, likely by causing insulin resistance at a post-receptor site, and may also increase glucagon secretion, contributing to altered glucose metabolism.
Glycated haemoglobin (HbA₁c) is a key measurement for long-term glucose management and is used as a target in diabetes treatment, reflecting average blood glucose levels over 8–12 weeks, though it does not capture short-term fluctuations such as hypoglycaemia or post-prandial hyperglycaemia. Insulin therapy aims to mimic the body's natural insulin release in response to glucose and other stimuli. Advances in glucose monitoring, insulin delivery, and data management technologies are improving diabetes care by better tracking and responding to glycaemic patterns, particularly in insulin-treated diabetes.
Educational interventions for foot care in diabetes have shown improved patient behavior but lack evidence of reducing recurrent foot ulcers. Patients often struggle to understand the concept of neuropathy and may feel reassured by the absence of pain or discomfort in their feet. Visual aids such as the Neuropad, which changes color based on sweating, can help patients recognize abnormalities in their feet, with a lack of color change indicating a high-risk foot due to absent sweating. Another tool, the PressureStat (Podotrack), is a low-cost semi-quantitative footprint mat that identifies high plantar pressures by producing darker footprints in areas of increased pressure, serving as an educational aid to help patients understand specific regions of their feet at risk for ulceration.
Metformin use requires careful consideration in patients with impaired renal function, defined as serum creatinine >130 μmol/L, creatinine clearance <60 mL/min, or eGFR <45 mL/min/1.73 m², and is contraindicated in significant cardiac or respiratory insufficiency, conditions predisposing to hypoxia or reduced tissue perfusion such as hypotension or septicemia, and in significant liver disease, alcohol abuse, or history of metabolic acidosis. Due to the risk of acute deterioration in organ function, precise cutoffs for initiating or discontinuing metformin therapy cannot be defined, though it can be used in the elderly if renal and other contraindications are absent. Additionally, metformin may promote ovulation in women with anovulatory polycystic ovarian syndrome, although this is an unlicensed use not related to diabetes.
HbA₁c offers a non-fasting alternative for diabetes testing with less intraindividual variation compared to glucose testing. Concerns have been raised that using a single HbA₁c threshold of 53 mmol/mol (7%) for screening may miss some cases of diabetes. Current guidance for people with diabetes recommends aiming for HbA₁c levels between 48–59 mmol/mol (6.5–7.5%). A potential approach to simplify diagnosis involves combining fasting blood glucose and HbA₁c measurements using an algorithm based on comparisons with oral glucose tolerance test results. Ongoing discussions suggest that an HbA₁c level of 48 mmol/mol (6.5%) could be diagnostic of diabetes, although HbA₁c testing is unlikely to replace glucose criteria globally due to limited availability in some regions.
Anti-IL-21 at a dose of 12 mg/kg intravenously every 6 weeks and liraglutide at 1.8 mg administered as a daily subcutaneous injection are being evaluated in a phase II clinical trial involving 308 adults aged 18–45 years with newly diagnosed type 1 diabetes. The study uses a 2×2 factorial design and measures the primary outcome as the 4-hour C-peptide area under the curve during a mixed-meal tolerance test at week 54 compared to baseline. The trial has been completed, but the results have not yet been published.
The regulation of insulin secretion involves adenylate cyclase, which is activated by receptor agonists such as glucagon, glucagon-like peptide 1, and pituitary adenylate cyclase activating polypeptide through the Gs protein. This activation leads to the production of cyclic AMP, which in turn activates protein kinase A and EPACs, both of which enhance glucose-stimulated insulin secretion. Glucose itself can activate adenylate cyclase, though the resulting increase in cyclic AMP is typically smaller compared to that induced by receptor agonists. Inhibitory agonists like norepinephrine and somatostatin act through the inhibitory Gq protein, reducing adenylate cyclase activity and lowering cyclic AMP levels, thereby decreasing insulin secretion.
Frequent self-monitoring of blood glucose is crucial for diabetes management, especially for individuals treated with insulin or insulin secretagogues, as it helps detect hypoglycemia, identify its symptoms, and guide adjustments in therapy. Monitoring is particularly important before critical tasks like driving, especially for those with impaired hypoglycemia awareness. While traditional self-monitoring provides a snapshot of glucose levels at a single point in time, it does not indicate trends. Continuous glucose monitoring (CGM) addresses this limitation by offering real-time data, although subcutaneous measurements lag behind plasma glucose by 10–15 minutes and have some inaccuracy. Despite these issues, CGM use in adults with type 1 diabetes is associated with an average HbA1c reduction of 0.4–0.6% (4–6 mmol/mol) without increasing detected hypoglycemia. However, CGM systems have a sensitivity of 65% and specificity of 80% for detecting low glucose levels, leading to frequent false-negative and false-positive results.
Ageing is an important risk factor for type 2 diabetes and is associated with impaired mitochondrial biogenesis and accelerated mitochondrial apoptosis. Non-obese older individuals often exhibit insulin resistance, higher intramyocellular triglyceride (TAG) content, and approximately 30–40% lower rates of muscle ATP synthase flux and tricarboxylic acid (TCA) cycle oxidation. Age-related declines in mitochondrial function may contribute to ectopic lipid accumulation and muscle insulin resistance, potentially due to damage from accumulating reactive oxygen species (ROS). Similar reductions in mitochondrial activity have also been observed in the nervous system of healthy older individuals.
Majority of Type 1 diabetes patients die early due to infection and acute metabolic complications such as diabetic ketoacidosis (DKA), and if not treated properly, they do not live long enough to develop life-threatening vascular complications. For Type 1 diabetes patients below the age of 20, acute metabolic complications are the major causes of death. After a few years, diabetic nephropathy becomes a leading cause, contributing to 50% of mortality. Cardiovascular disease accounts for 10% of deaths, which is 12 times higher compared to non-diabetic individuals of the same age. Early-onset Type 1 diabetes patients are also susceptible to other microvascular complications such as retinopathy and neuropathy.
A basal bolus regimen is preferred for managing diabetes with insulin therapy, involving approximately 40% of the total daily dose as basal insulin analogue, such as glargine or detemir, and multiple daily doses of rapid-acting insulin analogues like lispro, aspart, or apidra, administered 10–15 minutes before meals. It is recommended to calculate the rapid-acting insulin dose based on insulin sensitivity factor for correcting hyperglycaemia and carbohydrate intake, rather than using fixed dosing, which increases the risk of both hyperglycaemia and hypoglycaemia. Fixed insulin dosing is more commonly prescribed among children and adolescents from minority racial/ethnic and low socioeconomic groups, despite being suboptimal. Alternative strategies, such as teaching mealtime bolus calculations or using insulin pumps, may improve diabetes management. In cases where basal insulin administration is inconsistent, insulin degludec may be considered due to its longer half-life of up to 72 hours compared to glargine's 20–24 hours.
In diabetes, the processing of proinsulin to insulin is altered, leading to increased secretion of proinsulin and its conversion intermediates, particularly des-31,32-split proinsulin, which may account for a significant portion of total immunoreactive insulin in the circulation during the basal state.
For people with diabetes using insulin or β-cell secretagogues, the development of hypoglycaemia is an indicator of being at the end of life, particularly when it occurs in those not previously prone to it, as it is a poor prognostic sign. This applies to both hospitalized individuals and out-of-hospital cases, with excess mortality linked to associated comorbidities rather than hypoglycaemia itself. Data from a UK audit showed that within one year after a paramedic call-out for hypoglycaemia, 4.4% of people with type 1 diabetes and 22% with type 2 diabetes had died. Hypoglycaemia in this context arises from factors such as reduced food intake, weight loss, and impaired kidney function without appropriate adjustment of hypoglycaemic medication.
Pregnancy in women with diabetes historically had very poor outcomes, with perinatal fetal losses ranging from 45–65% as late as 1950, significantly higher than in the general population. Improved outcomes were observed in specialized units led by Priscilla White at the Joslin Clinic and Jorgen Pedersen in Copenhagen, who emphasized optimal glucose management and multidisciplinary care involving a physician, obstetrician, and paediatrician. Pedersen's goal of achieving a fetal mortality rate of 6% was not widely realized in European or US units until the 1980s.
Nausea and vomiting associated with gastroparesis may be linked to impaired glycemic control and often lead to hypoglycemia, potentially due to insufficient delivery of food into the small bowel to match the effects of exogenous insulin.
Environmental factors such as maternal influences, viral infections, diet, high birth weight and growth rate, psychological stress, and toxic substances are associated with diabetes development. The presence of islet autoimmunity combined with factors that increase insulin resistance, like obesity and accelerated growth, may enhance the autoimmune destruction of beta cells. The hygiene hypothesis suggests that reduced exposure to pathogens due to improved sanitation leads to underdeveloped immune systems in children, making them more susceptible to autoimmune reactions. Additionally, younger children who receive low-level antibodies from their mothers may experience an increased risk of type 1 diabetes when exposed to infections such as enterovirus.
Inflammation and increased production of proinflammatory cytokines such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor α (TNF-α) may play a role in the association between depression and diabetes, potentially through perturbation of the HPA axis. These cytokines, which can be released in higher amounts from adipose tissue in conditions like diabetes and obesity, especially with aging, may interfere with insulin action.
Hypoglycemia in diabetes can present with autonomic symptoms such as trembling, rapid heartbeat, cold sweats, and pallor, as well as neuroglycopenic symptoms including difficulty concentrating, blurred or double vision, disturbed color vision, hearing impairment, slurred speech, poor judgment, confusion, memory issues, dizziness, unsteady gait, loss of consciousness, seizure, and even death. Behavioral changes like irritability, erratic behavior, and nightmares may also occur, along with non-specific symptoms such as hunger, headache, nausea, and fatigue. Recognizing early warning signs of hypoglycemia is particularly challenging in young children.
Diabetes is influenced by disturbances in lipid homeostasis, fat partitioning (lipodystrophy), insulin resistance, and mitochondrial dysfunction, with insulin resistance being a more significant factor than impaired insulin secretion. Antiretroviral therapy for HIV-1 infection, particularly with zidovudine, stavudine, and didanosine, is associated with complications such as lipodystrophy, dyslipidaemia (characterized by high triglycerides and low HDL cholesterol), and insulin resistance, which can increase the risk of diabetes. Adults with HIV on antiretroviral therapy also show higher rates of hypertension and cardiovascular morbidity. Additionally, individuals with HIV, even those not previously exposed to protease inhibitors, may experience insulin resistance linked to fat redistribution. HIV-related hypothalamic dysfunction can lead to hypogonadotropic hypogonadism and growth hormone deficiency, further contributing to metabolic abnormalities. Key predictors of diabetes in people with HIV include long duration of infection, weight gain, metabolic-associated fatty liver disease, and hypertension.
After meal ingestion, the primary site of glucose uptake shifts from insulin-independent organs to insulin-dependent tissues, a process that is particularly relevant in the context of diabetes where insulin function is impaired. Gluconeogenic substrates are derived predominantly from peripheral tissues, contributing to endogenous glucose production, which can be dysregulated in diabetes. Hepatic glycogen synthesis may occur via direct or indirect pathways, with the latter involving gluconeogenesis, a process often elevated in diabetic states due to insulin resistance or deficiency.
Insulin is a critical hormone for managing diabetes, with fasting and post-meal concentrations of 15–20 mU/L and 60–80 mU/L, respectively. Insulin therapy aims to mimic the natural insulin profile while avoiding hypoglycemia, and various insulin types are available, including rapid-acting analogs, soluble insulin, NPH insulin, lente insulins, and long-acting analogs. Insulin can be administered via injections using appropriate needle lengths (5–12 mm) to ensure subcutaneous delivery, and injection technique involves pinching the skin and holding the fold for 5–10 seconds. Alternative methods like continuous subcutaneous insulin infusion are also effective. For type 1 diabetes, multiple-dose insulin therapy is common, combining long-acting insulin for basal needs with short-acting insulin for meals. Type 2 diabetes patients may use different regimens, such as once-daily long-acting insulin, combinations with short-acting insulin, twice-daily mixtures, or multiple-dose injections, often alongside non-insulin therapies.
Excess body weight and postnatal growth factors are associated with an increased risk of type 1 diabetes. Research suggests that children who develop type 1 diabetes tend to be taller, heavier, or gain more weight or height before diagnosis compared to their peers. Studies have shown that for each standard deviation (approximately 1 kg) increase in weight or weight gain up to age 12 months, the risk of type 1 diabetes or the development of multiple islet autoantibodies increases by about 20%. While many studies on this link are case-control designs that may be affected by selection bias, a large Mendelian randomization study supports a causal relationship between childhood body mass index and type 1 diabetes risk.
The development of type 1 diabetes is linked to the breakdown of immunological self-tolerance and the onset of islet autoimmunity, with an incidence peak during the second year of life. Early seroconversion for islet autoantibodies among children who develop type 1 diabetes indicates that environmental factors may play a role very early in life. Although there is limited geographical variation in the prevalence of islet autoimmunity, significant differences in the incidence of type 1 diabetes between countries suggest that environmental factors may influence the progression from islet autoimmunity to clinical disease. Most children with multiple autoantibodies eventually develop type 1 diabetes, and geographical differences in the prevalence of advanced islet autoimmunity are influenced by both the incidence of islet autoimmunity and the rate of progression to type 1 diabetes. The multinational TEDDY study, involving children with increased genetic risk, found modest differences between countries in both the incidence of islet autoimmunity and the progression to type 1 diabetes.
Among obstetric units serving extremely obese women with type 2 diabetes mellitus (T2DM), such as South Pacific Islanders, the risk of stillbirth is higher in those with T2DM compared to type 1 diabetes mellitus (T1DM). As obesity and T2DM rates increase among women of reproductive age, the difference in stillbirth rates between T2DM and T1DM may become more evident in women of Northern European ancestry.
In patients with diabetes, the collagen bundles in the dermis become thickened and disorganized due to irreversible non-enzymatic glycation, crosslinking, and "browning" of proteins. This process, which involves the formation of advanced glycation end-products (AGEs), damages collagen and reduces the ability of enzymes like collagenase to remodel collagen fibers. The modification of collagen, elastin, and other structural dermal proteins occurs gradually and irreversibly in normal aging but is accelerated in diabetes, particularly when the condition is poorly controlled.
Hyperglycaemia interferes with the prokinetic effect of intravenous erythromycin on gastric emptying in people with and without diabetes, and frequent monitoring of blood glucose is essential during treatment; however, improved glycaemia did not improve gastric emptying in people with suboptimally controlled type 2 diabetes.
Advances in diabetes management have significantly increased life expectancy for diabetic patients, with those having Type 2 Diabetes now expected to live nearly as long as non-diabetic individuals. This increased longevity, along with progress in medical and surgical treatments, means diabetic individuals are more likely to undergo surgery in their lifetime. During surgery, diabetic patients may experience metabolic challenges such as elevated counter-regulatory hormones, suppressed insulin secretion, excessive lipolysis, and ketogenesis, all of which can negatively impact their condition. Additionally, diabetes-related complications like microangiopathy, macroangiopathy, nephropathy, and neuropathy can increase the risks associated with anesthesia and surgery, leading to higher morbidity and mortality.
Serine phosphorylation of the insulin receptor β-subunit and IRS proteins, mediated by kinases such as inhibitor kappa-B kinase-β (IKKβ) and c-Jun N-terminal kinase (JNK), inhibits insulin signaling activity and contributes to insulin resistance, a key feature of diabetes. This mechanism is involved in the insulin resistance induced by the cytokine tumor necrosis factor α (TNF-α). Targeting these kinases, for example with salicylates that inhibit IKKβ or cell-permeable inhibitors of JNK, offers potential therapeutic approaches to alleviate insulin resistance in diabetes.
Hypoglycemia-associated autonomic failure (HAAF) is well established in type 1 diabetes mellitus (T1DM), where recent antecedent hypoglycemia, including asymptomatic nocturnal episodes, leads to reduced epinephrine response, diminished symptomatic and cognitive dysfunction responses to subsequent hypoglycemia, impaired detection of hypoglycemia in clinical settings, and decreased defense against hyperinsulinemia. Evidence from multiple studies shows that avoiding hypoglycemia for 2–3 weeks can reverse hypoglycemia unawareness and improve the weakened epinephrine response in most affected individuals, highlighting the reversible nature of this condition.
Supplementary vitamin D may offer protection against type 1 diabetes mellitus (T1DM), potentially by influencing T lymphocytes and suppressing cytokine production. Studies have reported lower vitamin D concentrations in children with T1DM, and low maternal vitamin D levels during pregnancy have been associated with an increased risk of T1DM in the child. High-dose vitamin D (2000 IU/day) is currently being evaluated in a randomized feasibility pilot study in Manitoba, Canada, to assess its potential in preventing T1DM in genetically susceptible infants up to four weeks of age.
GLP-1 receptor agonists (GLP-1RAs) are used in the treatment of type 2 diabetes, with native GLP-1 playing a role in glucose regulation. These drugs vary in their pharmacology, safety, and efficacy, and include the first orally available GLP-1RA, oral semaglutide (Rybelsus). GLP-1RAs are being explored for use in other disease areas and may influence future treatment approaches for type 2 diabetes.
Combined aerobic and resistance training programs in individuals with T1DM have been shown to lower HbA1c levels, decrease blood pressure, improve nerve conduction, enhance cardiorespiratory fitness and muscular strength, increase lean body mass, and improve lipid profiles.
Pregnant women with type 2 diabetes tend to be older, have higher rates of obesity and comorbidities, greater ethnic diversity, and greater socioeconomic deprivation compared to those with type 1 diabetes. They often present late to diabetes services and have lower rates of referral and attendance for prepregnancy counselling. Although women with type 2 diabetes have lower glucose concentrations and experience fewer preterm births, fewer large-for-gestational-age (LGA) babies, and fewer caesarean sections, adverse pregnancy outcomes such as congenital anomalies, stillbirth, and neonatal death are at least as common as in women with type 1 diabetes, with some evidence indicating higher perinatal mortality (OR 1.50; CI 1.15 to 1.96).
Supervised facility-based combined aerobic and resistance exercise training improves glycemic control, reduces body mass index, fasting glucose, and $\mathrm{HbA_{1c}}$, and enhances lipid profiles in individuals with type 2 diabetes mellitus (T2DM). Additionally, those using medication may experience a decrease in medication use with regular exercise, in contrast to a sedentary control group which may show an increasing trend in medication reliance.
In type 2 diabetes, environmental factors and genetic backgrounds interact to activate stress processes that contribute to functional abnormalities and progressive loss or dedifferentiation of beta cells, which are responsible for insulin production. This mechanism highlights the role of cellular stress, including endoplasmic reticulum (ER) stress, in the impairment and reduction of beta cell function and mass, playing a key role in the progression of the disease.
Type 2 diabetes is strongly associated with obesity, and gene transfer studies have aimed to improve insulin sensitivity and glucose tolerance by targeting adiposity, adipocyte dysfunction, adipose tissue inflammation, and energy expenditure. AAV-mediated gene transfer of bone morphogenic protein 4 (BMP4) to the liver of mice increased circulating BMP4 levels, enhanced whole-body energy expenditure, and promoted browning of white adipose tissue (WAT), protecting the mice from obesity while improving insulin sensitivity and glucose tolerance. In obese animals, AAV-BMP4 treatment did not affect body weight, WAT browning, or energy expenditure but still significantly improved whole-body insulin sensitivity and glucose tolerance. This improvement was associated with increased insulin signaling and glucose uptake in adipose cells and skeletal muscle, along with reduced hepatic glucose production, decreased liver gluconeogenic enzymes, and enhanced insulin action.
Metformin lowers blood glucose levels primarily by reducing hepatic glucose production, increasing hepatic insulin sensitivity, and decreasing hepatic glycogenolysis and gluconeogenesis. It enhances insulin-stimulated glucose uptake in skeletal muscle by promoting GLUT-4 translocation and glycogen synthase activity. Independently of insulin, metformin suppresses fatty acid oxidation, which may reduce triglyceride levels and rebalance the glucose-fatty acid (Randle) cycle to favor glucose utilization. Metformin does not stimulate insulin release and its glucose-lowering effect is not sufficient to cause hypoglycemia when used alone. Accumulation of high cellular concentrations of metformin in the intestine can inhibit the mitochondrial respiratory chain at complex 1, contributing to its glucose-lowering effect and possibly preventing weight gain by increasing glucose-lactate turnover.
In diabetes, particularly in states of acidosis such as diabetic ketoacidosis, serum potassium levels may be elevated despite total body potassium being depleted. Insulin administration can lead to a decrease in serum potassium, so potassium is often started early in treatment. It is typically administered at a dose of 1 mL/L of intravenous fluid. Potassium should not be given if the patient has not passed urine. Bicarbonate is rarely used, generally only in cases of severe acidosis that result in cardiorespiratory compromise.
Children and young adults with type 1 diabetes, along with their caregivers, should receive age-appropriate and culturally relevant education for self-monitoring blood glucose, with guidance on testing frequency ranging from a minimum of five times daily and higher, and continuous glucose monitoring (CGM) is also recommended. While glucose concentration targets are comparable to those for adults, HbA1c targets show greater variation depending on the specific clinical guidelines followed.
The table provides data on clinical trials evaluating the effects of GLP-1 receptor agonists and SGLT-2 inhibitors in relation to cardiovascular outcomes in patients with diabetes. GLP-1 receptor agonists, including drugs like Liraglutide, Semaglutide, and Dulaglutide, demonstrate varying reductions in the risk of major adverse cardiovascular events (MACE) and cardiovascular death. For example, Liraglutide reduces MACE with a hazard ratio of 0.87 and cardiovascular death with a hazard ratio of 0.78, while Semaglutide shows a lower MACE hazard ratio of 0.74 but no significant reduction in cardiovascular death. SGLT-2 inhibitors such as Empagliflozin and Canagliflozin also show cardiovascular benefits, with Empagliflozin reducing cardiovascular death with a hazard ratio of 0.62 and Canagliflozin showing a trend toward reduced MACE. These findings suggest that certain GLP-1 receptor agonists and SGLT-2 inhibitors may offer cardiovascular benefits in patients with diabetes.
Advanced long-term complications of diabetes can affect the safety of certain types of exercise. Individuals with proliferative or severe non-proliferative retinopathy may be advised to avoid vigorous aerobic and resistance activities due to the potential risk of vitreous hemorrhage or retinal detachment, although mild to moderate activity remains acceptable. For those with peripheral neuropathy, weight-bearing exercises might theoretically increase the risk of skin breakdown, infection, and Charcot joint destruction, but recent evidence suggests that walking does not increase the risk of foot ulcers compared to non-exercising individuals, supporting the recommendation of low-impact activities such as walking, swimming, or bicycling. In cases of autonomic neuropathy, cardiac evaluation is recommended before starting or changing an exercise routine due to increased cardiovascular risk, decreased cardiac responsiveness, postural hypotension, possible hypoglycemia from gastroparesis, and impaired thermoregulation. There is no evidence to support specific exercise restrictions for individuals with diabetic nephropathy.
Hepatoselective insulins have been developed to target insulin action specifically to the liver, with one approach involving PEGylation to increase the size of the insulin molecule, promoting its retention in the liver. Insulin peglispro, a hepatoselective insulin, was shown to reduce HbA1c and body weight in early trials but was associated with elevated transaminase and triglyceride levels, leading to the discontinuation of its development. Another investigational insulin analogue, NNC0123-0327, which has a C20 fatty diacid attached at position A22K, binds strongly to serum albumin and exhibits reduced trans-endothelial transport, potentially increasing hepatic insulin clearance. Before approval, these hepatoselective insulins must demonstrate safety, particularly concerning the risks of steatohepatitis and hypoglycaemia.
Environmental factors such as intra-uterine environment, adult health behaviours like diet and physical activity, neighbourhood environment, and poverty mediate the association between diabetes and depression and are also relevant to the links between diabetes and severe mental illness (SMI). Additionally, inflammatory and neuroendocrine changes, including HPA dysfunction, occur in SMI and may be connected to diabetes.
Pramlintide administration reduces postprandial glycemic levels in patients with type 1 and type 2 diabetes, likely due to decreased gastric emptying and suppression of glucagon response. This glucagon suppression leads to reduced endogenous glucose production, which is particularly relevant in type 2 diabetes where postprandial glucagon excess is common. Studies have shown that pramlintide can reduce postprandial plasma glucagon levels, contributing to an approximate 25% reduction in plasma glucose. During hypoglycemic conditions in type 1 diabetes, pramlintide does not significantly alter insulin sensitivity or plasma adrenaline and noradrenaline levels, though plasma glucagon tends to be higher with pramlintide use, as does cortisol, while growth hormone is significantly increased.
Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fractures, including those of the hip, forearm, foot, and spine. Meta-analyses of observational studies report relative risk estimates for hip fractures ranging from 1.4 to 1.7 in T2DM, which is lower than in type 1 diabetes mellitus (T1DM), and risk estimates for fractures at other sites range from 1.2 to 1.4. The Women's Health Initiative (WHI) Observational Study, involving over 5000 postmenopausal women with T2DM, confirmed increased risks of any fracture and specifically at sites such as the hip, spine, foot, and upper arm, with risk estimates between 1.2 and 1.5. While the WHI study found an increased risk of spine fractures, evidence remains inconclusive regarding the association between T2DM and vertebral fracture risk, as other studies have not consistently shown such a link.
Insulin secretory granules contain insulin and C peptide, which together account for approximately 80% of granule protein, and also include various minor components such as peptidases and biologically active peptides. These granules have high concentrations of divalent cations like zinc (~20 mmol/L), which plays a key role in insulin crystallization and stabilization. Calcium (~120 mmol/L) and magnesium (~70 mmol/L) are co-released with insulin during exocytosis and may function as extracellular signaling molecules via the cell surface calcium-sensing receptor, potentially influencing insulin secretion or other metabolic processes. Adenine nucleotides (~10 mmol/L) within the granules may also serve extracellular signaling roles upon release.
Women with diabetes, particularly type 1 and type 2, are at increased risk of sexual dysfunction, with prevalence rates varying by menopausal status and diabetes type, ranging from 20-44% in premenopausal women with type 1 diabetes to 42-75% in postmenopausal women with type 2 diabetes. Women with diabetes are twice as likely to experience sexual dysfunction compared to those without diabetes. Higher body mass index (BMI) in women with diabetes is also associated with a greater likelihood of sexual dysfunction, as measured by the Female Sexual Function Index. Additionally, depression, as indicated by scores on the Beck Depression Inventory, is linked to an increased risk of sexual dysfunction in women with type 1 diabetes.
Common variants in and upstream of the HNF1A gene influence transcriptional activity and insulin secretion in vivo, with some variants associated with a modestly higher risk of diabetes in subsets of elderly overweight individuals. Mutations in HNF4A and IPF1 genes are found in families with late-onset type 2 diabetes mellitus (T2DM). IPF-1/Pdx-1 plays a dosage-dependent role in regulating β-cell-specific gene expression, aiding in the maintenance of euglycemia, and variants affecting its expression or regulation may contribute to T2DM susceptibility. Common variants near the HNF4A P2 promoter have been linked to T2DM in Ashkenazi and Finnish populations, with similar associations observed in Danish and UK populations but not in French or other Caucasian groups, indicating genetic heterogeneity in HNF4A-related diabetes susceptibility.
A higher number of capillary blood glucose measurements and a higher daily number of boluses are associated with better glycaemic control in children and adults. The use of real-time continuous glucose monitoring (CGM) in addition to pump therapy improves HbA1c levels, as shown in the Sensor-augmented Pump Therapy for A1C Reduction (STAR-3) study, where mean HbA1c dropped by 0.8% (9 mmol/mol) in the sensor-augmented pump group compared to 0.2% (2 mmol/mol) in the multiple daily injection (MDI) group. The additional training and education provided to the sensor-augmented pump group during the first five weeks may have contributed to the improved outcomes. The real-world Comparison of Sensor-Augmented Insulin Regimens (COMISAIR) study indicates that the primary benefit of sensor-augmented pumps comes from the use of real-time CGM.
Current continuous glucose monitoring (CGM) software provides an initial evaluation using the ambulatory glucose profile (AGP), which displays the median glucose progression from measurements over several days, showing the mean glucose curve at each point in time during a standard day. The AGP graphically represents glucose variability through the interquartile range (IQR), where 50% of glucose values lie, and the interdecile range (IDR), encompassing 80% of readings between the 10th and 90th percentiles. These visualizations allow healthcare providers to quickly assess an individual's median glucose levels and the extent of glucose variability over a 24-hour period.
The development of diabetic nephropathy may be influenced by the complement system, and several compounds that modify this system are already used clinically for other diseases. However, targeting the complement system to prevent or slow diabetic nephropathy must consider its critical role in host defense. Blocking complement signaling could increase the risk of infections, such as recurrent bacterial infections in individuals deficient in components of the lectin or classical pathways, or Gram-negative bacterial infections in those with alternative pathway deficiencies. Deficiencies in the terminal complement pathway also raise the risk of meningococcal sepsis and meningitis. To minimize complications, strategies should aim to minimally disrupt normal complement function and target pathways as far downstream as possible. The long-term safety of complement inhibition in diabetes remains uncertain.
Incretins, such as GLP-1 and GIP, are hormones released by the gut in response to food intake that enhance insulin release, contributing to the incretin effect where oral glucose elicits a greater insulin response compared to intravenous glucose despite similar blood glucose levels. These hormones also promote insulin biosynthesis and secretion, support beta-cell replication, and inhibit beta-cell apoptosis in vitro, with studies in rodent models showing an increase in beta-cell mass.
Insulin initiation for people with type 1 diabetes mellitus (T1DM) was historically conducted as an inpatient or day case in hospital diabetes centers, but has shifted to outpatient settings due to increased confidence in the use of purer animal insulins, human insulins, and analog insulins, as well as advancements in delivery methods such as disposable syringes, pen injectors, and needles. Insulin initiation, especially for patients with type 2 diabetes mellitus (T2DM), is increasingly performed in community settings like health centers and general practitioner (GP) surgeries due to a growing emphasis on community-based diabetes care. Older algorithms for determining when and where to initiate insulin have been replaced by national and local guidelines that account for varying levels of expertise, infrastructure, and service delivery across different healthcare settings.
GLP-1RAs (glucagon-like peptide-1 receptor agonists) are medications used in the treatment of diabetes, and during their pre-clinical development, an increased incidence of medullary thyroid carcinoma was observed in rodents but not in monkeys. This discrepancy is thought to be due to lower abundance of thyroid C cells and reduced expression of GLP-1 receptors on these cells in humans compared to rodents. Extensive monitoring in clinical trials and post-marketing surveillance has not shown an increased risk of thyroid cancer in humans treated with GLP-1RAs.
Hypersensitivity to insulin injections is uncommon, though it can occur locally or systemically and is extremely rare with newer human insulin. Repeated insulin injections at the same site can lead to lipohypertrophy, which is the accumulation of fat and fibrous tissue, or lipoatrophy, which is the atrophy of fat at the injection site, though the latter is very rare. Painful injections may result if the needle penetrates deeply into muscle, so subcutaneous injection is preferred. Insulin leakage can occur, and to minimize it, the needle should be withdrawn slowly with gentle pressure applied. Bruising and bleeding are more common with intramuscular injections, and air bubbles in insulin should be removed before administration.
People with diabetes and atrial fibrillation should be anticoagulated with warfarin to a target International Normalized Ratio (INR) of 2.0–3.0, resulting in a 68% risk reduction and lowering the annual stroke rate from 4.5% to 1.4%. The benefit of anticoagulation is so significant that it would require 295 falls in a year for the risk of subdural haematoma from trauma to outweigh the treatment's advantages, and this risk-benefit profile is assumed to be the same for individuals with diabetes.
Women with pre-gestational type 2 diabetes mellitus (T2DM) are typically insulin-resistant before pregnancy and have relative insulin deficiency. The increased metabolic demands during pregnancy often require treatment escalation from diet alone to insulin early in pregnancy to maintain glycemic control, with many women needing high insulin doses, sometimes exceeding 300 units per day by late pregnancy, although they may not require insulin after childbirth. The combination of insulin resistance, reduced insulin secretion, and increased lipolysis can lead to diabetic ketoacidosis (DKA) in ketosis-prone obese pregnant women with diabetes, particularly among Black Afro-Caribbean women with pre-gestational T2DM or gestational diabetes mellitus (GDM).
Increased production of intracellular advanced glycation end-products (AGE) precursors contributes to cellular damage in diabetes through three mechanisms: modification of intracellular proteins, alteration of the extracellular matrix, and interaction with AGE receptors such as RAGE in endothelial cells and macrophages, leading to activation of pathways involving NFκB and increased reactive oxygen species (ROS).
The long-acting sulfonylureas glibenclamide and chlorpropamide are associated with a higher risk of hypoglycemia in patients with diabetes, with 20% of patients treated with glibenclamide reporting symptoms of hypoglycemia within six months. Severe hypoglycemia requiring hospital admission is less likely with tolbutamide compared to glibenclamide or chlorpropamide, and shorter-acting sulfonylureas such as tolbutamide, gliclazide, and glipizide carry a lower risk of severe hypoglycemia than glibenclamide, with a reported risk of two episodes per 1000 persons per year for glibenclamide, over twice that of the shorter-acting agents.
The classification of diabetes has evolved, with terms like IDDM and NIDDM being replaced due to confusion and limited clinical usefulness, particularly in cases such as insulin-treated type 2 diabetes mellitus (T2DM). The updated classification, informed by Kuzuya and Matsuda, emphasizes both etiology and clinical stages of the disease. It recognizes that diabetes can progress through various stages, such as from normoglycemia to ketoacidosis, while stemming from a single cause, like an autoimmune attack on beta cells. It also acknowledges that individuals with T2DM may transition from requiring insulin to managing the condition through lifestyle changes alone. The primary categories of diabetes include type 1 diabetes mellitus (T1DM), T2DM, other specific types, and gestational diabetes, with T2DM largely serving as a diagnosis by exclusion. As new causes of diabetes are identified, they are incorporated into the "other specific types" category, as seen with maturity-onset diabetes of the young (MODY).
National and international diabetes associations have been instrumental in supporting scientific and clinical research, providing practical and moral assistance to people with diabetes, and advocating for them. The first such organization, the Portuguese Association for the Protection of Poor Diabetics, founded in 1926, aimed to provide free insulin and education. Similar groups followed in the UK in 1934, and later in France, the USA, and Belgium, with such organizations now existing in most countries.
GLP-1 receptor agonists improve glycemic control similarly to or more effectively than oral antidiabetic drugs, induce an average weight loss of 2–3 kg, and are well tolerated though commonly cause gastrointestinal side effects such as nausea and vomiting. GLP-1 itself potentiates meal-induced insulin secretion, may promote beta-cell proliferation and prevent their apoptosis in preclinical models, inhibits glucagon secretion, delays gastric emptying, and suppresses food intake and appetite. It is not yet known whether GLP-1 receptor agonists can delay the progression of type 2 diabetes mellitus.
This type of ketosis-prone diabetes, also known as Flatbush diabetes, is commonly observed in African American populations and has also been reported in Asian and Indian populations. It often lacks the human leucocyte antigen (HLA)-related genotypes or autoantibodies typical of autoimmune type 1 diabetes, and some individuals with this condition have obesity and insulin resistance. An acute hyperglycemic event in these individuals can be triggered by sepsis, often exacerbated by consuming sugar-sweetened beverages to relieve thirst. The exact mechanisms behind the initial ketotic presentation are unclear, but factors like lipo-glucotoxicity and acute inflammatory conditions, such as infections, may impair β-cell function, which might already be compromised due to genetic factors or obesity, ultimately leading to metabolic decompensation.
Women who develop gestational diabetes mellitus (GDM) in early pregnancy are more likely to be older, multiparous, have a higher BMI, and a family history of type 2 diabetes, and uptake of oral glucose tolerance testing (OGTT) in early pregnancy is low, with one study showing only 23.2% compliance. Fasting plasma glucose (FPG) testing may be more practical in early pregnancy, though a Chinese study found that only 37% of women with FPG ≥5.1 mmol/L in the first trimester had a positive OGTT at 24–28 weeks, and due to changing glucose metabolism during pregnancy, there is no expert consensus on diagnostic thresholds for early pregnancy.
In European individuals aged 65–84 years, the prevalence of diabetes was higher in women compared to men, with 87.1% of women and 64.9% of men affected, in contrast to those without diabetes where the prevalence was 55.2% in women and 25.9% in men. Metabolic syndrome is considered a risk factor for cardiovascular disease, but studies in older populations have shown that while it serves as a marker for cardiovascular disease, it does not improve risk prediction beyond what is provided by its individual components.
Inhibition of somatostatin receptors in the gut and pancreas by pasireotide treatment blocks the secretion of incretin hormones and insulin, leading to glucose intolerance in more than 70% of individuals, necessitating close monitoring of glucose levels during treatment.
Hyperinsulinemia in individuals with diabetes can occur due to the peak action of regular insulin during exercise, especially when the previously injected limb is exercised, as this accelerates insulin absorption. The use of intermediate or long-acting insulin often results in higher peripheral insulin levels compared to non-diabetic individuals of similar body composition, which can lead to hypoglycemia unless the insulin dose is reduced or additional carbohydrates are consumed. Hyperinsulinemia may also impair the normal increase in lipid mobilization during exercise, reducing the availability of non-esterified fatty acids as an energy source.
Most antipsychotic drugs are associated with an increased risk of developing diabetes, though causation has not been definitively proven. Newer atypical or second-generation antipsychotics may have a slightly higher propensity to cause diabetes compared to older drugs, with differences in risk estimated at 10–30%. Among newer agents, clozapine is likely associated with the highest risk, although this is not consistently observed. Weight gain is a common side effect of most antipsychotic medications, and observational studies suggest a trend where drugs causing more weight gain also carry a higher diabetes risk, though this relationship is not universal. Randomized trials, however, have not shown differences in diabetes rates between drugs despite significant variations in weight gain, highlighting the complexity of determining the true risk due to limitations in both study types.
Defects in β-cell function are evident at the time of type 2 diabetes mellitus (T2DM) diagnosis, with β-cell function reduced by 50% according to HOMA assessments, and continue to deteriorate over time regardless of treatment. Key abnormalities include the absence of the first-phase and reduced second-phase insulin release in response to hyperglycemia, as observed in hyperglycemic clamp studies. Responses to mixed meals and non-glucose stimuli are delayed or blunted, along with a decrease in maximal secretory capacity. Additionally, abnormal oscillatory patterns are present, characterized by smaller and less regular insulin pulses, both rapid and ultradian, with the latter showing reduced amplification after meals and a weaker correlation with plasma glucose fluctuations.
Various organizations recommend different approaches for diabetes screening and diagnosis, particularly in pregnant women. Risk factors commonly considered include high BMI, family history of diabetes, high-risk ethnicity, and previous gestational diabetes mellitus (GDM). Some organizations suggest testing women with risk factors during the first prenatal visit using methods such as HbA1c, fasting plasma glucose, or oral glucose tolerance tests (OGTT). For gestational diabetes, screening typically occurs between 24-28 weeks of pregnancy using a 2-hour 75g OGTT or a 50g glucose challenge test followed by a 3-hour 100g OGTT if positive. Some guidelines also recommend early testing for women with a history of GDM or other risk indicators such as polycystic ovary syndrome (PCOS), hypertension, or low HDL cholesterol.
Obstructive sleep apnoea (OSA) is an independent risk factor for the development of type 2 diabetes, with studies showing a 40% higher risk of diabetes in individuals with OSA. The risk increases linearly, with an 8% rise in type 2 diabetes risk for every 5-events/h increase in the apnoea-hypopnoea index, which measures OSA severity. OSA severity has also been linked to higher levels of hyperglycaemia in people with type 2 diabetes.
Diabetes is defined by fasting plasma glucose levels of 7.0 mmol/l (126 mg/dl) or higher, or 2 h plasma glucose levels of 11.1 mmol/l (200 mg/dl) or higher according to WHO (2006/2011) and ADA (2003/2010), while HbA1c levels of 6.5% (48 mmol/mol) or higher are also indicative of diabetes provided the assay is standardized and accurately measured. Impaired glucose tolerance is characterized by fasting plasma glucose below 7.0 mmol/l (126 mg/dl) and 2 h plasma glucose between 7.8 and 11.1 mmol/l (140 and 200 mg/dl) according to WHO, whereas ADA defines impaired fasting glucose as fasting plasma glucose between 6.6 mmol/l (100–125 mg/dl) and 2 h plasma glucose below 7.8 mmol/l (140 mg/dl). WHO defines impaired fasting glucose as fasting plasma glucose between 6.1 and 6.9 mmol/l (110–125 mg/dl) with 2 h plasma glucose below 7.8 mmol/l (140 mg/dl).
SGLT-2 inhibitors have demonstrated benefits in reducing cardiovascular mortality and major adverse cardiovascular events (MACE), although there is observed heterogeneity in their effects, particularly on cardiovascular mortality, which may reflect differences between individual drugs. These inhibitors also show positive effects on kidney outcomes, with canagliflozin, dapagliflozin, and empagliflozin demonstrating consistent improvements in renal function without heterogeneity, while other trials like VERTIS-CV showed no benefit, contributing to variability in composite kidney endpoint analyses.
The overall prevalence of diabetes in Australians aged ≥25 years was 7.5%, with higher rates in males (8%) than females (7%), and it rises significantly with age, reaching 24% in those aged ≥75 years; the prevalence has more than doubled since 1981. Half of the diabetes cases identified were previously undiagnosed, and the combined prevalence of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) was 16%, indicating that nearly 25% of Australians aged 25 years or more have abnormal glucose metabolism. Type 2 diabetes mellitus (T2DM) accounts for over 85% of cases, while type 1 diabetes mellitus (T1DM) accounts for 10%, and projections suggest the prevalence of diabetes will rise from 7.6% in 2000 to 11.4% by 2025.
SGLT inhibitors, including dapagliflozin, canagliflozin, empagliflozin, and ertugliflozin, are medications used in diabetes management. These drugs should be taken as normal under typical circumstances but should be withheld on the day of surgery and omitted until the patient is eating and drinking normally. Sotagliflozin, an SGLT-1/2 inhibitor, is also used in diabetes care, though specific dosing instructions around surgery or dietary changes are not provided in the given information.
In diabetes, elevated blood glucose levels result in increased delivery of glucose to the kidneys, where excess glucose is typically reabsorbed in the proximal tubules primarily by the sodium-glucose co-transporter 2 (SGLT2), with approximately 10% being reabsorbed by SGLT1. SGLT1 and SGLT2 are members of the solute carrier group SLC5 and are distinguished by their high capacity for glucose transport, with SGLT1 having a relatively higher affinity for glucose.
Bile acids interact with the nuclear receptor farnesoid X receptor (FXR), which plays a role in glucose homeostasis. FXR receptor knockout mice exhibit impaired plasma glucose clearance during glucose and insulin tolerance tests, indicating a role for FXR in maintaining normal glucose metabolism. Administration of FXR agonists in a diabetic mouse model reduces fasting glucose and insulin levels, suggesting improved insulin sensitivity. FXR signaling influences insulin signaling pathways, as evidenced by changes in Akt phosphorylation in FXR knockouts and after FXR agonist administration. Additionally, FXR is involved in downregulating genes responsible for hepatic gluconeogenesis and may play a role in glucose-induced insulin secretion from pancreatic β cells.
Sleep disturbance may negatively impact diabetes outcomes by reducing the effectiveness of diabetes self-care behaviors, which are essential for managing the condition and preventing complications; it can act as a critical barrier to proper self-care and management in both type 1 and type 2 diabetes.
Diabetes in special groups refers to the unique considerations and management strategies required for individuals with diabetes who belong to specific populations, such as pregnant women, children and adolescents, elderly individuals, and those with comorbid conditions. In pregnant women, diabetes can manifest as gestational diabetes mellitus (GDM) or pre-existing type 1 or type 2 diabetes, and requires careful monitoring to prevent maternal and fetal complications. Children and adolescents with diabetes are more commonly diagnosed with type 1 diabetes, although the prevalence of type 2 diabetes is increasing in this age group due to rising rates of obesity. Elderly individuals with diabetes may present with atypical symptoms, have a higher risk of hypoglycemia, and often require individualized treatment plans to balance glycemic control with the risk of adverse events. Patients with comorbid conditions such as chronic kidney disease, cardiovascular disease, or psychiatric disorders may face additional challenges in diabetes management, requiring a multidisciplinary approach to care. Special attention is also given to ethnic and racial groups with higher susceptibility to type 2 diabetes, emphasizing the need for culturally sensitive and tailored prevention and treatment strategies.
Serum alpha-tocopherol (vitamin E) has been suggested in some studies to be linked with a lower risk of type 1 diabetes mellitus (T1DM), but findings from the DIPP study indicate no association between vitamin E and advanced islet autoimmunity or T1DM in early life, leaving the role of nutritional factors in T1DM uncertain.
Insulin signalling pathways, such as the $\mathrm{IR}\rightarrow \mathrm{IRS}\rightarrow \mathrm{AKT}\longrightarrow \mathrm{FOXO1}$ cascade, are investigated using techniques like Cre-loxP technology or viral-mediated expression to understand their tissue-specific roles in metabolic regulation. These studies are important because insulin signalling is rarely completely lost in common metabolic diseases such as diabetes, and disruptions in one tissue can affect other tissues through secreted peptides, metabolites, or neuronal connections, complicating the analysis of whole-body gene deletion effects.
Screening for diabetes is recommended for high-risk groups, including individuals with severe mental illness (SMI), regardless of antipsychotic treatment. Guidelines suggest screening before starting or changing treatment, a few months after initiation to detect rapid onset cases, and annually thereafter. While the oral glucose tolerance test is effective in some settings, it is not widely used in general practice. More practical alternatives include measuring fasting or random glucose, or HbA1c. There is ongoing discussion regarding the sensitivity and specificity of these tests, but random glucose and HbA1c are generally preferred for their convenience. However, HbA1c may give false-negative results when glucose levels rise rapidly, such as soon after starting treatment, making a combined approach using both HbA1c and glucose measurements advisable in such cases.
Metformin carries a risk of accumulation and lactic acidosis, requiring caution when eGFR is below 40 mL/min/1.73 m² and discontinuation when it falls below 35 mL/min/1.73 m². Sulfonylureas such as glibenclamide, gliclazide, and tolfonyamide are primarily excreted by the kidneys and may require dose reduction. Meglitinides are approximately 10% excreted via the kidney and are generally considered safe. Thiazolidinediones are predominantly metabolized by the liver but their use may be limited due to fluid retention. DPP-4 inhibitors like sitagliptin are 80% renally excreted, potentially necessitating dose reduction. Among GLP-1 analogs, vildagliptin is hepatically metabolized and considered safe, exenatide is renally excreted and contraindicated in end-stage renal disease, while liraglutide does not undergo renal excretion and is considered safe. Insulin is excreted by the kidneys and may require dose reduction or switching to shorter-acting preparations in cases of renal impairment.
The Diabetes Prevention Program demonstrated that a lifestyle modification program targeting a 7% weight loss and at least 150 minutes of weekly exercise significantly reduced the incidence of type 2 diabetes mellitus (T2DM) in individuals with impaired glucose tolerance. The program included 16 lessons over 24 weeks covering diet, exercise, and behavior modification, with continued support through at least two supervised exercise sessions per week and monthly contact. This intervention resulted in a 58% lower risk of developing T2DM compared to placebo and a 39% lower risk compared to metformin use. Additionally, each kilogram of weight loss was associated with a 16% reduction in diabetes risk, and achieving over 150 minutes of moderate exercise weekly led to a 46% reduction in risk, highlighting the importance of physical activity in both weight loss and diabetes prevention.
Somatostatin analogs may induce hyperglycemia in individuals with type 2 diabetes but not in those with type 1 diabetes.
Some genetic variants, including ENPP1 K121Q rs1044498 $\mathrm{A} > \mathrm{C}$, IRS1 rs1801278 $\mathrm{A} > \mathrm{C}$, and SOD2 rs4880 $\mathrm{C} > \mathrm{T}$, have been linked to diabetes-related processes such as insulin signaling, lipid metabolism, inflammation, and oxidative stress, which are also involved in the progression of non-alcoholic fatty liver disease.
Candidal overgrowth is frequently observed in people with poorly controlled diabetes, and erythrasma, caused by corynebacteria, is seen more frequently in obese individuals with diabetes. Vitiligo shares an autoimmune pathogenesis with type 1 diabetes, and necrolytic migratory erythema is an unusual rash that is diagnostic of the glucagonoma syndrome. Insulin injections can cause both lipoatrophy and lipohypertrophy, and allergic insulin reactions, which are now rare due to purer insulin availability, can be subdivided into immediate-local, general, delayed, or biphasic responses. Sulfonamides are well-recognized causes of multiple cutaneous drug reactions.
Diabetes patients in different countries receive various forms of treatment, with a portion being managed through diet and/or exercise, oral hypoglycemic agents (OHA), insulin, or a combination of both OHA and insulin. In the USA, 16% of patients are treated with diet and/or exercise, 57% with OHA, 14% with insulin, and 13% with both OHA and insulin. In Germany, the proportions are 28% for diet and/or exercise, 44% for OHA, 16% for insulin, and 11% for combined therapy. In France, data for diet and/or exercise is unavailable, but 80% of patients are treated with OHA, 14.7% with insulin, and 5.3% with both OHA and insulin.
Hyperglycemia and dyslipidemia contribute to diabetes-associated atherosclerosis, as shown in a mouse model where deficiency in the LDL receptor was combined with expression of a viral protein under the insulin promoter, leading to T cell-mediated destruction of pancreatic beta cells similar to human type 1 diabetes. These mice developed accelerated atherosclerosis even on a normal diet, indicating a role for hyperglycemia in driving the condition, and showed further acceleration of atherosclerosis on a high-fat diet, suggesting synergistic effects of glucose and lipids. Features of plaque instability, such as plaque disruption and intraplaque hemorrhages, were also observed in this model.
Reduced IRS1 expression can result from transcriptional repression by factors like AP2β or coactivators such as p/CIP and SRC1, while IRS2 transcription is influenced by CREB, CRTC2, FOXO1/3, NFAT, TFE3, HIF2α, and SREBP1. Both IRS1 and IRS2 undergo degradation via multiple pathways, including cytokine-induced SOCS1/3 upregulation, CRL7, CBLB, and MG53, particularly under conditions of chronic inflammation, nutrient excess, and hyperinsulinemia. Phosphorylation of numerous serine/threonine residues also modulates IRS1 and IRS2 function. In pancreatic β cells, which are crucial for insulin secretion and are continuously exposed to insulin and IGF, proper function, growth, and survival depend on tightly regulated IRS-mediated signaling under multifactorial transcriptional control.
Fixed-dose combinations of oral antidiabetic agents with different mechanisms of action are increasingly used in the management of type 2 diabetes mellitus (T2DM) to achieve early and intensified glycemic control. These combinations, available as single tablets, aim to provide bioequivalent efficacy while potentially enhancing blood glucose-lowering effects through formulation adjustments. Advantages include improved convenience, reduced pill burden, simplified administration, and increased patient adherence compared to separate tablets. Common combinations include metformin with a sulfonylurea, thiazolidinedione, gliptin, or meglitinide, as well as thiazolidinedione-sulfonylurea combinations. Using lower doses of multiple agents instead of high doses of one agent may help achieve efficacy while minimizing dose-related side effects. Although single tablets may limit titration flexibility, most commonly used dosage combinations have been designed to accommodate clinical needs.
Glucose control should aim for HbA1c as low as possible without undue hypoglycemia, and all patients should receive RAS inhibition unless absolutely contraindicated; blood pressure targets are <125/75 mmHg if proteinuria or eGFR <60 mL/min/1.73 m², and <130/80 mmHg for others, with lipid management involving statin therapy for all and additional therapy if total cholesterol >4.0 mmol/L, LDL cholesterol >2.0 mmol/L, or triglycerides >2.1 mmol/L, while daily aspirin at 75 mg is recommended for all, along with smoking cessation and maintaining a BMI <25.0 kg/m², and a 6-month trial of reduced dietary protein intake to 0.9g/kg body weight per day if proteinuria is present.
Patients should be empowered to self-manage aspects of their diabetes care, including glucose monitoring, food choices, and insulin administration, when appropriate.
Most patients use premixed insulin twice a day, before breakfast and the evening meal, with insulin initiation in T2DM often starting as once daily with the main meal and increasing to two injections based on blood glucose and HbA1c levels. Some patients with T1DM and more commonly T2DM may progress to three injections a day, including one before lunch, where a 50:50 premixed insulin formulation may be more suitable than the 25:75 or 30:70 mixtures typically used twice daily.
Nutritional management for a diabetic child involves cooperation between the child and parents, with the child consuming the same types of food as before diagnosis but with structured meal timing to prevent hypoglycemia. Meals are divided into three main meals and three snacks throughout the day, with 20% of calories at breakfast, 20% at lunch, 30% at dinner, and the remaining 30% distributed among the snacks. This distribution helps maintain stable blood glucose levels and avoids large fluctuations. A healthy diet is recommended for the entire family, and sweets are not strictly prohibited but can be consumed in moderation with appropriate insulin adjustment. Emphasis is placed on regularity of food intake and consistency in carbohydrate consumption, with meal planning tailored to the individual child's needs to achieve long-term glycemic control, support optimal growth, and prevent diabetes-related complications. Adequate nutrition is essential to ensure continued physical growth in diabetic children.
The prevalence of diabetes in Singapore increased from 2% in 1975 to 9% by 1998, with later surveys suggesting a stabilization in the rate of rise, and a 2010 survey reporting a prevalence of 11.3%. Ethnic Indians and Malays, particularly Malay women, have the highest rates of diabetes, ranging from 14.3% to 16.7%, as well as the highest rates of obesity. Additionally, 15% of the adult population in Singapore has impaired glucose tolerance. Type 2 diabetes in childhood is noted as an emerging problem, and the rise in diabetes prevalence is closely associated with obesity and the adoption of a Westernized diet and lifestyle. In Malaysia, the prevalence of diabetes more than doubled over 20 years, reaching 22.6% in a recent nationwide survey compared to 11.6% in 2006.
Pre-diabetes is associated with increased lacunar infarcts and white matter hyperintensities, comparable to 2.1 years of brain ageing, and is linked to smaller total and white matter volume as well as accelerated cognitive decline. Diabetes, alongside pre-diabetes, independently contributes to this cognitive decline, and pre-diabetes is also associated with reduced occipital grey matter volume and impaired white matter integrity. Corneal nerve loss is connected to white matter hyperintensities and cognitive decline in individuals with mild cognitive impairment and dementia.
Studies have shown that individuals with first-episode psychosis, particularly those who are drug naive, may exhibit abnormalities in glucose metabolism, including impaired fasting glycemia and increased insulin resistance compared to healthy controls. These individuals also tend to have higher waist-to-hip ratios and greater visceral fat, which are predictors of insulin resistance. Additionally, some research indicates elevated non-fasting blood glucose levels in first-episode psychosis patients compared to healthy controls, although not all studies have consistently reported glucose-related differences.
Monogenic diabetes involves subtypes of diabetes characterized by predominant $\beta$-cell failure from causes other than autoimmunity, often presenting with young onset and in individuals with lean body mass. These patients may experience delayed diagnosis due to the insidious nature of symptoms, potentially leading to complications. Awareness of these non-classic presentations of type 1 diabetes mellitus (T1DM) is important for proper clinical management and family screening, especially given the rising prevalence of young-onset diabetes in low and middle-income countries.
pTEN heterozygosity can increase peripheral insulin sensitivity and improve glucose tolerance in mice, as their small islets produce sufficient insulin until around 10 to 12 months of age, indicating a complex interplay between insulin action, nutrient homeostasis, and cancer in the context of partial pTEN deficiency.
Individuals with type 2 diabetes mellitus (T2DM) exhibit hepatic and peripheral insulin resistance along with hyperinsulinemia in the fasting state. During moderate intensity exercise, peripheral glucose uptake increases more than hepatic glucose production, leading to a decline in blood glucose concentration. Plasma insulin levels decrease during exercise, and the risk of exercise-induced hypoglycemia is low in individuals with T2DM not using exogenous insulin, even during prolonged activity. Moderate intensity exercise reduces glycogen content similarly in those with and without diabetes, but glycogen and plasma glucose levels decrease more in obese individuals with diabetes compared to those without, regardless of body weight. The impact of moderate exercise on glucose tolerance and insulin sensitivity is consistent whether performed in a single session or multiple bouts of the same total duration. Additionally, moderate aerobic exercise helps reduce the rise in circulating triglyceride levels after consuming a high-fat meal.
Increased glucose turnover is associated with diabetes, and insulin resistance involves impaired receptor and postreceptor insulin signaling. Hyperinsulinemia is characterized by reduced fasting and often postprandial insulin levels. Impaired glucose tolerance (IGT) can progress to type 2 diabetes. Dyslipidemia may show modest improvement when addressed.
For older patients with type 2 diabetes mellitus (T2DM) who have single system involvement and no other major co-morbidities, a target HbA1c (DCCT aligned) range of 7.0 – 7.5% is recommended, with the precise target depending on existing cardiovascular risk, presence of microvascular complications, and the individual's ability to self-manage.
In diabetes, abnormalities of IGFBP can alter the regulation of the GH-IGF-I axis. Specifically, IGFBP-1 levels are increased in type 1 diabetes mellitus (T1DM) due to portal and hepatic insulin deficiency, and these levels rise with worsening insulin deficiency and higher HbA1c concentrations. Elevated IGFBP-1 levels inhibit IGF-I bioactivity, which can be attributed to the lack of insulin in T1DM.
The different contributions of risk factors to obstetric complications and adverse pregnancy outcomes in women with type 1 diabetes or type 2 diabetes are unclear. For type 2 diabetes, the NDIPA highlighted lower rates of folic acid use and lower rates of prepregnancy counselling, indicating problems with pregnancy planning, with most women having community-based diabetes care. At diagnosis, 6-7% of women with type 2 diabetes have microalbuminuria, up to 20% have retinopathy, up to 70% have dyslipidaemia, 80+% have obesity, and around one-third have hypertension, largely due to the metabolic syndrome. Vascular complications are more common in type 2 diabetes and are related to adverse outcomes.
Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder resulting from a combination of genetic and environmental factors that negatively impact β-cell function and tissue insulin sensitivity. Approximately 85% of patients have "garden variety" T2DM, which is polygenic, while 10% have a late-onset form of autoimmune diabetes and up to 5% have autosomal dominantly inherited forms such as maturity-onset diabetes of the young and mitochondrial diabetes. Genetic factors primarily affect β-cell function, while acquired factors like obesity, physical inactivity, and glucose and lipid toxicity mainly cause insulin resistance. Impaired β-cell function can be detected in genetically predisposed individuals even when they have normal glucose tolerance and insulin sensitivity. T2DM develops due to a progressive deterioration in β-cell function combined with acquired insulin resistance that the β-cell cannot compensate for, and at diagnosis, β-cell function is already reduced by about 50%. Common insulin secretion abnormalities include absent first-phase and diminished second-phase release, reduced responses to meals and non-glucose stimuli, smaller and less regular secretory pulses, and an elevated proinsulin to insulin release ratio. Many of these defects are already present in individuals with impaired glucose tolerance or a genetic predisposition to T2DM.
Hypoglycaemia is a recognized factor in motor vehicle incidents, particularly among individuals with diabetes, though its exact frequency and direct causal link to specific accidents are challenging to determine. Blood glucose levels are rarely measured immediately after road traffic accidents, making evidence of prior hypoglycaemia largely circumstantial. In the Diabetes Control and Complications Trial, hypoglycaemia was the main cause of non-fatal motor vehicle accidents, occurring three times more frequently in intensively treated participants, yet the rate of major accidents did not increase, possibly due to improved precautionary measures. Other studies indicate that the frequency of hypoglycaemic episodes during driving correlates with the total number of accidents, and hypoglycaemia-related driving incidents are associated with the number of severe hypoglycaemic events in the preceding year. Overall, hypoglycaemia-related accidents occur less frequently than those caused by alcohol and drugs.
A typical diabetes self-management programme may meet once or twice monthly for seven or more sessions, discussing specific self-care strategies such as glucose monitoring and physical activity, role-playing appropriate behaviours, using homework assignments to practise learned skills, and resolving problems or barriers encountered during diabetes management. Variations may include 6- or 12-monthly booster sessions to review and reinforce previously learned material. Interventions initially developed for individuals without diabetes who experience high psychological distress are increasingly applied to those with diabetes, with both cognitive behavioural therapy (CBT) and motivational interviewing or motivational enhancement therapy programmes resulting in modest improvements in HbA1c levels and self-reported quality of life.
Individuals with generalized lipodystrophy, both inherited and acquired, lack significant adipose tissue and consequently develop excessive hypertriglyceridemia and ectopic fat deposition due to limited triglyceride storage capacity. These individuals also exhibit lower levels of inflammatory cytokines and leptin, leading to hyperphagia. Severe generalized lipodystrophy is associated with hepatic steatosis, hepatic and muscle insulin resistance, and even overt type 2 diabetes. Insulin resistance and diabetes in these individuals improve significantly with leptin replacement therapy, suggesting that visceral lipid content may serve more as a marker of hepatic steatosis rather than a direct cause of insulin resistance.
Diabetes is defined by specific thresholds of plasma glucose and glycated haemoglobin (HbA1c) levels, which are used to identify individuals at risk of micro- and macrovascular complications. However, due to incomplete understanding of the causal relationships between glycaemia and various complications, and the inability to fully account for the duration of diabetes, there exists a grey zone where misclassification can occur, particularly in type 2 diabetes. This issue is increasingly relevant in individuals with mild diabetes caused by other conditions such as infections, acute illness, cancer, and heart failure, where diabetes may be secondary to stress responses and hormone activation. In these cases, the excess mortality may not be directly due to diabetes itself, and the U-shaped relationship between HbA1c and mortality in type 2 diabetes may reflect differing causes of death depending on HbA1c levels. Certain endocrine disorders can lead to secondary diabetes through the overproduction of counter-regulatory hormones like growth hormone, catecholamines, steroids, glucagon, and thyroid hormones, which interfere with glucose homeostasis and can result in a phenotype resembling type 2 diabetes.
In congestive heart failure (CHF) patients with diabetes, myocardial energy production is affected, and metabolic modulators act at specific sites to influence this process; the illustration highlights these sites of action, involving key components such as co-enzyme A (CoA), free fatty acids (FFA), and pyruvate dehydrogenase (PDH).
In individuals without diabetes, insulin and counter-regulatory hormones adjust during exercise based on the exercise type, helping to balance liver glucose production with skeletal muscle glucose uptake, and blood glucose levels remain relatively stable before, during, and after exercise.
Glycosuria, which can be detected through semi-quantitative or quantitative glucose methods, is relevant to diabetes management. Urine dipstick analysis using dry reagent test strips offers a cost-effective and portable means of detection, though visual interpretation of color changes can pose challenges, especially for individuals with diabetes who may have associated visual difficulties. To ensure accurate results, urine specimens should be analyzed immediately or properly preserved. Automated urinalysis machines provide a more reliable alternative for color assessment, offering rapid and cost-effective screening. Quantitative analysis of glucose in urine can also be performed using enzymatic methods such as hexokinase or glucose dehydrogenase.
SGLT-2 inhibitors are a class of glucose-lowering agents that reduce glucose reabsorption in the kidneys, promoting glycosuria. These drugs contribute to a negative energy balance by increasing urinary glucose excretion and shifting energy substrate utilization toward lipids. They have shown favorable effects on liver steatosis, necro-inflammation, and fibrosis, particularly in the context of non-alcoholic fatty liver disease (NAFLD), although their long-term efficacy on liver histology remains uncertain due to limited data from short-duration, small-scale randomized controlled trials.
Islet transplantation is a treatment approach for diabetes, with various anatomical sites considered for implantation. The pancreatic bed is not preferred due to the risk of acute pancreatitis, while the liver, spleen, renal subcapsule, and omental pouch are commonly used. The liver is frequently selected for human islet transplantation because it allows portal drainage, which mimics the normal route of insulin delivery. However, concerns exist regarding whether islet venous drainage reaches the portal sinusoids or systemic circulation and the potential for increased exposure to immunosuppressive drugs and their associated toxicity. The splenic site is linked to islet infarction, and although the omental pouch and renal subcapsule allow for easier retrieval of islets for histologic examination, all non-native sites have the disadvantages of reduced oxygenation and elevated intra-islet blood pressure. Liver vascularization may support islet angiogenesis, offering a potential advantage in transplantation success.
Neurons in various hypothalamic regions, including the paraventricular nucleus (PVN), lateral hypothalamic area (LH), dorsomedial hypothalamic nucleus (DMN), ventromedial nucleus (VMN), arcuate nucleus (ARC), and median eminence (ME), are involved in the central regulation of glucose homeostasis. Melanocortin 4 receptor signaling in PVN neurons is activated by the agonist α-MSH produced by proopiomelanocortin (POMC) neurons and suppressed by the inverse agonist agouti-related peptide (AGRP) from AGRP neurons located in the medial ARC. AGRP neurons also inhibit POMC neurons, and both neuron types project into the median eminence, which lacks a complete blood-brain barrier, enabling these neurons to detect circulating glucose levels.
Patients with $HNF1A$ and $HNF4A$ mutations are highly sensitive to sulfonylurea therapy, which is recommended as first-line treatment, offering better glycemic control than insulin with a fasting glucose-lowering effect four times greater than that in type 2 diabetes mellitus (T2DM). Most patients can successfully transition to sulfonylureas, though insulin may be needed as the disease progresses. Due to the risk of hypoglycemia even at low doses, initial doses should be low, such as 40 mg/day gliclazide or 2.5 mg/day glibenclamide in adults. If hypoglycemia occurs with standard agents, short-acting alternatives like nateglinide may be appropriate. Given the increased cardiovascular disease risk in $HNF1A$, statin therapy is suggested for all patients over 40 years of age.
Allosteric activators of glucokinase (GK) and molecules that prevent GK from binding with its inhibitory regulatory protein have been shown to increase hepatic glucose metabolism and reduce blood glucose concentrations in normal and diabetic rodents. Clinical studies are needed to determine whether the combined effects of increased hepatic glucose disposal and increased insulin secretion can be balanced to avoid overt hypoglycemia.
Diabetes can be associated with acromegaly, a condition caused by excessive growth hormone production, often due to a pituitary adenoma. In this case, a patient with acromegaly was found to have a random blood glucose level of 13 mmol/L during preparation for sinus surgery, indicating hyperglycemia. The patient exhibited characteristic facial features of acromegaly and a large pituitary adenoma detected by magnetic resonance imaging. Following successful trans-sphenoidal removal of the tumor, glucose tolerance returned to normal, demonstrating that the hyperglycemia was likely secondary to the growth hormone-secreting tumor.
The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial in 2012 involved 12,537 individuals with impaired glucose tolerance or type 2 diabetes who were randomly assigned to receive insulin glargine or standard care. The primary focus of the trial was cardiovascular non-fatal events or deaths, but due to concerns about potential cancer links with insulin glargine in the late 2000s, the investigators also analyzed cancer incidence and mortality by treatment group. With a median follow-up of 6.2 years, the study found no differences between the treatment groups in overall cancer incidence or deaths, nor were there differences in the risk of specific reported cancer types.
Impaired pancreatic β- and α-cell function contributes to reduced hepatic activation of Akt and nuclear exclusion of FOXO1, leading to transcription-mediated hepatic gluconeogenesis. Subclinical inflammation can diminish insulin action through secreted (adipocytokines), interfering with insulin signaling and increasing hepatic gluconeogenic protein transcription via NF-κB/INK/ceramide pathways. An alternative mechanism suggests that macrophage-induced lipolysis may regulate hepatic gluconeogenesis independently of canonical insulin receptor signaling, linking subclinical inflammation to fasting hyperglycemia. IL-6 and TNF-α, released from adipose tissue macrophages, inhibit insulin-mediated lipolysis in white adipose tissue, increasing fatty acid and glycerol delivery to the liver, which raises hepatic acetyl-CoA concentrations and stimulates gluconeogenesis through allosteric activation of pyruvate carboxylase and increased glycerol conversion to glucose. Insulin-resistant adolescents with obesity show elevated IL-6 levels and impaired insulin-mediated suppression of lipolysis and endogenous glucose production. Hepatic gluconeogenesis is not solely controlled by direct insulin action on the liver, as insulin rapidly reduces endogenous glucose production in individuals with type 2 diabetes, and there is no clear correlation between hepatic gluconeogenic protein expression and fasting hyperglycemia in humans with or without type 2 diabetes.
Temporary basal rate reduction is used in diabetes management during exercise, as people with diabetes who use basal insulin analogues cannot naturally reduce insulin secretion like those without diabetes. Continuous subcutaneous insulin infusion (CSII) allows for temporary basal insulin reduction or suspension to prevent exercise-induced hypoglycaemia. Rapid-acting insulin peaks at 90–100 minutes, necessitating pre-exercise basal rate adjustments, with a 50–80% reduction 90 minutes before moderate-intensity aerobic exercise helping to reduce immediate hypoglycaemia risk. This method is more effective than stopping insulin at the start of exercise, as it minimizes hypoglycaemia while maintaining post-exercise glucose control. Continuous glucose monitoring (CGM) studies show a risk of delayed hypoglycaemia hours after exercise due to increased insulin sensitivity, which may require post-activity or nighttime basal rate adjustments based on individual needs.
Certain factors have been identified as promoting islet survival in diabetes, including hepatocyte growth factor (HGF), X-linked inhibitor of apoptosis (XIAP), manganese superoxide dismutase (MnSOD), B-cell lymphoma 2 (Bcl-2), and haem oxygenase-1 (HO-1), which are known for their mitogenic, pro-survival, and anti-apoptotic properties.
Type 2 diabetes mellitus (T2DM) is strongly associated with coronary heart disease (CHD), with individuals with diabetes having a two- to fourfold higher risk of developing CHD compared to those without diabetes. The age- and sex-adjusted cardiovascular mortality risk in patients with diabetes is comparable to that of non-diabetic individuals who have had a prior myocardial infarction. Common precursors linking T2DM and cardiovascular disease (CVD) include insulin resistance, visceral adiposity, and excessive inflammation. Multiple mechanistic processes such as oxidative stress, increased atherogenicity of cholesterol particles, abnormal vascular reactivity, heightened hemostatic activation, and renal dysfunction collectively contribute to the elevated CHD risk in T2DM. Glucose control alone has not been shown to significantly reduce CVD events or mortality in large randomized controlled trials, at least in the short term. As a result, individualized comprehensive multifactorial risk management addressing all comorbidities is recommended for people with T2DM, which increases the burden on patients, healthcare providers, and health systems.
Patients with diabetes have an equivalent cardiovascular risk to those who have previously experienced coronary heart disease, indicating that diabetes significantly increases the likelihood of cardiovascular events such as myocardial infarction.
The rising prevalence of overweight and obesity is contributing to an increase in type 2 diabetes among younger populations, with an age of 40 years often used to distinguish young from older individuals with the condition. Those diagnosed before age 40 face a fourfold higher risk of myocardial infarction compared to those diagnosed later, and this group includes women of childbearing age who need specialized care. Early-onset type 2 diabetes leads to more aggressive cardiovascular complications compared to age-matched individuals without diabetes, despite older adults having a higher overall rate of cardiovascular disease. Younger individuals with type 2 diabetes often have additional conditions such as psychological disorders, non-alcoholic fatty liver disease, sleep apnoea, and vitamin D deficiency. These health issues can impact productivity and place a significant economic burden on society, emphasizing the need for strong healthcare leadership and tailored management strategies to effectively engage and treat this group, particularly to address highly prevalent and undertreated cardiovascular risk factors.
Hyperglycemia can independently induce insulin resistance in human skeletal muscle, a phenomenon known as "glucose toxicity," which contributes to reduced insulin-stimulated glucose uptake in patients with type 2 diabetes mellitus (T2DM) compared to non-diabetic individuals matched for weight, age, and gender, even when glycemia and insulinemia levels are similar. Despite this chronic insulin resistance caused by sustained high glucose levels, acute glucose utilization can still be enhanced through the mass action effect of glucose, allowing patients with T2DM to utilize glucose at rates comparable to those without diabetes when blood glucose levels are normalized.
Telemedicine has become increasingly important for delivering outpatient care to individuals with type 1 diabetes, particularly following the global Covid-19 pandemic. Due to the uneven distribution of paediatric diabetes subspecialists, with greater concentrations in urban and academic settings, many regions face limited access to specialized diabetes care. Telemedicine helps overcome geographical and financial barriers, improving access to type 1 diabetes management. Evidence suggests that telemedicine visits can be comparable to in-person consultations, with some studies indicating improved diabetes-specific and psychosocial outcomes, along with equal cost-effectiveness. During the pandemic, telemedicine became essential for continuing diabetes care, prompting rapid adoption and optimization by paediatric diabetes providers worldwide. Observational studies support its effectiveness in managing type 1 diabetes during this period.
Tight glycemic control has been shown to slow the progression of diabetic retinopathy in both type 1 and type 2 diabetes, as demonstrated by the DCCT and UKPDS trials. In the UKPDS, maintaining HbA1c below 53 mmol/mol (7.0%) reduced the risk of retinopathy progression by 25%, while improved blood pressure control further reduced the risk by 37%. Although no specific intervention studies have been conducted in elderly patients with T2DM, general principles of glycemic and blood pressure control are considered applicable. However, challenges such as hypoglycemia and postural hypotension often limit the ability of elderly patients to achieve tight control.
In patients with type 2 diabetes mellitus (T2DM), insulin resistance is further worsened by chronic hyperglycemia, which itself causes insulin resistance. Insulin resistance and inflammation characterize the adipose tissue of those with fatty liver, and this resistance contributes to overproduction of glucose, VLDL, PAI-1, C-reactive protein, and coagulation factors, all of which increase cardiovascular risk. Genetic factors such as adiponutrin polymorphism and acquired factors like high intake of refined carbohydrates, high saturated fat consumption, and weight gain are involved in the accumulation of fat in the liver.
Insulin replacement therapy is the only effective and feasible treatment for type 1 diabetes mellitus (T1DM), as it can reverse metabolic disturbances and restore near-normal quality of life. Despite healthcare advances, increased morbidity and mortality remain common due to complications that typically develop within 10–12 years of disease onset. Improved understanding of T1DM's natural history has enabled the design of prevention and intervention clinical trials aimed at stopping islet autoimmunity (primary prevention), reducing autoimmune β-cell destruction (secondary prevention), or suppressing/modulating the immune response to halt β-cell killing and promote regeneration (tertiary prevention). Trials involving dietary changes, insulin administration, or immune-modulating agents are ongoing, with alum-formulated GAD65 showing promise in reducing β-cell loss, and anti-CD3 monoclonal antibodies demonstrating some benefit in newly diagnosed patients.
Inhibition of glucagon secretion, gastric emptying, and food intake due to neuronal actions can contribute to weight loss, which may have implications in the management of diabetes.
Activation of liver X receptors (LXRs) improves hepatic insulin sensitivity and lowers glycemia in diabetic animals by suppressing genes that encode key gluconeogenic enzymes, PEPCK and G-6-Pase, thereby reducing gluconeogenesis and hepatic glucose output. Insulin enhances LXRα expression, contributing to these effects. In pancreatic β-cells, activation of LXRβ with a synthetic agonist increases glucose-induced insulin secretion and insulin content, while LXRβ deletion impairs insulin secretion. LXRβ activation also upregulates pancreatic duodenal homeobox 1, insulin, and GLUT-2 genes through a SREBP-1-regulated pathway, further supporting its role in enhancing insulin secretion and mRNA expression. These findings indicate that LXR and SREBP-1 pathways play important roles in regulating both liver glucose production and pancreatic β-cell function in diabetes.
In situations of insufficient insulin intake or increased insulin resistance, such as from poor glycaemic management or illness, exercise may be dangerous due to the uninhibited action of counter-regulatory hormones. Children with diabetes should avoid strenuous exercise if pre-exercise blood glucose levels are high (> 250 mg/dl or > 14 mmol/l) and urine or blood ketones (≥ 0.5 mmol/l) are present, and exercise should be postponed until ketones have cleared.
In low- and middle-income countries such as those in sub-Saharan Africa, diabetes care is largely managed by specialists but faces resource competition from infectious disease management, and the lack of financial, infrastructural, and human resources significantly hinders effective diabetes service implementation, leading to lower life expectancy in people with diabetes; care provision often involves non-specialized nursing and allied healthcare professionals managing all chronic diseases, including diabetes, without disease-focused specialization, which may be a viable approach in contexts of multimorbidity and limited resources.
Panretinal photocoagulation may be used to treat rapidly accelerating peripheral ischemia associated with macular edema in young patients with type 1 diabetes mellitus.
Direction and support from the paediatric diabetes team are essential to help teenagers gradually take over self-care tasks, aiming to maintain optimal diabetes management and achieve target glycated haemoglobin (HbA₁c) levels while minimizing the risk of acute and chronic complications. Since adolescents vary in their ability to handle diabetes care independently, collaboration between healthcare professionals, parents, and the individual is crucial to set realistic goals. Fostering self-efficacy in diabetes self-management during adolescence is vital, particularly before transitioning to adult clinics where independence is expected, with the ultimate aim of enabling effective self-care in adulthood without experiencing diabetes burnout.
An oral glucose tolerance test (OGTT) is more effective than a fasting glucose test at identifying women with impaired glucose tolerance or diabetes, particularly in high-risk groups; in low-risk groups, using a fasting glucose test followed by an OGTT only for women with a fasting glucose level of 6 mmol/L or higher has shown high sensitivity (100%) and specificity (94%) for detecting postpartum diabetes.
Remote digital interventions using mobile devices, web-based education, pedometers, text message reminders, internet forums, emails, and apps have been tested in randomized controlled trials for women with previous gestational diabetes mellitus, showing some success in post-intervention weight loss though no significant changes in glycaemic indices between intervention and control groups.
In the USA, a two-step procedure is used for diagnosing gestational diabetes, beginning with a 50-g glucose load, and if the 1-hour venous plasma glucose is ≥140 mg/dL (7.8 mmol/L), a follow-up test with either a 100-g or 75-g glucose load is conducted, with diagnostic cutoffs of 95 mg/dL (5.3 mmol/L) fasting, 180 mg/dL (10 mmol/L) at 1 hour, and 155 mg/dL (8.6 mmol/L) at 2 hours, regardless of the glucose load used.
Skin-related vascular changes, such as reddening and telangiectasia, are observed in people with diabetes, resembling premature aging of the skin. Individuals with diabetes are more prone to bacterial, fungal, and yeast infections, which also tend to be more severe compared to those without diabetes. Certain skin conditions, including psoriasis, generalized granuloma annulare, pruritus, perforating disorders, vitiligo, and lichen planus, occur more frequently in people with diabetes. Reactions to recombinant human and analogue insulin, as well as newer anti-diabetes medications, are rare, though glues used in medical devices for diabetes management may cause contact sensitivities.
Insulin resistance in the liver is characterized by impaired insulin-mediated suppression of hepatic glucose production, increased gluconeogenesis, and decreased glycogen synthesis. Insulin activates its receptor, leading to tyrosine phosphorylation of insulin receptor substrate (IRS) and activation of downstream pathways such as the phosphatidylinositol 3-kinase (PI3K)-phosphoinositide-dependent kinase-protein kinase B (AKT) and the RAS-extracellular-signal regulated kinase (ERK) pathways. Pro-inflammatory pathways can interfere with insulin signaling by inhibiting phosphorylation of IRS, with the inhibitor of NFκB kinase β (IKKβ) playing a key role in promoting insulin resistance through activation of NFκB and downstream inflammatory signaling.
Aggressive lipid-lowering therapy is essential in managing type 2 diabetes, involving high-dose, high-efficacy statins, and in some cases, ezetimibe for acute coronary syndrome (ACS) or PCSK9 inhibitors for those intolerant to statins or with persistently high LDL cholesterol. These lipid-lowering recommendations are often extended to type 1 diabetes based on limited evidence and expert consensus. LDL cholesterol targets are generally set below 2 mmol/l, though recent evidence suggests that a target below 1.5 mmol/l may be more appropriate, with European guidelines recommending below 0.8 mmol/l for ultra-high-risk individuals with ACS and additional risk factors including diabetes. Even with optimized lipid management in type 2 diabetes, registry studies emphasize the continued importance of smoking cessation and improved glucose control. Overall, better management of risk factors has led to a reduction in cardiovascular disease events in both type 1 and type 2 diabetes.
Recurrent diabetic ketoacidosis (DKA) can be mitigated through comprehensive management strategies, including addressing potential mental health issues such as deliberate insulin omission or eating disorders, and alcohol-related concerns, with support from appropriate agencies. Patients should be educated on sick-day rules and self-care practices, and have access to glucose and ketone monitoring equipment. Providing educational materials and care plans to families and caregivers, along with specialist follow-up when needed, further supports prevention. Hospitalizations for DKA have decreased with diabetes education programs and access to diabetes nurses or educators.
SGLT-2 inhibitors have emerged as a significant treatment for diabetic nephropathy, showing benefits beyond cardiovascular safety, including reduced hospitalization for heart failure and a lower risk of incident or worsening nephropathy. Studies such as CREDENCE demonstrated that canagliflozin reduced the risk of a composite outcome including ESKD, doubling of serum creatinine, or death from renal or cardiovascular causes in patients with type 2 diabetes, high urine albumin creatinine ratio, and moderate eGFR. These findings were supported by other cardiovascular outcome trials with empagliflozin and dapagliflozin, and further confirmed by the DAPA-CKD study, which extended the benefits of dapagliflozin to a broader population including those with CKD with or without diabetes.
Type 2 diabetes is the most common form of chronic disease globally, affecting approximately 95% of people with diabetes in most populations. In 2021, an estimated 536.6 million individuals worldwide had diabetes, with 75% residing in low- and middle-income countries. Among adults aged 20–79 years, approximately 10.5% had diabetes, and nearly 44.7% of these cases remained undiagnosed. The Western Pacific region had the highest number of cases at 205.6 million, while the Middle East and North Africa had the highest prevalence rate at 16.2%. Other estimates, such as those from the NCD Risk Factor Collaboration based on 751 population-based studies involving 4.4 million participants, indicated that 422 million adults had diabetes globally in 2014.
Acute painful neuropathy, referred to as "insulin neuritis," can occur several weeks after starting insulin treatment. Painful symptoms tend to improve gradually over 3–8 months, allowing for discontinuation of analgesic therapy. Careful correction of glucose levels is important in patients with long-standing uncontrolled diabetes, as rapid improvement in glycemic control may lead to transient deterioration of pre-existing retinopathy. Sural nerve biopsy findings in such cases show chronic neuropathy with regenerative activity, along with epineurial arteriovenous shunting and a fine network of vessels that may cause ischemia in the endoneurium, similar to changes seen in diabetic retinopathy.
As symptoms improve and euglycaemia is restored, consuming a solid snack or meal such as fruit, bread, or cereal helps prevent recurrence, and blood glucose should be retested within 20–30 minutes to confirm that the target glucose level has been maintained.
Periodontitis has been shown to negatively affect metabolic control in rats with type 2 diabetes, leading to a 30% increase in glucose tolerance and elevated levels of IL-1β in adipose tissue. In pre-diabetic rats, periodontitis also significantly impairs glucose tolerance, suggesting that it may contribute to the progression toward overt diabetes. Additionally, pre-diabetic rats with periodontitis exhibit early signs of kidney damage, including renal hypertrophy and a tendency toward increased glomerular volume.
Diabetes prevalence increases with age, with the highest rates observed in individuals aged 60–79 years. In France, prevalence reaches 14.2% in those aged 65–74 years and peaks at 19.7% in men and 14.2% in women aged 75–79 years. In the USA, 14% of the population is estimated to have diabetes, with the highest prevalence in those aged 65 years and older. By 2050, diabetes prevalence in the US could reach 33%. In those aged 75 years and older, the total prevalence of diabetes, including both diagnosed and undiagnosed cases, is 28.3%, with nearly 47% of cases undiagnosed. Pre-diabetes, defined as impaired fasting glycaemia or impaired glucose tolerance, affects 46.7% of those aged 75 years and older, leading to a combined diabetes and pre-diabetes prevalence of approximately 75% in this age group.
Glibenclamide, a sulfonylurea used to treat gestational diabetes, crosses the placenta and can stimulate fetal insulin secretion, increasing the risk of macrosomia and neonatal hypoglycaemia. Women with HNF1A or HNF4A variants who are treated with sulfonylureas before conception and have good glycaemic control should consider switching to insulin either before conception or during the second trimester to mitigate risks to the fetus. Additionally, in pregnancies complicated by HNF1A or HNF4A maturity-onset diabetes of the young (MODY), glibenclamide should be avoided during the third trimester to prevent excessive fetal weight gain.
In individuals with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM), abnormal alpha-cell function includes impaired suppression by hyperglycemia, excessive responses to amino acids or mixed meals, and diminished responses to hypoglycemia; these changes may be secondary to reduced beta-cell function and involve mechanisms such as glucose toxicity, lipotoxicity, and insulin resistance.
Islet cell transplantation is considered for individuals with type 1 diabetes, particularly those with a high burden of cardiovascular disease. Cardiovascular complications such as coronary artery disease, cerebrovascular disease, and peripheral vascular disease are reported in less than 10%, less than 3%, and less than 5% of islet cell transplantation recipients respectively, though these figures may be underreported as studies have found around 43% of asymptomatic candidates show signs of coronary artery disease on angiography. Cardiovascular death rates are generally lower in individuals with a successful islet cell transplant compared to those with unsuccessful transplants. The incidence of coronary artery disease events following islet cell transplantation is slightly higher than in the general type 1 diabetes population, with 11 events per 1000 person-years compared to 8.9 events per 1000 person-years.
Insulin pump therapy offers advanced features such as setting short-term temporary basal rates, which allow for a 10–100% increase or decrease in basal insulin delivery, aiding in glucose management during changes in activity levels or illness. Users can also manually suspend all insulin delivery, including basal and bolus doses. Around 60% of pump users take advantage of the temporary basal function, and habitual use is linked to improved glycaemic control. Additionally, individuals using continuous subcutaneous insulin infusion (CSII) alongside continuous glucose monitoring (CGM) are more likely to adjust basal rates, reflecting more active self-management of insulin therapy.
Atypical antipsychotic medications can contribute to the development of diabetes, potentially through mechanisms involving weight gain, insulin resistance, or direct effects on glucose metabolism. In some cases, switching antipsychotics may help manage diabetes, but this can also risk relapse of psychiatric conditions like schizophrenia. Once diabetes develops in this context, it may be difficult to control and may require a balance between psychiatric stability and metabolic health. Risk factors such as family history, poor diet, lack of exercise, and smoking can further predispose individuals to diabetes.
Self-management education is a well-known concept in the diabetes community, involving the traditional role of diabetes educators who provide patients with knowledge and skills. In contrast, self-management support does not necessarily require a diabetes educator and can be facilitated by peer coaches to help patients define problems, set priorities, establish goals, and create treatment plans. This collaborative approach often includes resources such as community-based organizations and peer support programs, with individualized strategies addressing the patient's primary concerns, emphasizing coaching to educate and empower. Innovative methods using information technology to deliver patient coaching are being explored to expand access to self-management support.
Glycated haemoglobin (HbA₁c) is used for both diagnosing type 2 diabetes and monitoring long-term glycaemic control in people with diabetes, alongside blood glucose levels. HbA₁c values are reported in SI units (mmol/mol) and derived percentage units based on a standardized equation, with all measurement methods needing to align with the IFCC reference procedure. For individuals with type 1 diabetes, HbA₁c should be monitored every 2–6 months, depending on the stability of blood glucose levels and any changes in treatment.
For older patients with type 2 diabetes mellitus (T2DM) who have single system involvement and no other major co-morbidities, a fasting glucose range of 6.5–7.5 mmol/L is considered indicative of good glycemic control, with an HbA1c level of 53–58 mmol/mol recommended by the IFCC, supported by evidence level 2++ and grade of recommendation B.
ACE inhibitors are contraindicated in people with or without diabetes who have renal artery stenosis due to a high risk of renal impairment, which can be either reversible or permanent, and significant renal artery stenosis may be present in up to 20% of patients with both hypertension and type 2 diabetes mellitus.
Patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease who are managed by a pharmacist-doctor team experience a 50% risk reduction in death and end-stage renal disease compared to those managed in conventional care settings.
In women with pre-existing diabetes, renal assessment should occur at booking if not done in the previous 12 months. If the serum creatinine is abnormal (≥120 μmol/L), the urine-to-albumin creatinine ratio is >30 g/mol, or the total protein excretion exceeds 2 g/d, referral to a nephrologist should be considered. Women with known renal disease should be carefully monitored with regular blood pressure, urine albumin/protein excretion measurements, and serum creatinine. A rising serum creatinine has serious implications. Suitable antihypertensive agents should be started with a target blood pressure <130/85 mmHg. Thromboprophylaxis should be considered for women with proteinuria >5 g/d.
Type 1 diabetes mellitus (T1DM) typically results from cell-mediated autoimmune destruction of beta cells in susceptible individuals, following a variable preclinical period during which islet autoantibodies to insulin, glutamine acid decarboxylase (GAD), insulinoma-associated antigen 2 (IA-2), and other autoantigens can be detected. These autoantibodies are markers of ongoing beta-cell destruction rather than causative agents. The distinction between autoimmune T1DM (type 1A) and non-autoimmune T1DM (type 1B) is not always useful in clinical or epidemiological settings due to challenges such as measurement errors of autoantibodies, the presence of undiscovered autoantibodies like zinc transporter 8 autoantibodies, and the transient nature of these autoantibodies. Longitudinal studies, such as DAISY, indicate that some patients diagnosed with T1DM may be autoantibody-negative at diagnosis despite having previously tested positive.
Prolonged breastfeeding or delayed introduction of cow's milk has been suggested to reduce the risk of type 1 diabetes, but many case-control studies on this topic are susceptible to recall bias and the evidence remains controversial. Large prospective studies have not found a clear association between the duration of exclusive or total breastfeeding and the risk of islet autoimmunity or type 1 diabetes. Observational studies find it difficult to distinguish the effects of breastfeeding duration from the timing of weaning food introduction. The TRIGR trial investigated whether delaying the introduction of intact cow's milk proteins could prevent type 1 diabetes but found no protective effect regardless of breastfeeding duration.
GLP-1 and GIP are involved in increasing nutrient-induced insulin secretion, increasing insulin biosynthesis, and enhancing β-cell mass, with GLP-1 additionally suppressing glucagon secretion and increasing somatostatin secretion. GLP-1 also slows gastric emptying, promotes satiety and weight reduction, while GIP decreases gastric acid secretion and promotes lipogenesis.
Insulin glargine and insulin degludec, an ultra-long-acting basal insulin, have been evaluated for their cardiovascular safety in people with diabetes and high cardiovascular risk. In the ORIGIN trial, targeting a fasting plasma glucose of 95 mg/dL or less with insulin glargine did not significantly change the risk of heart failure hospitalization compared to standard care over six years, with rates of 4.9% and 5.3% respectively. Similarly, the DEVOTE trial found no difference in heart failure risk between insulin degludec and insulin glargine in patients with type 2 diabetes and high cardiovascular risk.
Islet cell and whole pancreas transplantation are therapeutic options for diabetes, with differences in patient characteristics and outcomes. Those undergoing islet cell transplantation tend to be older, have a longer duration of diabetes, and a higher prevalence of coronary artery disease compared to those receiving whole pancreas transplants, leading to lower survival rates. These differences may be influenced by treatment eligibility criteria, as older individuals may not qualify for whole pancreas transplantation and sicker patients may undergo islet cell transplantation instead of combined procedures. Whole pancreas transplantation is associated with higher rates of early mortality and post-transplant complications such as relaparotomy. Regarding insulin independence, some studies report higher rates and longer duration following simultaneous pancreas-kidney transplantation compared to islet cell or islet-after-kidney transplantation, while others find no difference when comparing whole pancreas and islet cell transplantation alone.
Albiglutide is a long-acting GLP-1 receptor agonist used in the treatment of diabetes, developed by fusing two recombinant human GLP-1 molecules to recombinant human albumin. It inhibits gastric emptying and appetite, though the extent of its anorectic effect may be limited by reduced blood-brain barrier permeability. With a circulating half-life of 6–7 days, it is administered weekly, biweekly, or monthly. A weekly dose of 30 mg has demonstrated greater efficacy than exenatide twice daily in reducing HbA1c levels with fewer gastrointestinal side effects such as nausea. Albiglutide is under phase 3 clinical development for diabetes management.
SGLT-2 inhibitors have been shown to significantly reduce MACE by 17%, hospitalization for heart failure by 38%, and a kidney composite outcome by 34% in individuals with type 2 diabetes and chronic kidney disease. These benefits extend to individual MACE components and all-cause mortality, with positive effects observed even in those with an eGFR of less than 45 ml/min/1.73 m².
Genome-wide association studies (GWAS) have been instrumental in identifying genetic loci associated with type 2 diabetes, with meta-analyses involving large cohorts, such as those conducted by the DIAGRAM consortium, leading to the discovery of new susceptibility loci. Collaborative efforts and the use of custom genotyping arrays like the CardioMetabochip, which includes around 200,000 polymorphisms related to metabolic disorders, have enabled more precise replication and fine mapping of genetic signals, resulting in the identification of additional type 2 diabetes-associated loci in European populations.
Patients with diabetes more often develop symptoms of atherosclerotic complications, tend to develop them at a younger age, and are more difficult to treat, particularly with invasive treatments, leading to more complications during treatment.
Human insulin can be produced through three methods: direct isolation from human cadaveric pancreata, semi-synthesis by chemically converting porcine insulin, and recombinant DNA technology. The first method was limited by insufficient human tissue supply, while the second involves altering porcine insulin by replacing one amino acid to match the human sequence. Recombinant DNA technology, introduced in 1980, revolutionized insulin production by inserting the human insulin gene into host cells like yeast or Escherichia coli, enabling large-scale synthesis. The resulting insulin is then purified to a high degree, typically achieving 99.5–99.9% purity, significantly reducing immune-mediated side effects compared to earlier preparations.
Sulfonylureas target $\mathrm{K_{ATP}}$ channels in $\beta$ cells, which are composed of Kir6.2 and SUR1 subunits, and their effectiveness in type 2 diabetes stems from their ability to close these channels, bypassing the usual glucose-dependent pathway for insulin secretion. ATP and sulfonylureas bind to Kir6.2 and SUR1 respectively to induce channel closure, while ADP activates the channels via SUR1. Variants in genes encoding Kir6.2 and SUR1 have been linked to increased risk of type 2 diabetes, and activating mutations in Kir6.2 cause permanent neonatal diabetes (PNDM), which can be treated with sulfonylureas. In contrast, loss of functional $\mathrm{K_{ATP}}$ channels in $\beta$ cells contributes to congenital hyperinsulinism, a condition marked by excessive insulin secretion due to mutations in Kir6.2 or SUR1 subunits.
Anti-CD3 treatment, using formulations such as teplizumab and otelixizumab, has been studied in individuals with newly diagnosed type 1 diabetes, showing generally greater β-cell preservation and a slower decline in C-peptide over time, though dose dependency in C-peptide preservation and adverse effects has been observed; a meta-analysis of eight randomized trials with 866 participants found higher C-peptide AUC at 24 months in the teplizumab group compared to placebo, but no difference in HbA1c levels at any time point from onset to 24 months.
Hyperglycaemia, measured by glucose or $\mathrm{HbA_{1c}}$, is used to diagnose type 2 diabetes, but endogenous hyperinsulinaemia often precedes hyperglycaemia and is linked to cancer risk and progression. Hyperinsulinaemia, once thought to result from insulin resistance, is now recognized as a contributor to the development of insulin resistance. Genetic studies using the UK Biobank show that higher fasting insulin levels are associated with increased risk of uterus, kidney, pancreas, and lung cancers, and in women with early-stage breast cancer, elevated fasting insulin correlates with poorer outcomes.
Erectile dysfunction, which is the persistent or recurrent inability to achieve and maintain penile erection sufficient for satisfactory sexual activity for at least three months, occurs in approximately 50% of men with diabetes and is more severe and less responsive to treatment compared to men without diabetes. Risk factors for erectile dysfunction in men with diabetes include persistent hyperglycaemia, metabolic syndrome, hypertension, dyslipidaemia, lower estimated glomerular filtration rate (eGFR), and higher albumin-to-creatinine ratio.
To prevent complications such as nerve, eye, kidney, and vascular diseases, early diagnosis of type 2 diabetes is crucial. However, in 2019, half of the 463 million adults with diabetes were unaware of their condition, often due to the slow progression and lack of early symptoms, which delays testing and preventive care. Undiagnosed diabetes is more prevalent in low-income compared to middle-income countries, with 75% versus 46% respectively, and 84% of all undiagnosed cases are estimated to be in low- and middle-income countries (LMIC), particularly in Pacific Island nations. These findings highlight the urgent need for improved diabetes screening programs.
Beta-cell replacement therapies are effective alternatives for managing difficult-to-control diabetes and persistent problematic hypoglycemia that do not respond to conventional treatments. These therapies have seen significant advancements over time, with improved outcomes since their early development. The connection between the pancreas and diabetes was recognized as early as 1892 by Von Mering and Minkowski, which led to early attempts at reversing diabetes through pancreatic tissue transplantation. The first known transplant involving sheep pancreatic tissue was conducted in 1894 by Watson-Williams and Harsant in a child with diabetic ketoacidosis, followed by James Allan’s use of feline pancreatic tissue in another individual. In 1916, Charles Pybus conducted the first human transplantation using cadaveric pancreatic fragments placed subcutaneously in two men with diabetes. However, these early attempts largely failed to achieve normal blood glucose levels, likely due to immune rejection, as the field of transplantation immunology was not yet developed. The discovery and success of insulin therapy further led to a decline in interest in beta-cell replacement therapies for several decades. Renewed interest emerged in the 1960s with the introduction of steroid and new immunosuppressive therapies that enabled successful kidney transplants, thereby revitalizing research into both whole pancreas and islet cell transplantation.
Management of diabetes includes providing access to screening and early intervention to prevent or limit complications; in low resource settings, certain complications like proteinuria can be easily screened using dipstick testing and at-risk foot identification with a monofilament, while screening for retinopathy remains challenging due to difficulties in performing ophthalmoscopy, although the use of a fundal camera may offer a feasible solution.
Insulin suppresses triglyceride breakdown by inhibiting hormone-sensitive lipase and reduces ketogenesis in the liver, which is relevant in the context of diabetes where insulin deficiency or resistance leads to increased lipolysis and ketone production. Additionally, insulin promotes cholesterol synthesis by activating HMGCoA reductase and inhibits cholesterol ester breakdown through dephosphorylation of cholesterol esterase, highlighting its role in lipid metabolism disturbances seen in diabetes.
Subcutaneous route is usually used for routine insulin administration, with injection sites including the front or lateral aspect of the thigh, lower abdomen below the umbilicus, buttocks, and lateral aspect of the arm, requiring rotation of sites to avoid complications and returning to the original site only after a month; intravenous route is used during Diabetic Ketoacidosis.
Vildagliptin, when combined with a sulfonylurea or a thiazolidinedione, improves glycemia in patients with type 2 diabetes mellitus (T2DM) over trials lasting 24–52 weeks. In patients not adequately controlled with metformin, adding vildagliptin at 100 mg/day is non-inferior to pioglitazone, with both treatments reducing HbA1c by an additional 1% (11 mmol/mol). Vildagliptin is also available in a fixed-dose combination with metformin. When added to insulin therapy, vildagliptin provides a small additional HbA1c reduction of approximately 0.3% (3 mmol/mol) compared to placebo. Studies have also shown that vildagliptin suppresses glucagon response to a glucose challenge and slightly improves glucagon increment during insulin-induced hypoglycemia.
Reduced muscle lipid oxidation may contribute to lipid accumulation in skeletal muscle and insulin resistance. Lean individuals who are first-degree relatives of people with type 2 diabetes show approximately 40% lower flux rates through muscle ATP synthase, a measure of basal mitochondrial phosphorylation, compared to insulin-sensitive individuals. In response to insulin stimulation, muscle ATP synthase flux doubles in insulin-sensitive individuals but is nearly abolished in those with a family history of type 2 diabetes. Additionally, individuals with type 2 diabetes who are not obese exhibit about 25% lower mitochondrial phosphorylation rates in the fasting state and no increase during insulin stimulation, even when glucose availability is increased. This impairment may result from reduced capacities of the electron-transport chain or phosphorylation system, or from diminished insulin-stimulated phosphate transport into muscle cells.
Restricted sleep reduces insulin sensitivity and increases insulin resistance in healthy individuals, contributing to diabetes risk. Long sleep duration is associated with higher insulin resistance and elevated insulin and glucose levels during an oral glucose tolerance test in people without diabetes, with these associations remaining significant after adjusting for age, sex, family history of diabetes, obesity, depression, physical activity, and after excluding those with severe sleep apnoea and insomnia.
Diuretics suitable for use in diabetic hypertension include furosemide, bendroflumethiazide (≤2.5 mg/d), hydrochlorothiazide, spironolactone, and indapamide, with low dosages preferred, sometimes combined with potassium supplements or potassium-sparing drugs like amiloride. If diuretics are ineffective, they should be combined with another first-line drug such as an ACE inhibitor or an angiotensin II receptor blocker rather than being increased in dosage. Spironolactone should not be combined with an ACE inhibitor due to the increased risk of hyperkalaemia, and furosemide is particularly useful in individuals with renal impairment or oedema.
The table summarizes clinical trials involving patients with diabetes, highlighting the impact of intensive versus conventional glucose-lowering therapies on microvascular and macrovascular outcomes. In the UKPDS post-trial follow-up, intensive therapy resulted in a 25% relative risk reduction in microvascular complications and a 16% reduction in macrovascular complications compared to conventional therapy. Similarly, in the ADVANCE trial, intensive therapy led to a 14% relative risk reduction in microvascular complications and a 6% reduction in macrovascular events, although the latter was not statistically significant. The ACCORD trial showed a 33% relative risk reduction in microvascular complications and a 10% reduction in macrovascular complications with intensive therapy. In the VADT trial, intensive therapy resulted in a 2.59% relative risk reduction in microvascular complications and a 12% reduction in macrovascular events, though neither reached statistical significance for macrovascular outcomes. These trials involved patients with varying baseline HbA1c levels, with intensive therapy generally achieving lower HbA1c levels compared to conventional therapy, and followed patients for durations ranging from 3.5 to 10 years.
Diabetes in pregnancy is associated with several complications, including congenital anomalies, intrauterine growth restriction, and intrapartum hypoxia-ischaemia. It can also lead to macrosomia, obstructed labour, and birth injury, as well as neonatal death and metabolic disturbances such as polycythaemia, jaundice, hypoketonaemia, and hypoglycaemia. Additional risks include hypocalcaemia, hypomagnesaemia, and hypertrophic cardiomyopathy. Complications may also arise from obstetric interventions, preterm delivery, and caesarean sections, which can result in respiratory distress and difficulties with breastfeeding. Inappropriate separation of the mother and baby or unnecessary formula supplementation can further negatively impact breastfeeding outcomes.
South Asian individuals with type 2 diabetes have a higher risk of developing complications compared to white Europeans, influenced by factors such as genetic predisposition, earlier onset of diabetes, delayed diagnosis, elevated glucose levels, and a greater likelihood of treatment being omitted or inadequately dosed.
Fixed ratio combinations of GLP-1 receptor agonists (GLP-1RAs) with basal insulin are available as a single injection, offering improved glycaemic control while balancing weight gain and the risk of hypoglycaemia.
Geographical variations in the incidence of type 1 diabetes among children have been observed globally, with differences noted between regions within countries such as Finland, Sweden, and Norway. In Italy, incidence rates varied significantly between Sardinia and mainland regions, with children from Sardinian families maintaining higher rates even after relocating to mainland Italy. In New Zealand, a 1.5-fold higher incidence in the South Island compared to the North Island was attributed to a higher prevalence among children of European origin compared to Mbaris. In China, there was a 12-fold geographical variation in incidence, with higher rates generally in the north and east, and notable differences between ethnic groups such as the Mongol and Zhuang. A nationally representative sample in China during 2010–2013 showed a 3.6-fold variation in incidence across 13 large regions.
Visual loss in diabetes is primarily caused by diabetic retinopathy, a complication resulting from chronic damage to the retinal blood vessels due to prolonged hyperglycemia. This condition progresses through stages, beginning with nonproliferative retinopathy characterized by microaneurysms and retinal edema, and advancing to proliferative retinopathy where abnormal new blood vessels form, increasing the risk of hemorrhage and severe vision loss. Diabetic macular edema, a swelling of the macula, is a leading cause of visual impairment in diabetic patients. Early detection through regular eye examinations, including fundus photography and optical coherence tomography, is critical for timely intervention. Management strategies include tight glycemic control, blood pressure regulation, anti-VEGF therapies, laser photocoagulation, and in advanced cases, vitrectomy surgery to preserve vision.
LADA, or latent autoimmune diabetes in adults, is estimated to have a prevalence of approximately 10% among adult populations who present with a clinical picture of type 2 diabetes, though this figure can vary significantly based on factors such as the clinical definition used, age at diagnosis, ethnicity, and the specific assay methodologies applied in detection.
Insulin activates the mTOR pathway through signaling involving the class III PI₃ kinase hVps34, as shown by the blocking of amino acid- and insulin-induced S6K1 activation when hVps34 is knocked down, though this does not affect Akt/PKB activation. Rapamycin inhibits mTOR by binding to its receptor FKBP12, which then interacts with the FRB domain of mTOR to suppress its activity. Rapamycin has been shown to enhance insulin-mediated glucose uptake by inhibiting mTOR-dependent S6K phosphorylation and reducing IRS serine phosphorylation. The activation of the mTOR pathway is regulated by the tuberous sclerosis complex (TSC), which integrates signals from both the insulin signaling cascade and the AMPK pathway. These mechanisms involved in nutrient sensing through the mTOR pathway are potential therapeutic targets for treating insulin resistance in metabolic diseases caused by nutrient excess, such as type 2 diabetes mellitus (T2DM) and obesity.
Remission of diabetes requires an HbA1c measure immediately prior to intervention, with testing intervals varying by treatment type: for lifestyle interventions, testing should occur greater than 6 months after the start of the intervention and greater than 3 months after stopping pharmacotherapy, while for pharmacotherapy and surgery, testing should occur greater than 3 months after treatment cessation or the procedure and greater than 3 months after stopping pharmacotherapy, with subsequent measurements of HbA1c occurring greater than 3 months and less than 1 year later.
Approximately one in three people with diabetes is affected by distal symmetric polyneuropathy (DPN), a major health issue that can cause severe neuropathic pain and lead to significant morbidity, increased mortality, and reduced quality of life. Neuropathic pain notably interferes with sleep, daily activities, and overall enjoyment of life. Treatment for DPN involves four main approaches: intensive diabetes therapy and multifactorial risk intervention, treatment targeting pathogenetic mechanisms, symptomatic treatment, and avoidance of risk factors and complications. Experimental studies suggest a multifactorial origin of diabetic neuropathy, and clinical applications based on these mechanisms are under evaluation in trials. Managing chronic painful DPN requires careful drug selection, dosage adjustment, and monitoring for efficacy and side effects, with lack of improvement being assessed after 2–4 weeks of adequate treatment. Combination therapy may be considered, while accounting for possible drug interactions due to frequent polypharmacy in diabetes. Epidemiological evidence also highlights the role of excessive alcohol consumption and traditional cardiovascular risk factors such as visceral obesity, hypertension, hyperlipidemia, and smoking in the onset and progression of diabetic neuropathy, emphasizing the need for their prevention and management.
Gestational diabetes (GDM) can be diagnosed during early pregnancy using a random plasma glucose test, which should be confirmed by a fasting plasma glucose or HbA1c test. The 75 g oral glucose tolerance test thresholds are based on the average glucose levels at which the odds of increased birth weight, percent body fat, and cord blood C-peptide (indicating fetal insulin) exceed 1.75 times the estimated odds compared to the average glucose values in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) population.
Diabetes in older individuals is associated with significant morbidity, primarily due to long-term complications such as ischemic heart disease, stroke, and peripheral vascular disease, with reported incidence rates of 56, 22, and 146 cases per 1000 person-years, respectively, in a study of patients over 60 years old. These rates were higher compared to those in the Framingham study, likely due to the older age of the study population. Other complications include retinopathy and cataract, occurring at rates of 60 and 29 cases per 1000 person-years, respectively, while proteinuria with albumin concentration >300 mg/L occurred at a rate of 19 cases per 1000 person-years. The incidence of these complications appeared unrelated to sex or duration of diabetes, although stroke and peripheral vascular disease increased significantly with age.
Patients with type 1 diabetes mellitus (T1DM) or those receiving insulin must be aware of the potential for changing insulin requirements during infections and the risk of severe complications like diabetic ketoacidosis. Additionally, many patients with type 2 diabetes mellitus (T2DM) not on insulin may require temporary insulin therapy during illness, as the stress of sickness often impairs glycemic control. Hospital admission becomes necessary if there is significant destabilization of blood glucose levels or if symptoms such as nausea and vomiting occur.
The target range for time in range (TIR) in diabetes management is defined as 70–180 mg/dl (3.9–10.0 mmol/l). Hypoglycaemia between 54 and 70 mg/dl (3.0–3.9 mmol/l) is classified as level 1, or relevant hypoglycaemia, while values below 54 mg/dl (3.0 mmol/l) are classified as level 2, or serious, clinically relevant hypoglycaemia. For hyperglycaemia, values above 250 mg/dl (13.9 mmol/l) are considered level 2, or serious hyperglycaemia, and values between 181 and 250 mg/dl (10.1–13.9 mmol/l) are classified as level 1, or relevant hyperglycaemia. In cases of severe hyperglycaemia, testing for ketone bodies in the blood or urine may be necessary to detect impending ketoacidosis. Individualized glucose targets closer to the physiological normal range may be set based on factors such as age, concomitant diseases, or self-management capabilities. Nocturnal glucose control refers to the period between midnight and 6 a.m., and for clinical trials, TIR and coefficients of variation should be reported separately for night, day, and 24-hour periods.
Repaglinide is ideally taken 15–30 minutes before a meal, starting with a low dose of 0.5 mg, with gradual titration every two weeks based on glycaemic levels up to a maximum of 4 mg before each main meal. If a meal is skipped, the corresponding dose should be omitted. It can be used cautiously in patients with moderate renal impairment, where some sulfonylureas and metformin may be contraindicated.
Type 2 diabetes prevalence, especially when associated with obesity, is increasing among pregnant women and now exceeds type 1 diabetes in some populations, leading to similarly poor pregnancy outcomes. Consensus guidelines aim to standardize the diagnosis of hyperglycaemia in pregnancy, though approaches vary by country and the balance of risks, costs, and benefits of interventions remains debated. Early pregnancy screening using glycated haemoglobin (HbA1c), fasting plasma glucose, or other blood glucose assessments is recommended to detect undiagnosed type 2 diabetes and pre-diabetes, as well as severe hyperglycaemia. Metformin, often combined with dietary changes, is increasingly used to manage gestational diabetes mellitus (GDM) and type 2 diabetes in overweight women, though insulin is still recommended as first-line therapy by some health authorities due to metformin's placental transfer. Early postnatal follow-up offers a critical opportunity to assess and address cardiometabolic risks, prevent or delay the onset of type 2 diabetes, and provide guidance on contraception and future pregnancies. Hyperglycaemia during pregnancy has significant long-term health consequences for both mother and child, which should be considered in economic evaluations.
The release of insulin from $\beta$-cells is a complex process initiated by an increase in extracellular glucose, which leads to elevated ATP and cyclic adenosine monophosphate (cAMP) levels, closure of ATP-sensitive potassium channels, depolarization of the $\beta$-cell membrane, and influx of calcium through voltage-sensitive calcium channels. This sequence of events results in increased intracellular calcium, which triggers the movement of insulin-containing granules toward the $\beta$-cell membrane for release, with the first phase of insulin release lasting about 10 minutes and the second phase being more sustained and involving synthesis of new insulin molecules and mobilization of stored granules. Normal $\beta$-cell function depends on glucose entry and metabolism, insulin synthesis, and structural components like microfilaments and microtubules that aid in granule transport and membrane fusion.
Women with type 1 diabetes have reduced bone mineral density at diagnosis, and despite the expectation that obesity in type 2 diabetes might protect against osteoporosis, these women still face an increased risk of hip fracture. A large study found that postmenopausal women with diabetes had a 1.7-fold higher risk of hip fracture compared to those without diabetes, suggesting that hormone replacement therapy (HRT) could provide at least equal benefits in reducing osteoporotic fracture risk in women with diabetes as in those without, and should be considered for postmenopausal women with diabetes and osteoporosis.
Insulin pumps have been found to be cost-effective, particularly for individuals with suboptimal glycaemic management or high levels of hypoglycaemia. Continuous subcutaneous insulin infusion (CSII) combined with self-monitoring blood glucose is more cost-effective than multiple daily injections (MDI) with self-monitoring blood glucose in 56% of studies reviewed. Incremental cost-effectiveness ratios (ICERs) below willingness-to-pay thresholds in the USA range from $21,000 to $57,000 per quality-adjusted life year (QALY) gained. However, a health economics analysis of the REPOSE study showed that when pumps were compared with MDI with equivalent structured education, the ICER was unlikely to fall below $30,000 per QALY gained, indicating that pumps may not be cost-effective for those without an immediate clinical need.
The prevalence of erectile dysfunction (ED) in men with diabetes increases with age, rising from 25% at age 40–44 years to 70% at age 65–70 years. Cardiovascular disease further elevates the risk of ED in men with diabetes, with prevalence rates of 40% in those with diabetes and heart disease and 46.5% in those with diabetes and hypertension, compared to 31.7% in men with diabetes only. Additionally, the prevalence of ED increases with the duration of diabetes, and men with diabetes who smoke and have low physical activity levels experience a fourfold increase in ED prevalence.
Understanding diabetes and developing self-management skills is crucial for individuals with diabetes, particularly regarding treatment, goals, and the use of equipment such as blood glucose meters and insulin devices. People with newly diagnosed diabetes should consult with a diabetes healthcare professional to gain a clear understanding of the condition. For those with type 1 diabetes, ketone testing is important and should be explained. When self-monitoring is recommended, individuals must be taught how to interpret their results and respond appropriately.
Pregestational diabetes increases the risk of preterm birth, with delivery before 37 weeks’ gestation occurring 2–3 times more frequently compared to women without diabetes, largely due to elective preterm delivery which is 6–7 times higher, and spontaneous preterm delivery also being increased by approximately 50%. Women with pregestational diabetes, including both type 1 and type 2 diabetes, have high caesarean section rates globally, ranging from 50% to 65%, as reported in the 2013 NDIPA study. Infants born to mothers with type 1 diabetes often require admission to the NICU due to iatrogenic prematurity.
Poverty and social deprivation contribute to the increasing prevalence of type 2 diabetes among inner-city residents, as seen in inner-city Manchester where the age-standardized prevalence among white Europeans reached 20%. Social deprivation often co-occurs with obesity, physical inactivity, and smoking, which may explain the higher diabetes rates. Dietary factors also play a role, as high dietary energy density and unhealthy dietary patterns—marked by high intake of sugar-sweetened beverages, burgers, sausages, and snacks—are linked to incident type 2 diabetes. The Ely Study found a 10-year cumulative incidence of diabetes at 7.3 per 1000 person-years. In the UK, the National Health Service spends at least £10 billion annually on diabetes, with 80% of that used to treat complications, accounting for about 10% of its total budget.
Elevated glycaemia and longer duration of diabetes exposure are strongly linked to microvascular complications, as demonstrated in the UK Prospective Diabetes Study (UKPDS). Glycated haemoglobin $(\mathrm{HbA_{1c}})$ is identified as an independent and continuous risk factor for macrovascular disease. An increase in $\mathrm{HbA_{1c}}$ from $5.5\%$ $(37\mathrm{mmol / mol})$ to $9.5\%$ $(80\mathrm{mmol / mol})$ corresponds to a 10-fold rise in microvascular disease endpoints, whereas the risk for macrovascular disease endpoints increases by only twofold.
Agents such as aspirin may be useful in people with diabetes, with evidence suggesting that higher doses are often required to provide cardiovascular benefits. Other drugs to consider in diabetes include clopidogrel and abciximab, which has been reported to be particularly effective in people with diabetes.
In later stages of kidney disease with macroalbuminuria, protein intake should be limited to 0.8g per kilogram of body weight per day, and blood pressure should be tightly controlled, particularly in the context of CVD risk; in diabetes management, maintaining HbA1c as close to normal as possible without causing significant hypoglycemia is emphasized, especially during acute illness.
The renin angiotensin system (RAS), particularly with components like angiotensin converting enzyme 2, contributes to macrovascular disease in diabetes, and RAS inhibitors have shown reduced endothelial dysfunction and atherosclerosis in animal models by suppressing inflammation, fibrosis, and oxidative stress, with clinical evidence supporting vasculoprotection. Other vasoactive components such as endothelin and urotensin II also play a role in macrovascular complications and interact with the RAS. Novel factors like TNF-related apoptosis inducing ligand, osteoprotegerin, and the complement system are under investigation for their involvement in atherosclerosis. Treatments reducing oxidative stress and inflammation, including peroxisome proliferator activated receptor agonists, show anti-atherosclerotic effects in experimental and some clinical studies. A multifactorial approach addressing both conventional cardiovascular and diabetes-specific risk factors is considered optimal for reducing cardiovascular disease burden in diabetes.
Pioglitazone and rosiglitazone are agents used in the management of diabetes, with dose ranges of 15–45 mg/day and 4–8 mg/day respectively, and both have a duration of action of approximately 24 hours. Pioglitazone has active metabolites and is primarily eliminated through bile, while rosiglitazone has inactive metabolites and is mainly excreted in urine.
Diabetes can lead to oesophageal dysmotility, with a prevalence as high as 63%, due to autonomic neuropathy and structural remodelling of the oesophageal musculature, resulting in abnormal peristalsis, spontaneous contractions, and reduced lower oesophageal sphincter tone. Symptoms such as dysphagia, retrosternal discomfort, and heartburn are uncommon and an obstructive lesion should be ruled out via endoscopy. Oesophageal motility disturbances can be detected using scintigraphic techniques and manometric studies show diminished pharyngeal and oesophageal contractions along with reduced lower sphincter tone. Prokinetic drugs may be used empirically for treatment, and individuals with reduced oesophageal motility should drink after taking medication to prevent delayed transit, tablet hold-up, localized mucosal ulceration, and delayed drug absorption.
Poor maternal nutrition during pregnancy can lead to low birth weight and cause permanent changes in glucose-insulin metabolism, potentially predisposing the individual to diabetes later in life. This is linked to the developmental origins of health and disease hypothesis, which suggests that intrauterine conditions influence chronic disease susceptibility. A reduced beta-cell mass due to intrauterine programming may contribute to diabetes risk, especially when increased insulin demands occur alongside obesity and insulin resistance. The gene KCNQ1 is an example of fetal programming, being maternally expressed and potentially influencing metabolic development.
Elevations in intracellular calcium within beta cells trigger insulin secretion through calcium-sensing mechanisms, including calcium-dependent protein kinases such as myosin light-chain kinases, calcium/phospholipid-dependent kinases, and calcium/calmodulin-dependent kinases (CaMKs), with CaMK II being particularly implicated in initiating insulin secretion in response to glucose and other nutrients. Cytosolic phospholipase A2 (cPLA2), another calcium-sensitive enzyme in beta cells, is activated by increased calcium levels and produces arachidonic acid, which can stimulate insulin secretion independently of glucose and calcium, and is further metabolized into prostaglandins, thromboxanes, hydroperoxyeicosatetraenoic acids (HPETES), hydroxyeicosatetraenoic acids (HETES), and leukotrienes via cyclooxygenase and lipoxygenase pathways.
Carrying one TCF7L2 risk allele may increase diabetes risk by 40% to 60%, with the rs7903146 T allele contributing to 10–25% of all diabetes cases in lean individuals within European populations, while in Eastern Asians, other specific risk alleles account for an estimated 18.7% of cases. The rs7903146 variant also influences progression to diabetes, with a hazard ratio of 1.81 for the homozygote TT group among participants in the Diabetes Prevention Program.
Metformin improves insulin sensitivity and is often used in combination with insulin therapy, allowing for reduced insulin dosages and less weight gain. It is also associated with fewer and less severe episodes of hypoglycemia. Metformin is indicated for diabetes prevention in some regions, particularly showing a 39% reduction in the incidence of diabetes in individuals with overweight or obesity and impaired glucose tolerance, though less effective than an intensive diet and exercise regimen which showed a 58% reduced risk. Its preventive effect is more pronounced in younger individuals and those with higher levels of obesity.
Lanifibronor, a pan PPAR agonist, has shown significant improvements in the resolution of NASH and regression of liver fibrosis in a phase 2b RCT involving 247 individuals with biopsy-proven NASH, 42% of whom had type 2 diabetes, suggesting its potential therapeutic benefit for people with diabetes and NASH.
Insulin has several actions that tend to raise blood pressure (BP), and these effects are more pronounced in insulin resistance (IR) states, possibly because sensitivity to insulin's effects remains preserved. Insulin promotes sodium (Na⁺) retention in the distal renal tubule, which contributes to increased total body Na⁺ content in obesity and type 2 diabetes mellitus (T2DM). Additionally, insulin stimulates the Na⁺-K⁺ ATPase pump in vascular smooth muscle cells, increasing intracellular Na⁺ levels, which can lead to elevated systolic calcium (Ca²⁺) levels, enhanced contractility, and increased peripheral resistance.
Traditional individualized and group therapy can offer emotional support to children and adults with diabetes, especially those facing complications like blindness. Research indicates that individual psychotherapeutic interventions, though rarely studied, may yield positive outcomes. A small randomized trial found that adults with type 1 diabetes who received a time-limited, problem-oriented individualized treatment experienced greater reductions in problem severity and HbA1c levels compared to those receiving standard insulin treatment counseling.
Type 2 diabetes has increased in Japan since the 1960s, with a prevalence of 9.1% in men and 10.8% in women in rural areas, and impaired glucose tolerance rates of 12% and 16.5%, respectively. A 2002 National Diabetes Survey reported a 9% prevalence, while the 2007 National Health and Nutrition Survey estimated 15.3% in men and 7.3% in women using HbA₁c measurements. Type 2 diabetes has become a critical issue among Japanese children, outnumbering type 1 diabetes in a 4:1 ratio, with an incidence rate of 4.1 per 100,000 person-years during 1981–1990, about twice that of type 1 diabetes. Nutritional factors are considered significant contributors, as diabetes prevalence among Japanese Americans is approximately double that of Japanese individuals living in Japan.
Islet cell transplantation is associated with changes in renal function, which is relevant to diabetes management. Compared to whole pancreas transplantation, most individuals undergoing islet cell transplantation do not have end-stage renal disease at baseline. Some studies have reported a decline in estimated glomerular filtration rate (eGFR) following islet cell transplantation, with a median rate of decline of 0.39 ml/min/1.73 m²/month, although there is wide inter-person variability. Post-transplant, there is also an observed increase in the proportion of individuals with micro- and macroalbuminuria. However, more recent studies indicate lower rates of renal function decline when measured by GFR using 99mTc-DTPA, with some showing no statistically significant reduction in eGFR even after 10 years of follow-up.
Painful diabetic neuropathy is managed with first-line treatments including certain antidepressants (tricyclic drugs, duloxetine) and anticonvulsants (pregabalin, gabapentin), while opioids are recommended as second-line options. Treatment decisions should consider the advantages and disadvantages of various drugs and drug classes in relation to diabetes-related co-morbidities and complications. Symptomatic therapies aim to modulate pain without addressing the underlying neuropathy, unlike agents derived from understanding its pathogenetic mechanisms. Establishing the diagnosis of the underlying neuropathic manifestation is essential to estimate its natural history before initiating treatment.
During exercise, insulin secretion is reduced while glucagon release is promoted, leading to a two- to fourfold increase in hepatic glucose production, which is controlled by the glucagon:insulin molar ratio at the portal vein, helping to meet the glucose demands of exercising muscle.
Pancreatic transplantation, including SPK, PAK, and PTA procedures, leads to varying rates of insulin independence and glycaemic control, with three-year graft survival rates at 86.9%, 78.8%, and 74.0%, respectively, and 10-year survival rates at approximately 55%, 38%, and 35%. Graft failure is often marked by a return to insulin dependence, and with a functioning graft, optimal glycaemic levels and prevention of severe hypoglycaemic episodes are typically achieved. However, even with functional grafts, about 50% of recipients may develop impaired glucose tolerance after 10 years, though the long-term clinical implications for diabetes-related complications remain unclear.
People with diabetes are at higher risk for necrotizing fasciitis, a severe and potentially fatal infection that can originate from minor wounds or ulcers. This condition presents with pain, swelling, and erythema, often mistaken for cellulitis, but can be distinguished by pain that is disproportionate to the visible signs and tenderness extending beyond the affected area. Necrotizing fasciitis progresses rapidly, causing extensive tissue damage and systemic toxicity, and is associated with high mortality despite treatment. Individuals with cellulitis and systemic features such as tachycardia, leucocytosis, marked hyperglycaemia, or acidosis should be evaluated for this condition, which requires aggressive surgical debridement and high-dose antibiotics based on blood and tissue cultures.
After metformin treatment failure, the current consensus algorithm suggests adding sulfonylurea or insulin, with newer drug classes like incretin mimetics and pioglitazone recommended later due to limited evidence of superior efficacy and potential adverse effects such as long bone fractures, increased risk of congestive heart failure with glitazones, and pancreatitis with onsetide. Treatment decisions should consider patient individualization, clinical judgment, and insights from clinical trials.
Combined aerobic and resistance exercise reduced HbA₁c by 0.5% (5 mmol/mol), with structured exercise of ≥150 minutes per week showing greater benefit compared to ≤150 minutes, resulting in a 0.9% (9 mmol/mol) versus 0.4% (4 mmol/mol) reduction, respectively.
Diabetes is a significant metabolic disorder linked to an increased risk of carpal tunnel syndrome, with prevalence rates of 14% in patients with diabetes but no diabetic polyneuropathy, and 30% in those with diabetic polyneuropathy. The risk of carpal tunnel syndrome rises with the duration of diabetes and is more common in individuals with microvascular complications such as retinopathy, nephropathy, and polyneuropathy. It is also more frequent in patients with limited joint mobility, potentially due to accelerated thickening and fibrosis of the flexor tendon sheaths within the carpal tunnel, possibly from glycosylation of collagen which reduces connective tissue compliance. Diabetic neuropathy can complicate the diagnosis of carpal tunnel syndrome due to atypical presentations and challenges in neurophysiologic assessments. Treatment approaches for carpal tunnel syndrome in diabetic patients are generally similar to those without diabetes, including surgical intervention with favorable outcomes. Local insulin injections combined with corticosteroids have shown positive effects on symptoms and neurophysiologic test results in women with type 2 diabetes and carpal tunnel syndrome.
Cost-effectiveness of diabetes therapies is determined by changes in HbA1c and hypoglycaemia rates, with HbA1c serving as a predictor for long-term complications and hypoglycaemia contributing to costs from lost productivity and emergency services. Cost-utility analyses comparing continuous subcutaneous insulin infusion (CSII) to multiple daily injections (MDI) are influenced by assumed treatment effects, with older studies modelling HbA1c reductions of 0.6–1.2% (7–13 mmol/mol) in favour of CSII based on meta-analyses, potentially overestimating its long-term benefits as recent data suggest more modest reductions. Some studies assumed equivalent hypoglycaemia rates between CSII and MDI, which may offset any positive bias towards CSII, and increasing the treatment effect for hypoglycaemia prevention significantly reduces the incremental cost-effectiveness ratio (ICER). Trials often lack power to assess treatment effects on severe hypoglycaemia and their short duration limits long-term hypoglycaemia risk modelling, yet overall economic evidence suggests CSII is cost-effective, particularly in populations with the most potential benefit.
A diminished effect of glucagon to increase hepatic glucose production over time, along with compensatory hyperinsulinaemia partly due to glucagon's paracrine stimulation of insulin secretion in pancreatic β cells, is described. Additionally, differential posttranslational processing of tumour-derived proglucagon can lead to the overexpression and secretion of other proglucagon-derived peptides such as GLP-1, GLP-2, glicentin, and oxyntomodulin, which may contribute to hypoglycaemia and other gastrointestinal symptoms.
In diabetes, dysregulation of glucagon secretion contributes to hyperglycemia, as elevated glucagon levels promote hepatic glucose production. The liver's role in clearing glucagon is important for modulating its effects, and impaired clearance may exacerbate glycemic dysregulation. Glucagon secretion is influenced by multiple factors, including nutrients, hormones, and neural signals, and the integration of these controls is altered in disease states such as diabetes, though the precise mechanisms remain incompletely understood.
Iatrogenic hypoglycaemia is a major challenge in the management of diabetes, particularly in individuals with type 1 diabetes and those with advanced type 2 diabetes, leading to significant biological, psychological, and social consequences. It can cause substantial morbidity and can be fatal in some cases. Recurrent episodes of hypoglycaemia impair the body's physiological and behavioural responses to falling plasma glucose levels, creating a cycle of repeated hypoglycaemic events. This condition hinders the achievement of near-normal glycaemic control, thereby preventing patients from realizing the benefits associated with maintaining glucose levels close to the target range.
People with type 2 diabetes can switch from a basal insulin to a mixed insulin formulation given twice daily with meals, which originated as a replacement for self-reconstituted combinations of regular and NPH insulin to suit a typical Western diet. However, this approach does not mimic normal insulin physiology and increases hypoglycaemia risk. Newer pharmaceutical options include a combination of basal insulin with an ultra-rapid insulin analogue (e.g., degludec and faster-acting insulin aspart), offering lower hypoglycaemia risk compared to standard premix insulins, and a combination of basal insulin with a GLP-1 RA (e.g., glargine/lixisenatide or degludec/liraglutide), aiming to provide both basal insulin benefits and additional glucose control without increasing hypoglycaemia risk.
Impaired counter-regulatory responses and impaired awareness of hypoglycaemia in diabetes are associated with absolute endogenous insulin deficiency, a history of severe iatrogenic hypoglycaemia, impaired awareness of hypoglycaemia, recent antecedent hypoglycaemia, prior exercise, sleep, and intensive glycaemic therapy characterized by lower HbA1c levels and glycaemic targets. The degree of β-cell failure determines the inability of insulin levels to decrease and glucagon levels to increase during falling plasma glucose concentrations due to therapeutic hyperinsulinaemia. A history of severe hypoglycaemia or impaired awareness suggests a long duration of diabetes or recent hypoglycaemic episodes, leading to attenuated sympathoadrenal and symptomatic responses to low blood glucose.
Studies using RAGE/apoE knockout mice have shown that the absence of RAGE leads to a marked reduction in atherosclerotic plaque area in both diabetic and non-diabetic conditions. In streptozotocin-induced diabetic RAGE/apoE knockout mice, there is a significant decrease in atherosclerotic plaque development compared to diabetic apoE knockout mice that express RAGE, and these changes are associated with reduced inflammation and less accumulation of pathological markers in the vasculature.
CSII (Continuous Subcutaneous Insulin Infusion) therapy was compared to MDI (Multiple Daily Injections) in the REPOSE study, which involved 317 adults with type 1 diabetes who received equivalent structured training in flexible insulin therapy. Both groups showed clinically significant improvements in glycaemic control and rates of severe hypoglycaemia over two years, though the improvement was slightly greater in the CSII group without reaching statistical significance in the primary analysis. A per protocol analysis, however, showed a significantly greater treatment effect in favor of CSII. The CSII group experienced more episodes of diabetic ketoacidosis (DKA) compared to the MDI group. While there was no significant difference in glycaemic outcomes, CSII therapy demonstrated superiority in treatment satisfaction and certain quality-of-life domains. Participants had longstanding diabetes (approximately 18 years) and suboptimal glycaemic control at baseline, with a mean HbA1c of 9.1% (76 mmol/mol), and were followed for changes in HbA1c levels and the proportion achieving HbA1c < 7.5% (58 mmol/mol).
Environmental factors play a significant role in the progression from islet autoimmunity to type 1 diabetes mellitus (T1DM), though the possibility of environmental triggers initiating autoimmunity is not excluded. These factors may influence both the immune system and metabolism. Research suggests that insulin-secreting β-cells actively hyperexpress islet autoantigens like GAD and are more vulnerable to the toxic effects of interleukin 1β. Factors increasing stress on β-cells, such as insulin resistance or processes linked to infections, puberty, and growth spurts, may contribute to the onset of clinical disease. Insulin resistance, although difficult to measure reliably in humans, has been associated with progression to T1DM, particularly when assessed in relation to first-phase insulin response during an intravenous glucose tolerance test. Various non-genetic factors are being studied for their potential involvement in the development of T1DM.
Higher titers of islet autoantibodies are associated with an increased risk of persistent autoimmunity and type 1 diabetes mellitus (T1DM), particularly when combined with a high-risk HLA genotype. The persistent detection of high titer autoantibodies may reflect the intensity of the autoimmune reaction and the rate of progression to clinical diabetes.
Insulin suppresses the expression of gluconeogenic genes such as G-6-Pase and PEPCK through multiple mechanisms involving transcription factors like SREBP-1, LXR, and PGC-1, in addition to the Foxo family. Phosphorylation of Foxo by Akt/PKB impairs its binding to insulin response elements (IREs) on these gene promoters, leading to nuclear exclusion of Foxo and reduced gene transcription. However, Foxo does not fully account for the suppression of G-6-Pase and PEPCK by insulin, suggesting other regulatory pathways are also involved.
DPP-4 inhibitors enhance glucose-dependent insulin secretion through their incretin-mediated effect, primarily acting during meals to lower postprandial hyperglycemia, with a carryover benefit for interprandial glycemia; these agents do not initiate insulin secretion or increase basal insulin levels and only suppress glucagon secretion in hyperglycemic states, resulting in a low risk of interprandial hypoglycemia.
Initial diabetes education and insulin therapy can occur in an outpatient setting in centers with appropriate resources, offering a cost-effective alternative to inpatient care. The introduction of continuous glucose monitoring (CGM) soon after a type 1 diabetes diagnosis is well accepted by children, adolescents, and their families, and is associated with improved HbA1c levels. Diabetes technology, including CGM, should be considered during initial education and offered shortly after diagnosis when possible.
Hepatocytes are being explored as target cells for ectopic insulin production due to their expression of glucose-sensing molecules like GLUT2 and glucokinase, which are also present in beta cells. These cells play a key role in carbohydrate metabolism, and several liver-expressed genes are regulated by glucose or insulin, allowing for the development of glucose/insulin-controlled expression systems. Promoters from genes such as GLUT2, PEPCK, G-6-Pase, and L-PK, as well as synthetic promoters, have been used to create gene expression cassettes that produce insulin in response to blood glucose and insulin levels. Lentiviral and AAV vectors have been used to achieve constitutive insulin expression in hepatocytes, showing efficacy in diabetic rodents. However, these systems do not yet match the rapid glucose-responsive insulin secretion of natural beta cells, leading to potential postprandial hyperglycemia followed by delayed hypoglycemia due to the slower transcriptional regulation of the engineered promoters.
Asparaginase (crisantaspase), an anticancer drug used in the treatment of acute lymphoblastic leukemia, induces insulin resistance leading to impaired glucose tolerance. In a clinical trial involving children, 10% of those treated developed hyperglycemia, and all exhibited glycosuria.
IL-1β contributes to the development of both type 1 and type 2 diabetes due to its direct pro-apoptotic action on pancreatic β-cells and its role in mediating β-cell glucotoxicity. Canakinumab, a human monoclonal anti-IL-1 antibody, and anakinra, a human IL-1 receptor antagonist, both block IL-1, which is involved in the pathogenesis of diabetes. However, no studies have yet reported altered serum levels of IL-1 or related mechanistic outcomes in individuals with type 1 diabetes.
The pathophysiology of hyperosmolar hyperglycaemic state (HHS) involves relative insulin deficiency and elevated counter-regulatory hormones, leading to increased gluconeogenesis and reduced glucose uptake in peripheral tissues. This results in severe hyperglycaemia, osmotic diuresis, dehydration, and hyperosmolality, which can progress to renal impairment, reduced glucose excretion, and haemoconcentration. Despite insufficient insulin to prevent hyperglycaemia, there is enough to limit hepatic free fatty acid oxidation and significant ketogenesis. Fluid deficits are substantial, and biochemical findings include hypernatraemia, hyperuraemia, and hyperglycaemia, alongside total body deficits of sodium, potassium, and chloride. HHS may coexist with diabetic ketoacidosis (DKA) in up to 50% of cases, presenting with metabolic acidosis, elevated lactate, and carrying a higher mortality rate compared to either condition alone.
Type 2 diabetes prevalence rises with age, making age distribution a crucial factor in study populations, which should be age-stratified and comparisons age-adjusted. Ascertainment methods, such as the use of oral glucose tolerance tests with or without preliminary blood glucose screening, also play a significant role in accurately identifying diabetes cases. The IDF Diabetes Atlas provides global and national diabetes prevalence estimates, but these should be interpreted with caution, especially for countries lacking updated prevalence studies, as the estimates may be modelled from nearby countries with similar demographic characteristics. Modelled estimates may not be as accurate or directly comparable to data from countries that have conducted nationwide epidemiological surveys, although recent updates to the Atlas have addressed some of these limitations.
Hypoglycaemia is associated with decreased cognitive functioning in children with type 1 diabetes, especially those diagnosed before age 5–6 years, and recurrent severe episodes may impair long-term memory, attention, and verbal IQ, although study results are inconsistent. Severe hypoglycaemia can also increase anxiety for both parents and individuals with diabetes, leading to poor sleep, emergency room visits, hospitalizations, reduced insulin doses, and worsened glycaemic control. Long-term follow-up from the DCCT indicates no permanent neurocognitive changes from hypoglycaemia in adolescents and young adults, suggesting age-dependent effects. Hyperglycaemia, on the other hand, affects brain function as seen in fMRI and neurological tests, highlighting the need to maintain euglycaemia.
Babies born to mothers with diabetes are significantly more likely to have high birth weights, with 49–63% being large for gestational age (LGA) and 20–25% weighing more than 4000 g. The rate of macrosomia in a recent UK cohort was 52%, and maternal obesity, which is increasing among women with type 1 diabetes, along with gestational weight gain, may contribute to these high rates of fetal overgrowth.
The table summarizes studies involving individuals with type 1 diabetes mellitus (T1DM) and the effects of different exercise interventions on glycemic control as measured by HbA1c levels. In one study, resistance training alone led to a reduction in HbA1c from 6.9 (1.4) to 5.8 (0.9) after 10 weeks. Another study examined combined aerobic and resistance training over 12 weeks and found a decrease in HbA1c from 7.72 (1.26) to 6.76 (1.07) in the T1DM group, while the control group without diabetes maintained stable levels. A third study compared aerobic training to resistance training, finding that while the aerobic group experienced an increase in HbA1c from 8.7 (1.6) to 9.8 (1.8), the resistance training group saw a decrease from 8.2 (2.9) to 7.6 (1.6). These studies suggest that resistance training, whether alone or combined with aerobic exercise, may have beneficial effects on glycemic control in individuals with type 1 diabetes, though the timing and composition of exercise programs may influence outcomes.
Time in range (TIR), which refers to the time during which glucose levels remain within a target range of 70–180 mg/dl (3.9–10.0 mmol/l), is used for assessing glycaemic control based on continuous glucose monitoring data. Glucose levels outside this range are associated with increased risks of hyperglycaemia, diabetic ketoacidosis, and hypoglycaemia. Lower TIR indicates higher glucose variability, which is linked to a greater risk of hypo- and hyperglycaemic complications, and in some studies, increased glucose variability or low TIR is associated with adverse outcomes.
In individuals without diabetes, pancreatic β-cells produce insulin both between meals and during meals to maintain blood glucose within a narrow physiological range. In type 1 diabetes mellitus (T1DM), where endogenous insulin production is absent, exogenous insulin must be administered to mimic normal insulin release, typically using a combination of rapid-acting insulin for mealtime glucose control and longer-acting or basal insulin for background glucose regulation. In type 2 diabetes mellitus (T2DM), where some insulin production may still occur, exogenous insulin can be added to oral hypoglycemic agents to achieve better blood glucose control.
Type 2 diabetes mellitus (T2DM) develops through five progressive stages. The first stage begins at birth, where individuals have normal glucose homeostasis but are genetically predisposed to T2DM due to diabetogenic genes or an adverse in utero environment that promotes obesity and limits pancreatic $\beta$-cell compensation for insulin resistance. Even with normal glucose tolerance, impaired $\beta$-cell function can be detected in genetically predisposed individuals. In stage 2, insulin sensitivity decreases, often due to unhealthy lifestyles, but $\beta$-cells initially compensate by increasing insulin secretion, maintaining normal glucose tolerance, although reduced $\beta$-cell function is still observable. Stage 3 is marked by further $\beta$-cell deterioration, leading to abnormal postprandial glucose tolerance during challenges like glucose tests or meals, while fasting glucose remains normal. Stage 4 involves more pronounced $\beta$-cell dysfunction, partly due to glucose toxicity from postprandial hyperglycemia, which also decreases insulin sensitivity, and fasting glucose rises due to increased basal endogenous glucose production. Stage 5 continues this progression with further deterioration in $\beta$-cell function.
Ageing contributes to increased insulin resistance due to decreased muscle mass, increased visceral fat, and reduced insulin secretion from diminished $\beta$-cell mass and function, which can lead to glucose intolerance and diabetes in genetically susceptible individuals. As life expectancy rises, diabetes is becoming more common in older adults, with a phenotype marked by multiple comorbidities, geriatric syndromes, and frailty. Diagnosis and annual follow-up in older individuals should include screening for cognitive and physical dysfunction. Given the heterogeneity of older adults—from fit community-dwelling individuals to frail persons with multiple comorbidities—management should be individualized, with metabolic targets ranging from optimal glycaemic control in fit individuals to a more conservative approach in frail ones. Particular attention should be given to managing undernutrition through improved nutrition and physical activity to preserve muscle mass and enhance function, with quality of life as a central focus in diabetes management for older people.
The table summarizes clinical trials evaluating the effects of various glucose-lowering drugs on heart failure outcomes in patients with diabetes. It includes trials of DPP-4 inhibitors such as alogliptin (EXAMINE), saxagliptin (SAVOR-TIMI 53), sitagliptin (TECOS), and linagliptin (CARMELINA, CAROLINA), showing varying hazard ratios for heart failure. It also includes GLP-1 receptor agonists such as lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6, PIONEER 6), exenatide (EXCELLE), albiglutide (HARMONY OUTCOMES), dulaglutide (REWIND), and efpeglenatide (AMPLITUDE-O), most of which demonstrate neutral or reduced risk of heart failure. Additionally, SGLT-2 inhibitors including empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS, CREDENCE), dapagliflozin (DECLARE-TIMI 58), and ertugliflozin (VERTIS CV) are associated with a reduced risk of heart failure in patients with diabetes.
Blood pressure management in people with diabetes is important, with a recommended target of ≤140/80 mmHg according to the 2018 ESC Guidelines for the Management of Arterial Hypertension. If treatment is well tolerated, a systolic blood pressure target of <130 mmHg may be considered to provide additional benefits for stroke prevention, although systolic blood pressure values <120 mmHg should be avoided.
Indigenous peoples in Canada have more than a twofold higher prevalence of diabetes compared to the general population. Native Hawaiians had crude prevalence rates of 20% for type 2 diabetes and 16% for impaired glucose tolerance in 1998, with the age-adjusted rate for type 2 diabetes being four times higher than that observed in the US NHANES II study population. Second-generation Japanese Americans had diabetes and impaired glucose tolerance prevalence rates of 16% and 40%, respectively, in 1991, with a high incidence rate of 17.2 per 1000 person-years. This increased susceptibility may be due to higher visceral adiposity in populations predisposed to impaired β-cell function. Asian Americans in the USA also face a high risk of diabetes, with linguistic barriers potentially limiting access to diabetes education and care.
In diabetes, elevated glucose levels lead to activation of the polyol pathway, where aldose reductase reduces glucose to sorbitol using NADPH as a cofactor; this process also reduces toxic aldehydes to inactive alcohols under normal glucose conditions. However, during hyperglycemia, aldose reductase activity can deplete reduced glutathione, increasing oxidative stress. Subsequently, sorbitol dehydrogenase oxidizes sorbitol to fructose using NAD+ as a cofactor, contributing to the metabolic imbalances associated with diabetes.
In healthy individuals, the incretin effect enhances insulin secretion during oral glucose intake, contributing to the regulation of postprandial glucose levels, and this mechanism may be relevant in understanding diabetes where such regulatory processes could be impaired.
Musculoskeletal disorders can cause pain and disability that interfere with diabetes management, and fibroproliferative conditions such as limited joint mobility, frozen shoulder, Dupuytren's contracture, trigger finger, and carpal tunnel syndrome are more common in individuals with diabetes, potentially leading to upper-limb disability. Charcot joint, a serious complication of diabetic peripheral neuropathy marked by disordered osteoclastogenesis, may benefit from bisphosphonate therapy as an adjunct to standard care. Additionally, people with diabetes have a higher risk of developing gout, especially when renal impairment or diuretic use is present, and treatment with sodium-glucose cotransporter 2 inhibitors can reduce gout episodes by up to 30%.
For islet transplantation, 5000 islet equivalents (IEQs)/kg of the recipient's body mass should be transplanted to achieve adequate glycaemia, with yields of >7000 IEQ/kg from a single donor correlating with a higher likelihood of resulting in insulin independence. For an adult weighing 75 kg, this would represent a fraction of the total mass of an endogenous β cell, meaning that only a small cell population may guarantee insulin independence. Multiple transplantation sites are being pursued as options for stem cell–derived insulin-producing cells. Microcapsules are often transplanted into the peritoneal cavity; intravascular macrocapsules are connected as a shunt to the systemic blood circulation, whereas extravascular microcapsules are typically implanted subcutaneously or intraperitoneally.
Alcohol should be consumed with carbohydrates in patients treated with insulin or insulin secretagogues to avoid hypoglycemia. When ingested alone, moderate alcohol intake has no acute effect on glucose and insulin; however, when consumed with carbohydrates, it may raise blood glucose. For patients with early stages of chronic kidney disease, such as microalbuminuria or a decline in glomerular filtration, a protein intake of 0.8–1 gram per kilogram of body weight per day is recommended.
Diabetic bullae are more prevalent in men and older individuals, particularly those with peripheral neuropathy, and typically manifest as sterile, asymmetrical blisters ranging from a few millimeters to several centimeters in size on the feet, lower legs, and hands. These blisters develop rapidly and resolve within weeks without scarring. The condition is associated with long-standing type 1 diabetes and complications such as microangiopathy and renal failure, with additional risk factors including fluctuations in blood glucose, and magnesium and calcium imbalances. Histologically, the blisters show a subepithelial split at the lamina lucida, though the exact cause remains unclear. Diagnosis involves ruling out other blistering conditions like porphyria cutanea tarda and bullous impetigo. Treatment is primarily supportive to avoid secondary infection, though interventions like aspiration, surgical debridement, and negative-pressure dressings may be used.
Excessive alcohol consumption is linked to chronic pancreatitis and secondary diabetes, while also contributing to central obesity and poor medication adherence, which can increase the risk of type 2 diabetes and hinder its management. However, most epidemiological studies show a J-shaped relationship between alcohol intake and diabetes risk, with moderate consumption associated with a lower risk of type 2 diabetes. In individuals with type 2 diabetes, moderate alcohol use is linked to a 35% reduction in total mortality and a lower risk of cardiovascular disease compared to abstaining. On the other hand, excessive alcohol intake leads to hypertriglyceridemia and resistant hypertension, increasing vascular risk. Ethanol impairs hepatic gluconeogenesis, heightening the risk, severity, and duration of hypoglycemia, and alcohol intoxication can mask the signs of hypoglycemia, making it harder to recognize and treat.
Higher body mass index (BMI) categories contribute more significantly to the overall prevalence of diabetes, as indicated by comparisons of National Health and Nutrition Examination Survey (NHANES) samples from 1976–1980 and 1999–2004.
Gastrointestinal symptoms are commonly reported in people with diabetes, although findings vary across studies. Some research indicates that individuals with diabetes experience gastrointestinal symptoms such as nausea, vomiting, dyspepsia, heartburn, irritable bowel syndrome, constipation, and faecal incontinence at rates similar to or only slightly higher than those without diabetes. For instance, in the Rochester Diabetic Neuropathy Study, only 1% of people with diabetes had symptoms of gastroparesis and 0.6% experienced nocturnal diarrhoea. Additionally, people with type 2 diabetes and men with type 1 diabetes tend to use laxatives more frequently than those without diabetes. While some studies show a lower prevalence of heartburn in people with type 1 diabetes, others, such as a study conducted in Australia, found a higher prevalence of upper and lower gastrointestinal symptoms in individuals with predominantly type 2 diabetes compared to those without diabetes.
In postmenopausal women with diabetes, oestradiol improves fasting blood glucose concentration and glycated haemoglobin. Observational studies have shown that hormone replacement therapy (HRT) is associated with improvements in glycated haemoglobin $\mathrm{(HbA_{1c})}$ in women with type 2 diabetes. However, according to NICE guidelines, HRT did not show any significant adverse effect or benefit on fasting blood glucose or $\mathrm{HbA_{1c}}$ at three or six months' follow-up in women with type 2 diabetes, although the evidence was considered low to very low quality due to small sample sizes. A Cochrane review found little or no evidence supporting the effects of HRT in women with type 1 diabetes.
The medical knowledge points related to diabetes include diagnostic and management targets such as HbA1c less than 48 mmol/mol (less than 6.5%), blood pressure below 130/80 mmHg, triglycerides below 1.7 mmol/L (below 150 mg/dL), and LDL cholesterol below 2.5 mmol/L (below 95 mg/dL).
HbA1c is a key measure of mid- to long-term glycaemic levels and predicts long-term microvascular and macrovascular complications in diabetes, although it has limitations. In the DCCT study, an HbA1c of 53 mmol/mol (7.0%) corresponded to higher average blood glucose levels in conventionally treated individuals compared to those receiving intensive treatment, leading to a greater risk of microvascular complications and hypoglycaemia in the conventional group. HbA1c is one component of optimal glycaemic management, with other factors including documented hypoglycaemia, type of treatment, age, and quality of life. For monitoring, younger children should have 4–6 HbA1c measurements per year, while older children should have 3–4 measurements annually.
Women, younger individuals, and those with chronic medical conditions, including diabetes, are at higher risk for developing anxiety disorders. Factors specific to diabetes that contribute to anxiety risk include longer duration of the disease, fear of hypoglycemia, and insulin use, although the risk of anxiety appears to be similar in both type 1 and type 2 diabetes. Additionally, depression is a risk factor for anxiety, which may be overlooked in diabetic patients presenting with depressive symptoms.
Islet transplantation research has demonstrated that islets from rodents and canines can maintain functional insulin secretion, with transplanted islets exhibiting a biphasic insulin response to glucose. Successful islet allotransplantation in animals and the isolation of human islets capable of functioning in diabetic nude mice suggest potential for islet transplantation as a therapeutic approach in diabetes.
In late pregnancy, maternal insulin sensitivity decreases by about 50%, reaching levels similar to those seen in type 2 diabetes mellitus (T2DM), requiring maternal β-cells to compensate by increasing first and second-phase insulin responses approximately threefold by the last trimester to maintain glucose tolerance. Increased insulin secretion during pregnancy is associated with morphological changes in the pancreas, such as β-cell hypertrophy and hyperplasia. While β-cells in rodents adapt by increasing both function and mass during pregnancy, it is uncertain whether this occurs in humans. Women with diabetes presumably have a reduced capacity for such β-cell adaptation.
Type 1 diabetes is associated with certain HLA class II and class I alleles, including the protective haplotypes $\mathrm{DQ6}(DQA1^{*}01:02 - B1^{*}06:02$ and $DQA1^{*}01:02 - B1^{*}06:03)$, as well as $DQA1^{*}01:01 - B1^{*}05:03$ and $DQA1^{*}02:02 - B1^{*}03:03$. Research continues to identify new genetic associations related to the disease.
Lifestyle changes involving reduced energy and dietary fat intake, increased fiber consumption, and regular physical activity (e.g., 150 minutes/week) have been shown to improve vascular risk factors such as dyslipidemia, hypertension, and markers of inflammation, in addition to significantly reducing the development of type 2 diabetes mellitus (T2DM) in individuals at high risk. However, clinical trials on the efficacy of low carbohydrate diets for the primary prevention of T2DM are currently unavailable.
Adrenal diabetes, induced by subcutaneous or intravenous injection of adrenal gland extract in various animals, causes glycosuria lasting 48 to 72 hours, accompanied by hyperglycemia, distinguishing it from renal diabetes or phlorizin-induced diabetes. Unlike typical diabetes, adrenal diabetes does not progress or reach the severe end-stage seen in human diabetes. Some authors, however, consider the glycosuria to be a benign toxic effect rather than a true form of diabetes.
Women with diabetes, particularly type 2 diabetes, may experience increased clitoral pulsatility index (PI), a marker of micro-atherosclerosis and vascular resistance, which is associated with obesity, metabolic syndrome, higher insulin resistance (as indicated by elevated HOMA index), and elevated triglyceride levels. Increased clitoral PI is also linked to reduced sexual arousal. While clitoral colour Doppler ultrasound can assess these vascular changes, it remains unclear whether treatment can improve clitoral PI or if PI can predict cardiovascular events in this population.
In several animal models of diabetes, neuronal changes such as reduced staining and, to a lesser extent, loss of inhibitory neurons expressing nitric oxide synthase (NOS) have been observed within the enteric nervous system. This reduction in nitrergic inhibitory functions may contribute to impaired gastric accommodation and accelerated intestinal transit. Additionally, reduced sympathetic inhibition may play a role in accelerating intestinal transit. Since nitric oxide (NO) mediates pyloric relaxation, the loss of NOS may impair pyloric relaxation and consequently retard gastric emptying. Furthermore, loss of intestinal cells of Cajal (ICC), documented in both animal models and case reports of diabetes, may contribute to gut dysmotility.
Existing frameworks such as DSME (Diabetes Self-Management Education) and the AADE7 approach (American Association of Diabetes Educators' seven self-care behaviors) are used to guide the assessment of current preferences and behaviors in individuals with diabetes, helping to identify potential benefits and barriers, facilitate problem-solving, and establish a mutually agreed plan for behavioral interventions.
Retinopathy progression in individuals with diabetes continues into the postpartum period, necessitating ongoing monitoring, although pregnancy itself does not generally alter the natural course of diabetic retinopathy, with baseline retinopathy status being the most important independent factor for progression.
α-Glucosidase inhibitors are used in diabetes management and require a diet containing complex digestible carbohydrates. These inhibitors should be taken with meals, starting with a low dose such as 50 mg/day of acarbose, and gradually increased over several weeks. Monitoring postprandial glycaemia is often beneficial. Hypoglycaemia is unlikely when used alone, but gastrointestinal symptoms commonly affect initial tolerability and dose titration, with symptoms typically decreasing over time, possibly due to intestinal adaptation, though overall tolerability remains poor.
Metformin lowers blood glucose levels by reducing hepatic glucose production through suppression of gluconeogenesis and glycogenolysis, enhancing hepatic insulin sensitivity, decreasing hepatic glucagon receptor signaling, and reducing the hepatic extraction of gluconeogenic substrates such as lactate. It does not mimic or activate insulin's genomic effects, nor does it stimulate insulin release, and thus does not typically cause hypoglycemia when used alone. Additionally, metformin can improve insulin-stimulated glucose uptake in skeletal muscle by promoting the translocation of GLUT4 glucose transporters to the cell membrane and increasing glycogen synthase activity, which supports glycogen synthesis.
Approximately 10-20% of children with newly diagnosed type 1 diabetes have an affected first-degree relative, and those with an affected sibling or parent have a cumulative risk of 3-7% up to about 20 years of age, compared to 0.2-0.8% in the general population. The cumulative incidence among monozygotic co-twins of individuals with type 1 diabetes is less than 50% even after more than 30 years of follow-up. Some geographical differences and familial aggregation may be explained by human leucocyte antigen (HLA) haplotypes. The incidence of childhood-onset type 1 diabetes has increased by 3-4% per calendar year, with a tendency toward younger average age at onset over time. Finland and a few other countries have experienced a plateau or decrease in incidence among children since 2005, though it is unclear whether this is due to random variation. The causes of these changing trends are unknown, though virus infections and nutritional factors have been implicated without any specific environmental risk factor being established. Despite improvements in insulin replacement therapy and other management advances, mortality in type 1 diabetes remains at least two times higher (approximately two- to eightfold) than in the background population in high-income countries, due to both acute and chronic complications, including cardiovascular disease from around 30 years of age. In low- and middle-income countries, mortality in type 1 diabetes remains very high.
Growth hormone (GH) can induce insulin resistance in normal individuals and is a characteristic feature of acromegaly. Insulin resistance affects both the liver and extrahepatic tissues, leading to reduced suppression of hepatic glucose production and decreased insulin-dependent glucose disposal. In skeletal muscle, insulin-mediated activation of glycogen synthase is impaired. The lipolytic action of GH increases non-esterified fatty acids (NEFAs), which further contribute to insulin resistance by increasing hepatic glucose production and inhibiting glucose utilization in muscle via the "glucose-fatty acid" cycle. Initially, pancreatic compensation through hyperinsulinemia can maintain normal blood glucose levels, but similar to type 2 diabetes mellitus (T2DM), prolonged insulin resistance leads to β-cell failure, impaired insulin response, and eventual hyperglycemia, a process likened to the Starling curve of the pancreas.
Personality traits and psychological factors can influence metabolic control in individuals with diabetes, as those with a strong need for achievement and high responsivity to social demands tend to have better metabolic control. In contrast, higher HbA1c values are observed in adults who are opportunistic, alienated, or exhibit poor impulse control, engage in self-destructive behaviors, and struggle with interpersonal relationships. Elevated neuroticism scores or higher levels of trait negative affect, which reflect being a worrier or highly emotional, may also be linked to poorer metabolic control, though findings are not consistent. In adults with T2DM, higher neuroticism levels have been associated with better metabolic control, suggesting that moderate worry might motivate older adults to manage their diabetes more effectively.
Glucagon, a 29 amino acid peptide secreted by islet α cells, plays a role in diabetes due to its regulation of blood glucose levels. It is involved in enhancing insulin secretion through G-protein (Gs)-coupled activation of adenylate cyclase, leading to increased intracellular cAMP. Glucagon secretion is stimulated by hypoglycaemia and sympathetic nervous input, highlighting its importance in glucose homeostasis. Additionally, a subpopulation of human α cells also synthesizes and secretes GLP-1, which functions as an incretin hormone and may exert local effects within the islets, further influencing insulin secretion.
Hyperglycemia associated with endogenous Cushing syndrome may be treated with sulfonylureas in some cases, though many require insulin therapy. In cases of Cushing syndrome caused by exogenous glucocorticoids, the timing and half-life of the drug can help predict the period of elevated glucocorticoid levels, allowing for tailored treatment. For example, prednisolone taken in the morning leads to elevated levels throughout the day, decreasing in the evening, which supports the use of intermediate-acting insulin administered at breakfast.
Improvement in depressive symptoms may not automatically lead to better self-care or diabetes outcomes, and additional focus on diabetes management is necessary as depression improves. Changes in behavior and routine due to depression treatment, such as improved appetite or increased activity levels, can affect insulin requirements, necessitating adjustments in the diabetic regimen.
Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes that occurs in young individuals but is not insulin-dependent, primarily due to β-cell dysfunction rather than insulin resistance. It can be subclassified based on the specific genetic variant involved, with at least 11 genes identified, including those encoding the glucose-sensing enzyme glucokinase (GCK) and various transcription factors affecting β-cell development and function. The clinical presentation varies significantly depending on the genetic cause, and distinguishing between these subtypes is crucial for accurate diagnosis and management.
Protease inhibitors used in the treatment of HIV infection, such as indinavir, nelfinavir, ritonavir, and saquinavir, have been associated with worsening pre-existing diabetes or the new onset of type 2 diabetes mellitus (T2DM) in 2–6% of patients. Transient elevations in glucose levels are common, and there is a fivefold increase in the incidence of sustained glucose intolerance. The condition shares similarities with T2DM in both pathogenesis and clinical presentation, and it has been recommended that its management follow the American Diabetes Association guidelines for T2DM, particularly addressing hyperinsulinemia and hyperglycemia.
Evidence-based nutritional recommendations for individuals with diabetes are developed through formal literature searches using standardized descriptors and relevant databases, with the strength of evidence graded based on study type, quality, and expert consensus. While ideal guidelines are derived from trials measuring clinical endpoints, surrogate markers such as glycemia, body composition, lipoprotein profile, blood pressure, insulin sensitivity, and renal function are commonly used to assess the impact of dietary changes on glycemic control and the risk of acute and chronic diabetes complications. Dietary guidelines for type 1 and type 2 diabetes, along with the assigned levels of evidence, are detailed in tables provided by the Diabetes and Nutrition Study Group of the European Association for the Study of Diabetes and the American Diabetes Association.
Pancreas transplantation for type 1 diabetes improves nephropathy and retinopathy, with a 10-year follow-up showing improvement in sudomotor function in the hand and foot within one year, maintained throughout the period, though no impact was observed on nerve conduction velocity or autonomic function. Simultaneous pancreas and kidney transplantation in individuals with type 1 diabetes and severe diabetic sensorimotor polyneuropathy leads to regeneration of corneal nerves within six months, with early improvement in small nerve fibers followed by symptom improvement at 24 months and nerve conduction improvement at 36 months. Islet cell transplantation also enhances nerve conduction velocity and amplitude scores, underscoring the importance of adequate trial duration or more sensitive endpoints such as corneal confocal microscopy (CCM) in clinical trials for disease-modifying treatments for diabetic neuropathy.
Tight blood pressure control is essential in slowing the progression of diabetic kidney disease, particularly in patients with type 1 diabetes mellitus (T1DM). Maintaining blood pressure below 140/80 mmHg reduces the annual decline in glomerular filtration rate (GFR) from 10–12 mL/min/year in untreated cases to less than 5 mL/min/year, and in some patients, can lead to regression from persistent proteinuria to microalbuminuria, further decreasing the GFR decline to less than 1 mL/min/year over a significant period.
The addition of a fast-acting human insulin or rapid-acting insulin analogue before the main meal can be a useful step in intensifying treatment after starting basal insulin in individuals with type 2 diabetes. Rapid-acting insulin analogues are increasingly preferred over fast-acting human insulins. The choice of main meal determines when the single injection of fast- or rapid-acting insulin is given, and prandial insulin should be titrated to a glucose target. The ideal time to assess the effect of prandial insulin, especially a rapid-acting analogue, is 90–120 minutes after the meal. Insulin dose adjustments should not occur more frequently than twice a week, though individuals may adjust doses based on meal size. When glycaemic targets become harder to achieve, a second prandial insulin injection before the second main meal may be necessary, using a similar titration process as for the first.
In normal physiological conditions, up to 180g/day of glucose is filtered by the glomerulus, and almost all of it is reabsorbed in the proximal tubule through an insulin-independent process, helping to conserve glucose. The renal threshold for glucose, which represents the maximal reabsorptive capacity, is typically reached when circulating glucose concentration is around 11 mmol/l. This threshold can vary between individuals and is influenced by factors such as renal function, age, pregnancy, insulin resistance, and glycaemic levels. When plasma glucose exceeds this threshold, excessive urinary loss of glucose occurs, which is a characteristic feature in diabetes.
Nailfold redness has been observed in diabetes, and nailfold capillaroscopy may reveal characteristic patterns such as tortuous, cross-linked capillaries, avascular zones, and ectasias. Thickening of nails with surface irregularities, known as onychauxis, may occur due to vascular insufficiency. Pterygium, which involves scarring of the proximal nailfold to the nail plate, can result from arterial spasm, and reduced circulation to the nail matrix can lead to thin, brittle nails that separate from the nail bed, a condition called onycholysis.
In the UK, individuals with insulin-treated diabetes must inform the DVLA when applying for or renewing a driving licence, as failure to do so can result in fines and invalidation of insurance claims. Doctors, including general practitioners, are responsible for informing patients with diabetes of this legal requirement and should offer practical advice. Drivers with diabetes managed by diet alone or with oral glucose-lowering medications do not need to notify the DVLA unless they have visual impairment or other diabetes-related complications affecting driving fitness. Driving licences for people with diabetes are typically valid for up to three years and require completion of a medical questionnaire for renewal. The DVLA may request additional medical reports, especially if there are issues like recurrent hypoglycaemia. GLP-1 receptor agonists are permitted without restriction except when used with sulfonylureas in drivers with vocational licences, which requires notification and assessment of medical fitness to drive.
Microalbuminuria typically appears within 5–15 years of diabetes onset, and in patients with normal urine albumin excretion, 1.5–2.5% develop microalbuminuria annually, with 50% developing persistent microalbuminuria at some point in their lives. One study reported a cumulative incidence of 25.4% for microalbuminuria after 40 years of diabetes, suggesting a potential decline in incidence. In type 1 diabetes patients with microalbuminuria, about one-third progress to proteinuria over 5–15 years, one-third remain microalbuminuric, and one-third revert to normal urine albumin excretion. Regression from microalbuminuria to normal excretion occurs in 58% of patients over 6 years, and is associated with shorter duration of microalbuminuria and lower HbA1c, systolic blood pressure, total cholesterol, and triglycerides. The long-term outcomes for those who regress or do not progress remain uncertain, but they likely remain at some risk.
Viral infections such as enteroviruses (especially Coxsackie B viruses), rubella, mumps, rotavirus, parvovirus, and cytomegalovirus have been associated with type 1 diabetes, though a direct causal relationship remains difficult to establish. Studies have detected enterovirus RNA in pancreatic biopsies of individuals with newly diagnosed type 1 diabetes, supporting the idea that viral infection may contribute to its development. This process may involve a dominant CD4 T-helper type 1 immune response, while a T-helper type 2 response may offer protection. Reduced exposure to infections and infestations in early childhood may weaken the innate immune system's ability to manage autoimmune responses, a concept linked to the hygiene hypothesis. Additionally, changes in the gut microbiome are being increasingly studied for their potential role in type 1 diabetes.
Pharmacological therapy that interrupts the renin-angiotensin-aldosterone system (RAAS) may provide special benefits in reducing cardiovascular disease (CVD) in people with diabetes. In a post hoc subgroup analysis of the Captopril Prevention Project (CAPP) study, participants with diabetes treated with captopril had significantly better outcomes compared to those on conventional therapy with beta-blockers and diuretics, particularly in terms of the primary endpoint, myocardial infarction, all cardiac events, and total mortality. The beneficial effects of ACE inhibitor therapy were most pronounced in those at highest risk, such as individuals with elevated fasting glucose or higher blood pressure. In contrast, the UK Prospective Diabetes Study (UKPDS) found comparable cardiovascular benefits in people with type 2 diabetes treated with either captopril or atenolol, which may reflect the lower CVD risk among individuals with newly diagnosed diabetes in that study.
Thickening of skin, tendons, and tendon sheaths has been observed in patients with limited joint mobility, and histologic examination of the skin reveals altered mucopolysaccharide distribution, elastin and collagen changes, and reduced vascular lumen. Non-enzymatic glycosylation and collagen accumulation are involved in the development of these changes, and disordered glycosaminoglycan (GAG) metabolism is also present, with pronounced hyaluronan expression in the epidermis and reduced levels in the dermis and basement membrane in patients with severe joint mobility issues. Elevated urinary GAG excretion has been reported in these patients. Reduced levels of circulating insulin-like growth factor I (IGF-I) are linked to limited joint mobility, suggesting a role for the growth hormone-IGF-I axis in this complication. Microvascular abnormalities, including impaired palmar microvascular flow in response to thermal challenge, also contribute to the condition.
The prevalence of type 1 diabetes is rising globally, influenced by both improved survival rates and increased incidence, potentially linked to environmental and lifestyle changes such as rapid weight gain and inappropriate feeding during infancy. In 2019, approximately 600,900 children and adolescents aged 0–14 years and 1.1 million aged 0–19 years had type 1 diabetes worldwide, with high numbers in Europe and North America where incidence is still growing. Countries with the largest populations of children and adolescents living with type 1 diabetes in 2019 included India (95,600), the USA (94,200), and Brazil (51,500).
The prevalence of nephropathy among individuals with undiagnosed diabetes was found to be 26.5% based on a spot urine albumin-creatinine ratio, according to data from the US National Health and Nutrition Examination Survey (NHANES) 1992–2002. High prevalence of microalbuminuria has also been observed in studies such as the UK Prospective Diabetes Study (UKPDS) in the UK and the Hoorn Screening Study in Dutch populations. Additionally, elevated rates of microalbuminuria have been reported in individuals with prediabetes.
Ramipril is supported for use in patients with type 2 diabetes mellitus (T2DM) due to their elevated cardiovascular risk, low doses of thiazide diuretics are beneficial in elderly diabetic patients for preventing stroke and reducing all-cause mortality, and beta-blockers, when combined with low-dose aspirin, are recommended as secondary prevention after myocardial infarction in the absence of serious contraindications.
Blood sugar levels guide the administration of intravenous insulin using an infusion pump. For capillary blood glucose measurements, insulin dosing is adjusted as follows: if the level is less than 140 mg/dl, insulin is omitted; for levels between 141 and 180 mg/dl, 1 unit per hour is given; between 181 and 220 mg/dl, 2 units per hour; between 221 and 260 mg/dl, 3 units per hour; and for levels above 261 mg/dl, 4 units per hour are administered.
Hyperglycemia in conditions like DKA and HH is often triggered by infectious diseases or cardiovascular events, with symptoms typically developing over several days. This hyperglycemia results from a cycle where relative insulin deficiency and elevated stress hormones increase glucose production and reduce glucose uptake. The resulting high blood sugar leads to hyperosmolality and dehydration, which further heighten the stress hormone response, worsen insulin secretion, and perpetuate the cycle.
SGLT-2 is the main transporter responsible for glucose reabsorption from renal proximal convoluted tubules, and SGLT-1 also contributes to this process, making these transporters relevant targets in diabetes management.
Patients with psychotic disorders should undergo routine screening for diabetes at least annually, with more frequent testing if other risk factors are present. Fasting blood glucose estimation is considered ideal for screening, but when not feasible, a random glucose test alone or in combination with an HbA1c test may serve as an acceptable alternative despite lower sensitivity and specificity.
In older people with diabetes, the effectiveness of traditional cardiovascular risk factors like hyperglycaemia in predicting cardiovascular disease risk diminishes with age, partly due to a reverse metabolism linked to malnutrition and chronic disorders. Low body mass index, low cholesterol, and high insulin sensitivity in non-diabetic individuals have been associated with higher mortality, and markers like low albumin and high C-reactive protein further limit the prognostic value of cardiometabolic factors. As frailty and comorbidity increase, the benefits of tight metabolic control decline, making functional status an important consideration in diabetes management.
Oral hypoglycemic agents other than metformin and glibenclamide are not recommended during pregnancy, and women with pre-pregnancy diabetes who are on oral hypoglycemic therapy should be switched to insulin if their HbA1c levels are above target, although metformin may be continued in some cases.
People with diabetes have an increased prevalence of gallstones due to altered gallbladder contractility and are more susceptible to mesenteric ischaemia caused by generalized atherosclerosis; however, altered gallbladder contractility alone, without gallstones, is not strongly evidenced to cause symptoms. Additionally, thoracolumbar radiculopathy may cause girdle-like abdominal pain that does not cross the midline, and specific diagnostic tests are warranted if clinical features suggest such disorders, emphasizing the importance of obtaining a thorough medical history.
In diabetes, insulin-like growth factor binding protein 1 (IGFBP-1) binds to insulin-like growth factor I (IGF-1), reducing its bioavailability, which leads to decreased negative feedback inhibition on the hypothalamus and pituitary, resulting in increased growth hormone (GH) secretion; insulin inhibits IGFBP-1 expression.
Psychologic problems may be present in individuals with diabetes, yet they may be reluctant to discuss these issues during consultations. All members of the diabetes care team should be capable of identifying and managing basic psychologic concerns, but psychologists play a key role in addressing more complex issues such as eating disorders. Unfortunately, the psychological needs of people with diabetes are often unmet due to a shortage of trained healthcare professionals.
New discriminatory tools, such as the type 1 diabetes genetic risk score, have been developed to help differentiate MODY from type 1 diabetes by analyzing common genetic variants linked to type 1 diabetes risk and combining their weighted effects into a numerical score.
Abnormalities of glucose metabolism are more common in individuals with certain types of mental illness, and this association has been recognized for over a century. Some treatments for these mental disorders may also impact metabolic health. Patients with long-term mental illness have reduced life expectancy, with much of the early mortality linked to physical diseases such as diabetes and cardiovascular disease. Efforts to improve the physical health of these individuals now focus on detecting and managing metabolic and cardiovascular risk factors, including diabetes.
Bone and joint infections are a significant concern for people with diabetes, who are at increased risk for osteomyelitis and septic arthritis. Osteomyelitis can occur secondary to trauma, surgery, or joint prostheses; due to vascular insufficiency such as in diabetic foot infections; or through hematogenous spread. Diabetic individuals are more prone to these infections, particularly osteomyelitis of the foot, and also face a higher risk of vertebral osteomyelitis, often involving unusual organisms. Treatment typically requires prolonged antibiotic therapy, with early imaging via MRI or CT and bone sampling aiding in targeted antimicrobial treatment. A multidisciplinary approach, involving orthopaedic surgery, infectious diseases, and vascular surgery, is essential for effective management, with surgery considered if medical treatment fails or in cases of complications.
The effects of a 6.5-year difference in HbA₁c during the DCCT on retinopathy and nephropathy incidence persisted and widened over 14 years of follow-up, with individuals in the standard therapy group having a higher incidence of complications despite improved glycaemia, while those in the intensive therapy group had a lower incidence even with worsening glycaemia, a phenomenon known as glycaemic memory or the legacy effect. Glycaemic memory also occurs in type 2 diabetes, as shown by the UKPDS, where tight glucose management led to sustained reductions in microvascular risk and emerging reductions in acute myocardial infarction and death from any cause, despite early loss of glycaemic differences, with benefits evident during a 10-year post-trial follow-up among overweight participants.
Self-management support for diabetes focuses on equipping patients with the necessary knowledge to manage their condition effectively, emphasizing their central role in their care. This approach fosters the adoption of effective strategies for living with diabetes and highlights the individual's responsibility for their health. While diabetes education has long been considered essential, there is growing recognition of the importance of continuous support for patients.
Many skin conditions are associated with diabetes, occurring in approximately one-third of affected individuals, with some being specific to metabolic changes or treatment side effects, while others are nonspecific but more common in people with diabetes. Cutaneous changes can serve as the first sign of diabetes or appear at any stage of the disease. Autoimmune skin conditions are more prevalent in type 1 diabetes, whereas infections are more common in type 2 diabetes.
Obesity is associated with elevated insulin secretion and decreased hepatic insulin clearance, and studies suggest that β-cell volume increases by about 50% in healthy obese individuals, likely due to β-cell hypertrophy. Insulin release and insulin sensitivity are reciprocally related in a non-linear manner, and failure of this feedback system leads to a progressive decline in β-cell function and contributes to the development of type 2 diabetes mellitus (T2DM). Long-chain fatty acids stimulate insulin secretion from pancreatic β-cells through the generation of fatty acyl CoA and activation of protein kinase C, as well as through binding to the G-protein-coupled receptor GPR40, which increases intracellular calcium and promotes secretory granule exocytosis. However, chronic exposure of β-cells to excessive fatty acids impairs glucose-stimulated insulin secretion and reduces insulin biosynthesis. Elevated fatty acids may also impair insulin secretion via increased expression of uncoupling protein 2 (UCP-2) in β-cells, a process upregulated under glucolipotoxic conditions, with mitochondrial superoxide acting as a post-translational negative regulator of UCP-2 activity in islets.
Glucocorticoids are the medication class most consistently associated with hyperglycaemia, increasing blood glucose levels especially when administered intravenously or orally at supraphysiological doses. They can also raise blood glucose when given intra-articularly or epidurally, and in some cases with inhaled corticosteroids. While oral glucocorticoids have been linked to up to 2% of new-onset diabetes cases, studies show varying results for other administration routes. Cohort studies report an odds ratio for glucocorticoid-induced new-onset diabetes ranging from 1.36 to 2.31.
The level of β-cell loss required for hyperglycemia is age-dependent, with about 40% loss observed in individuals aged 20 years. β-cell regeneration may occur, contributing to the presence of approximately 50% viable β-cells at diagnosis. The destruction of β-cells varies in intensity and duration depending on the age at diagnosis, and direct assessments of β-cell loss in humans before and after diagnosis are currently unavailable. Much of the understanding of β-cell function prior to clinical onset comes from studies on laboratory animals such as NOD mice and bio-breeding rats. β-cell destruction in humans can be estimated indirectly through insulin secretion assessments during intravenous glucose tolerance tests (IVGTT), with FPIR measured by insulin or C peptide reflecting β-cell loss and predicting type 1 diabetes mellitus (T1DM). Data from the Diabetes Prevention Trial Type 1 indicate that post-challenge C peptide levels are significantly reduced six months before the clinical onset of the disease.
In obesity and type 2 diabetes, there is a rise in total body Na⁺ content, and insulin stimulates the Na⁺-K⁺ ATPase in vascular smooth muscle cells, potentially increasing intracellular Na⁺ concentrations and enhancing contractility by raising systolic Ca²⁺ levels, which may contribute to increased peripheral resistance. Insulin's effects on the central nervous system may also stimulate sympathetic outflow, theoretically increasing blood pressure, though direct evidence in humans is lacking. Additionally, insulin can promote vascular smooth muscle cell proliferation, leading to medial hypertrophy and further increasing peripheral resistance.
Glycated haemoglobin (HbA1c) is used as a measure in diabetes management, and to convert HbA1c from DCCT% to IFCC mmol/mol, the formula IFCC mmol/mol = 10.93 × DCCT% - 23.5 mmol/mol should be used. The UK Prospective Diabetes Study (UKPDS) and the Veterans Affairs Diabetes Trial (VADT) are major studies in diabetes research. In VADT, intensive therapy was discontinued after a median of 3.5 years due to increased mortality in the intensive group compared to the conventional group. Intensive therapy showed a reduction in new or worsening nephropathy but had no effect on the progression of retinopathy. Obesity is a relevant factor in diabetes, and myocardial infarction is among the complications associated with the condition. An increase in albuminuria is also a concern in diabetes management.
The potential role of soluble recombinant (sr)TRAIL in diabetes-induced atherosclerosis has been studied in streptozotocin diabetic $\mathrm{ApoE^{- / - }}$ mice, showing that repeated intraperitoneal injections of srTRAIL significantly reduced plaque development and stabilized atherosclerotic lesions by decreasing infiltrating macrophages and increasing vascular smooth muscle cells within the plaques. Diabetic rats treated with srTRAIL also exhibited improved endothelial function and suppressed inflammatory responses.
Cognitive impairment or dementia can influence diabetes management by leading to more lenient glycated haemoglobin (HbA₁c) targets, fewer investigations, and reduced specialist care involvement. Chronic hyperglycaemia, defined as HbA₁c greater than 9% (75 mmol/mol), and frequent hypoglycaemic episodes are more common in individuals with cognitive impairment. These hypoglycaemic episodes can further impair cognition, reduce performance on cognitive assessments like the sMMSE, and hinder medication adherence and self-care in people with diabetes and cognitive issues.
Antiplatelet treatment, particularly with aspirin, has been evaluated for primary prevention of major adverse cardiovascular events in people with diabetes, showing mixed results. Large trials and meta-analyses have failed to demonstrate a clear risk-to-benefit ratio, with some indicating only a small reduction in serious vascular events. A meta-analysis by the Antithrombotic Trialists' Collaboration found a 7% reduction in serious vascular events among nearly 5000 people with diabetes treated with aspirin, though the 95% confidence interval was too wide to confirm a significant benefit. The ASCEND trial found only a non-significant 12% risk reduction. As a result, current recommendations suggest low-dose aspirin (at least 70 mg/day) only for primary prevention in individuals with diabetes who are at high risk of cardiovascular events.
Combined aerobic and resistance exercise training in sedentary individuals with type 2 diabetes leads to a significant reduction in HbA1c levels by 0.3% (3 mmol/mol) compared to a non-exercising control group, whereas neither aerobic nor resistance exercise alone produces a significant change in HbA1c.
Insulin stimulation of glucose uptake in skeletal muscle is reduced in patients with type 2 diabetes mellitus (T2DM) compared to those without diabetes when measured under similar conditions of hyperinsulinemia and glycemia. At the molecular level, muscle insulin resistance in T2DM is associated with defects at multiple post-receptor sites, including impaired insulin receptor substrate 1 tyrosine phosphorylation, reduced activation of phosphoinositide 3-kinase (PI3K), and diminished glucose transporter 4 translocation, which mediates insulin-stimulated glucose uptake. Glycogen synthesis is also decreased in skeletal muscle in T2DM. Elevated levels of non-esterified fatty acids (NEFA) further interfere with glucose utilization and uptake by muscle.
Residents with diabetes should have an annual comprehensive foot examination to identify risk factors for ulcers and amputations, and regular podiatry input should be available. Additionally, they should undergo an initial comprehensive eye examination followed by annual exams, with domiciliary optometric services considered for those unable to travel.
Semaglutide is a GLP-1 analogue with 94% structural homology to native human GLP-1, modified to resist degradation and bind to albumin, resulting in a half-life of approximately one week, allowing once-weekly administration. It has been extensively evaluated as a treatment for type 2 diabetes and investigated in higher doses for weight management in overweight and obese individuals. In the STEP 1 trial, semaglutide led to significant weight loss of 14.9% after 68 weeks compared to 2.4% on placebo, with one-third of individuals losing ≥20% of their initial weight. Semaglutide also produced greater reductions in waist circumference and cardiometabolic risk factors. The STEP trials included participants with prediabetes but not type 2 diabetes, who were studied separately in STEP 2. The SELECT cardiovascular outcome trial is assessing the effects of semaglutide on heart disease and stroke in individuals with overweight or obesity without type 2 diabetes.
Gestational diabetes mellitus (GDM) is hyperglycemia first detected during pregnancy and differs from diabetes in pregnancy, which occurs in women who already have diabetes. Plasma glucose levels, both fasting and postprandial, are typically lower than normal in early pregnancy, so elevated levels at this stage are likely due to previously undiagnosed type 2 diabetes mellitus (T2DM). Screening for GDM is usually conducted around 28 weeks of pregnancy. GDM is associated with significant morbidity, including intrauterine fetal death, congenital malformations, neonatal hypoglycemia, jaundice, prematurity, and macrosomia. Risk factors for GDM include certain ethnic backgrounds, a history of GDM or abnormal glucose tolerance, advanced maternal age, obesity, and having previously given birth to large babies.
Children with diabetes should undergo annual screening for microalbuminuria starting at age 10 and after having diabetes for more than 5 years, using a random spot urine sample. If results are borderline or increasing, more frequent screening is recommended, and follow-up can involve a timed overnight or 24-hour urine collection. Diagnosis of microalbuminuria requires two abnormal results out of three over 3–6 months. Once confirmed, persistent microalbuminuria warrants evaluation to exclude non-diabetes-related renal causes, followed by initiation of an angiotensin-converting enzyme (ACE) inhibitor regardless of blood pressure status. Patients should also be advised on the importance of glycemic control and smoking cessation when relevant.
Iatrogenic hypoglycemia and hypokalemia are common and preventable complications in diabetes management when there is access to rapid glucose and potassium analysis and a competent medical team. Another frequent complication is the recurrence of diabetic ketoacidosis (DKA) or unnecessary prolongation of its course, typically due to insufficient insulin therapy. Thrombotic events are also not uncommon, particularly in hyperosmolar hyperglycemic state (HH) more often than in DKA.
The empowerment approach encourages clinicians to understand the individual experience of living with diabetes and supports people with diabetes in taking personal responsibility for their health through self-selected choices in self-management. A key aspect of empowerment is acknowledging that the person with diabetes is in control of and responsible for their own care. Knowledge plays a central role in empowerment, and empowerment programs aim to enhance the individual's ability to set realistic goals, solve problems, develop coping strategies, manage stress, increase social support, and improve self-motivation. Empowerment is achieved when healthcare professionals enable individuals with diabetes to make informed, autonomous decisions, and when individuals actively engage in making those decisions.
Exercise-induced stimulation of glucose uptake involves multiple factors that contribute to improved insulin sensitivity and glucose metabolism, which are relevant to diabetes management. These factors include enhanced post-receptor insulin signaling, increased glucose transporter protein and mRNA expression, and greater activity of enzymes such as glycogen synthase and hexokinase. Additionally, exercise reduces free fatty acid levels by decreasing their release and increasing their clearance, while also improving muscle glucose delivery through increased capillary density. Changes in muscle composition and adipose tissue distribution further support glucose disposal, and reductions in visceral fat lower levels of tumor necrosis factor α and free fatty acids, both of which are associated with decreased insulin resistance.
Screening for gestational diabetes mellitus (GDM) is typically performed between 24–28 weeks’ gestation due to the development of insulin resistance in later pregnancy, and the IADPSG diagnostic thresholds are specifically applicable for use between 24–32 weeks’ gestation, not earlier, as glucose metabolism changes with gestational progression. Early pregnancy testing for diabetes using plasma glucose or HbA1c is not recommended by NICE guidelines, even for identifying pre-existing type 2 diabetes, due to limited evidence on cost-effectiveness.
Poorly controlled type 1 diabetes mellitus (T1DM) in girls diagnosed before puberty is associated with delayed menarche, though most young women with T1DM can be reassured about their fertility. Women with T1DM also experience early menopause more frequently, with a reported mean age of menopause at 41.6 years in a U.S. study, compared to 49.9 years in non-diabetic sisters and 40.9 years in unrelated controls.
Diabetic retinopathy progression rates vary based on patient age, diabetes type, and insulin use, with patients having no diabetic retinopathy (DR) or only microaneurysms showing different risks of progressing to proliferative retinopathy over 4 years. Young patients (<30 years) with type 1 diabetes (T1DM) and no DR have a 0.4% progression rate, while older patients (≥30 years) with T1DM and no DR have 0% progression if using insulin and 0.6% if not using insulin. Those with microaneurysms or one hemorrhage in one eye have higher progression rates: 3.0% for young T1DM patients, 0% for older T1DM patients using insulin, and 1.5% for those not using insulin.
Chronic hyperglycaemia in diabetes triggers an inflammatory response in the vascular endothelium, promoting monocyte adhesion and migration into the subendothelial space. Elevated levels of advanced glycation end-products (AGEs) and their interaction with the receptor for AGEs (RAGE) lead to oxidative reactions that enhance the oxidation of low-density lipoprotein (oxLDL), further amplifying endothelial inflammation. Monocytes differentiate into macrophages, which accumulate lipids to become foam cells, contributing to the formation of early atherosclerotic fatty streaks that progress into advanced lesions with vascular smooth muscle cell infiltration, necrotic cores, and increased lipid deposition. These lesions may become unstable, leading to plaque rupture, intraplaque haemorrhage, and heightened thrombogenicity.
Diabetes technologies, such as insulin pump therapy and continuous glucose monitoring (CGM), have been effective in reducing hypoglycaemia in children and young people with type 1 diabetes. Insulin pump therapy allows for more precise and physiological insulin delivery, which has been linked to lower hypoglycaemia rates based on both clinical trials and real-world data. CGM provides round-the-clock glucose monitoring, enabling individuals and healthcare providers to identify glucose trends and intervene early to prevent hypoglycaemia. Additionally, CGM systems with remote monitoring capabilities can alert caregivers when a child's glucose levels are dropping, which has been shown to improve parental quality of life and sleep, as demonstrated in clinical trials and real-world studies.
For women on insulin, evening basal insulin is adjusted based on fasting glucose readings, while bolus insulin is adjusted according to 1- to 2-hour postprandial glucose levels, with prebed glucose readings helping determine the necessary bedtime snack size. Using 1-hour postprandial glucose measurements provides more useful information for adjusting insulin needs compared to preprandial readings. A randomized controlled trial involving women with gestational diabetes showed that those who self-monitored their glucose levels one hour after meals had fewer large for gestational age babies, fewer cesarean sections due to cephalopelvic disproportion, and less neonatal hypoglycemia compared to those who monitored immediately before meals.
Rapid-acting insulin analogs are more effective than regular insulin in mimicking the first-phase insulin release after meals and reducing postprandial hypoglycemia when used in insulin pumps, but they still require administration 10–15 minutes before a meal to achieve effective levels, with a longer lead time needed if preprandial blood glucose exceeds 150 mg/dL. Some patients, such as young children, picky eaters, and disorganized individuals, may have difficulty adhering to these timing requirements and predicting meal size, leading to strategies like administering half the meal bolus in advance and the remainder after the meal if needed. Common compliance issues include infrequent blood glucose testing, failure to respond to high blood glucose levels, incorrect carbohydrate counting, and missed boluses.
Men with diabetes may not have a higher risk of infection after penile prosthesis insertion compared to those without diabetes, but if infection does occur, it tends to be more serious; good preoperative control of diabetes is important to minimize this risk, and well-selected groups of men with diabetes have shown acceptable outcomes and good patient satisfaction following the procedure.
Several substances stimulate glucose uptake and utilization by muscle and adipose tissue, but few are suitable for treating type 2 diabetes due to challenges in controlling their effects and unfavorable side effect profiles. Examples of such substances include dichloroacetate, spermine, diamides, various peroxides, vitamin $\mathrm{K}_5$, deoxyfrenolicin, okadaic acid, and phorbol esters. Glycogen synthase kinase inhibitors have been shown to increase glycogenesis and lower blood glucose in insulin-resistant diabetic animals, yet concerns over potential adverse effects on cellular division have hindered their development as a treatment for type 2 diabetes.
People with diabetes are recommended to receive annual vaccination against seasonal influenza, as studies have shown no differences in immune responses to the vaccine compared to those without diabetes. Observational studies suggest that influenza vaccination provides protection against influenza- and pneumonia-related hospitalizations and all-cause hospitalizations. Population-level data from a Danish diabetes registry indicate that vaccinated individuals with diabetes had a 17% lower risk of all-cause death and a 16% lower risk of cardiovascular death, after adjusting for sociodemographics and comorbidities. Despite these benefits, vaccine coverage varies across countries, with high-income countries generally having higher coverage due to established guidelines and vaccination programs. Efforts are ongoing to increase awareness among healthcare professionals and the public to reduce the burden of vaccine-preventable diseases in people with diabetes.
Chronic stimulation of beta cells increases the synthesis of islet amyloid polypeptide (IAPP), which is co-localized with insulin secretory granules and produced alongside proinsulin. IAPP can form aggregates and fibrils, leading to amyloid plaque deposition that triggers inflammation, macrophage recruitment, and apoptosis. Although amyloid deposition occurs in other hypersecretory conditions like obesity and insulinoma without impairing beta-cell function, it is also found in up to 90% of individuals with type 2 diabetes, with the extent of deposition correlating with disease duration and severity. The harmful effects of amyloid may depend on concurrent glucolipotoxicity, offering a possible explanation for this paradox.
Exenatide, administered either as a daily dose or once weekly, effectively reduces HbA1c levels in patients with diabetes, with a greater reduction observed in those switched to the weekly formulation. Patients treated for 30 weeks experienced a decrease in HbA1c by up to 1.9%, and many achieved levels below 7.0% without severe hypoglycemia. Those with higher baseline HbA1c levels above 9.0% showed a reduction of up to 2.8% after one year. Both dosing regimens resulted in an average weight loss of approximately 4–4.5 kg, with some patients losing over 5% of their body weight. Nausea was a common side effect, reported in 26–35% of patients, and about 74% developed antibodies to exenatide, with some showing a diminished glycemic response. Systolic blood pressure also decreased, particularly in patients with baseline hypertension.
Chronic elevation of glucose concentrations impairs $\beta$-cell function and insulin action, a phenomenon known as glucotoxicity, which is associated with type 2 diabetes. High glucose levels lead to oxidative stress through increased glucose oxidation in mitochondria, mitochondrial dysfunction, and overproduction of reactive oxygen species (ROS). In type 2 diabetes, pancreatic islets show significantly increased markers of oxidative stress compared to normal islets, and these markers are inversely related to glucose-stimulated insulin secretion. Overexpression of antioxidant factors can reduce oxidative stress markers and improve $\beta$-cell responsiveness to insulin. The $\beta$-cell is particularly vulnerable to oxidative stress due to low expression of antioxidant enzymes and reduced DNA repair capacity.
Insulin binding and action are decreased in adipocytes of individuals with type 1 diabetes mellitus (T1DM), but remain normal in fibroblasts, suggesting that the reduced insulin binding in adipocytes may result from the abnormal metabolic environment rather than an inherent defect in insulin action. Improved chronic glycemic control is associated with enhanced whole-body insulin action, indicating a reversible component of insulin resistance in T1DM. Additionally, during a hyperglycemic hyperinsulinemic clamp, hyperglycemia may mask minor defects in insulin action by promoting glucose uptake and suppressing glucose release, a phenomenon known as glucose effectiveness.
Sulfonylureas, a class of medications used in the management of diabetes, vary in their pharmacokinetic properties, influencing their suitability for different patients. These drugs are generally well absorbed, reaching peak plasma concentration within 2–4 hours, and are highly bound to plasma proteins, which can lead to drug interactions with other protein-bound agents such as salicylates, sulfonamides, and warfarin. Displacement of sulfonylureas from plasma proteins can increase the risk of hypoglycaemia. They are metabolized in the liver into various active and inactive metabolites, which along with the unchanged drug, are excreted via bile and urine. Longer-acting formulations can be administered once daily but pose a higher risk of hypoglycaemia, particularly due to active metabolites. Metabolism and elimination rates are crucial considerations, especially in older adults and those with liver or kidney dysfunction or on multiple medications.
Nerve conduction studies are used to assess the severity of diabetic sensorimotor polyneuropathy, although they are limited in detecting early small-fibre neuropathy and exhibit variability due to factors like electrode placement and limb temperature.
Rosiglitazone and pioglitazone, which are thiazolidinediones, can be used in the elderly if there are no contraindications and may also be considered for patients with mild renal impairment, although there is a potential risk for edema. These medications can cause ovulation to resume in women with anovulatory PCOS, but they should not be continued during pregnancy.
Insulin therapy should continue during a sick day, though the dose may need adjustment depending on the child's condition, such as reduced food intake or vomiting. A fasting individual still requires about 40% of their usual daily insulin dose to meet basic metabolic needs and prevent ketoacidosis. Infections that occur with normal eating often necessitate an increase in basal insulin by 10–15%, and additional rapid-acting insulin doses are typically required to manage hyperglycemia, prevent ketoacidosis, and avoid hospitalization. These supplemental doses can be repeated every 2–4 hours as needed, guided by blood glucose and ketone levels.
GLP-1 produced by α-cells within the islet plays a role in regulating insulin secretion through local action, as demonstrated by studies showing that disruption of GLP-1 receptor signaling in rodent islets or pancreata reduces both basal and glucose-stimulated insulin secretion. This effect has been observed in mouse models with β-cell-specific deletion of the GLP-1 receptor and in humans, where infusion of a GLP-1 receptor antagonist decreases glucose-stimulated insulin secretion even at low circulating GLP-1 levels. These findings indicate that local islet production of GLP-1 contributes to α-to-β-cell communication and supports its relevance in maintaining proper insulin secretion, which is critical in diabetes regulation.
The Pacific Islands and Middle East have the highest diabetes prevalence rates, while Africa is expected to see the largest increase. Diabetes is linked to a twofold rise in mortality across most populations, though this excess risk diminishes with age. Rising diabetes prevalence, especially among young adults, combined with complications like microvascular and macrovascular diseases, is expected to increase healthcare costs and hinder economic growth. Some high- and middle-income countries show stable or declining diabetes incidence. Prevention involves public education and coordinated efforts promoting physical activity and healthy diets, with maternal health and the intrauterine environment offering key opportunities for intervention. Type 2 diabetes can go into remission through intensive lifestyle changes or metabolic surgery, emphasizing the role of weight loss, which may affect diabetes prevalence data.
Certain drugs can interact with sulfonylureas, which are medications commonly used to treat diabetes, potentially affecting their efficacy or increasing the risk of side effects.
High anion-gap ketoacidosis in some patients may be complicated by non-anion-gap hyperchloremic acidosis during treatment with insulin and saline infusions, due to the loss of alkali in the form of ketoanions with sodium or potassium in the urine. This can lead to prolonged acidosis, potentially confusing clinical evaluation, and some patients may benefit from bicarbonate therapy.
Individuals with diabetes and decreased salivary secretion are advised to have frequent dental check-ups and cleaning to prevent caries, and those with elevated HbA₁c may have poorer oral hygiene and visit the dentist less often. Early intervention, including dietary guidelines to reduce sugar intake, can help reduce the risk of both obesity and caries in high-risk individuals such as children and young people with obesity. Regular oral examinations are important for detecting candidal infections, oral pre-malignant lesions, and malignancies, which are more common in people with diabetes compared to healthy individuals.
A low-glycemic index diet improves glycemic control, whole-body glucose utilization, lipid profile, and fibrinolytic activity in individuals with type 1 and type 2 diabetes. High dietary fiber intake also has beneficial effects on glycemic control and lipid profiles in type 2 diabetes. Flexible dietary approaches, including low-glycemic index dietary advice and training in intensive insulin management such as dose adjustment for normal eating (DAFNE), can improve glycemic control and provide dietary freedom in type 1 diabetes. Carbohydrate content of meals influences insulin requirements in type 1 diabetic patients on a basal-bolus insulin regimen. Evidence-based nutritional recommendations emphasize the importance of fiber-rich, low glycemic index natural foods and carbohydrate management strategies in improving outcomes for individuals with diabetes.
Cellular encapsulation uses biomaterials to protect cells from immune responses and is a promising approach for eliminating the need for immunosuppression in diabetes treatment. This method is applicable to islet cell transplantation and stem cell-based therapies but not to whole pancreas transplantation. Advances in low-fouling, immune-friendly biomaterials and composite bioscaffolds have improved graft acceptance and prolonged diabetes reversal in preclinical models. These technologies are compatible with xenotransplantation and stem cell therapies. Clinical trials are currently underway using encapsulated human embryonic stem cell (hESC)-derived pancreatic endocrine progenitors that develop into islet-like structures in vivo, with early results showing survival of the cells for up to two years. Successful cellular encapsulation could expand the use of β-cell replacement therapies to treat various forms of diabetes.
In Scandinavia, the prevalence of type 2 diabetes (T2DM) among white Caucasians varies by region, with 8.1% prevalence reported in Northern Sweden. A study in Finland found an age-standardized prevalence of 10.2% in men and 7.4% in women aged 45 to 64 years, while Iceland showed lower prevalence rates.
Management of diabetes involves restoring nutritional and hydration status, alleviating symptoms, and stabilizing glucose levels. Early dietetic input is recommended, favoring multiple small meals low in fat and fiber over fewer large meals. When oral nutrition is insufficient, assisted nutrition is considered, with enteral nutrition preferred over parenteral due to lower risks of complications such as infection and thrombosis. Insulin treatment can be optimized using basal insulin and adjusting prandial injections. In a study involving individuals with gastroparesis and type 1 or type 2 diabetes, improved glycemic control, reduced hypoglycemia, and better gastroparesis symptom scores were observed with the use of sensor-augmented pumps or continuous glucose monitoring systems.
Type 1 diabetes mellitus (T1DM) exhibits significant geographic and ethnic variations in incidence rates globally. Within countries such as Finland, Sweden, and Norway, differences of up to 1.5-fold have been reported despite relatively homogenous populations. In Italy, the incidence among children in Sardinia (38 per 100,000/year) was three to six times higher than the mainland average, with a twofold variation between regions such as Campania (6.3 per 100,000/year) and Pavia (12.2 per 100,000/year). China shows a 12-fold geographic disparity (0.13–1.61 per 100,000), with higher rates in the north and east, and a sixfold difference between the Mongol (1.82 per 100,000) and Zhuang (0.32 per 100,000/year) ethnic groups.
Osmotic symptoms and superficial fungal infections can indicate new-onset type 1 or type 2 diabetes, with type 1 often linked to higher plasma glucose levels and ketonuria. Both types show elevated HbA1c levels due to prolonged hyperglycemia. If diabetes presents in the first half of pregnancy without remission post-delivery, especially with raised HbA1c, it suggests pre-existing diabetes.
Certain genetic variations in the KCNJ11 and ABCC8 genes, which encode subunits of the pancreatic β-cell ATP-sensitive potassium channel (IKATP), are associated with type 2 diabetes mellitus (T2DM). This channel plays a central role in glucose-induced insulin secretion by linking glucose metabolism to cell-membrane depolarization and insulin release. Inactivating mutations in these genes can cause familial persistent hyperinsulinemic hypoglycemia in infancy, while gain-of-function mutations lead to neonatal diabetes. A common variant, E23K, in the KCNJ11 gene has been linked to an increased risk of T2DM and reduced insulin secretion in glucose-tolerant individuals, with large-scale studies confirming this association with an odds ratio of 1.15.
Simplified and advanced patch pumps are available for diabetes management, particularly for type 2 diabetes, with simplified versions serving as disposable pen replacements changed daily. Advanced patch pumps offer full functionality for managing complex insulin regimens. Compared to conventional tubed pumps, patch pumps have lower upfront costs, are more discreet, attach directly to the skin, and eliminate issues related to insulin infusion sets such as priming, clogging, kinking, and air bubbles, which are common problems reported by over 50% of type 1 diabetes patients using conventional pumps. Patch pumps can be placed on various body parts, benefiting those with abdominal lipohypertrophy, and many are water resistant for use during showers or swimming. However, if a patch pump is removed, it must be discarded and replaced, leading to increased waste, and an additional control device is required for insulin infusion, making bolus delivery impossible if the control device is unavailable.
A single intramuscular administration of AAV1 vectors encoding for insulin and GCK in diabetic dogs resulted in normalization of fasting glycaemia, accelerated glucose disposal after oral challenge, and long-term therapeutic effects lasting over 4 years without hypoglycemic episodes. This approach also led to recovery of body weight, normal levels of glycated plasma proteins, and prevention of secondary complications. Gene transfer of either insulin or GCK alone did not fully correct diabetes, indicating the need for combined insulin and glucokinase action. Follow-up studies showed over 8 years of glycemic control without exogenous insulin, with normalization of serum fructosamine, triglycerides, and cholesterol levels, as well as improved oral glucose response. Vector genomes and transgene expression persisted in treated muscles, which maintained normal morphology, demonstrating long-term efficacy, safety, and adaptability of the therapy to changing metabolic needs as the animals aged.
The incretin system, involving glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and their receptors, plays a key role in glucose homeostasis by enhancing insulin secretion in response to nutrients such as glucose and amino acids. In the post-prandial state, GIP potentiates glucose-stimulated insulin secretion from $\beta$ cells and amino acid-stimulated glucagon secretion from $\alpha$ cells. The rise in glucagon and potentially GLP-1 enhances $\alpha$-to-$\beta$-cell communication through the GLP-1 receptor (GLP-1R) and glucagon receptor (GcGR). Activation of GLP-1R, GcGR, and GIP receptors in $\beta$ cells leads to maximal insulin secretion, which is important for maintaining glucose balance, a process impaired in diabetes.
FPG (fasting plasma glucose) is a simpler and cheaper alternative for diabetes screening, but requires an overnight fast which may be challenging for mothers with young children. $\mathrm{HbA}_{1c}$ has limitations in pregnancy due to increased red blood cell turnover and blood loss at delivery, yet offers advantages such as a single non-fasting blood test, high pre-analytical stability, ease of repetition, and availability of point-of-care testing, particularly in resource-limited settings. The OGTT (oral glucose tolerance test) is more sensitive in detecting glucose intolerance, including both diabetes and pre-diabetes, though its effectiveness is measured relative to itself as the gold standard rather than independent outcomes.
The spectrum of diabetes subgroups includes type 1 diabetes (T1D), characterized by onset before 35 years of age, C-peptide < 0.2 nmol/l, and glutamic acid decarboxylase (GAD) antibodies > 20, and type 1 diabetes with relative insulin deficiency defined by C-peptide 0.2 – 0.6 nmol/l. Type 2 diabetes (T2D) typically presents after 35 years of age with C-peptide > 0.6 nmol/l and GAD antibodies < 10, while type 2 diabetes with relative insulin deficiency also shows C-peptide 0.2 – 0.6 nmol/l. Latent autoimmune diabetes in adults (LADA) occurs in individuals over 35 years with GAD antibodies > 20, and LADA light is defined by GAD antibodies 10 – 20. The data highlight challenges in diabetes classification, with 19% of cases unclassifiable at diagnosis, and also mention maturity-onset diabetes of the young (MODY) as a distinct subgroup.
Tight glycaemic management in people with a longer duration of diabetes has not been shown to prolong life, as demonstrated by the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular disease: preterAx and diamicron MR Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VA-DT). Notably, the ACCORD trial found increased cardiovascular mortality among those receiving intensive glycaemic management, underscoring the importance of individualized glycaemic targets.
Early identification of chronic kidney disease (CKD) in individuals with diabetes allows for intensified therapy to slow kidney disease progression and manage the increased risk of other complications, especially cardiovascular disease (CVD). Guidelines recommend systematic screening, typically during an annual review, which includes measuring both urine albumin excretion (UAE) and glomerular filtration rate (GFR), as combining these measurements improves prediction of end-stage renal disease (ESRD). Screening should occur when the individual is not experiencing acute illness and has stable glucose control, as acute conditions and hyperglycemia can temporarily elevate UAE.
In the UK Prospective Diabetes Study (UKPDS), intensive management of blood glucose levels resulted in a mean $\mathrm{HbA_{1c}}$ of $53\mathrm{mmol / mol}$ $(7.0\%)$, compared to $63\mathrm{mmol / mol}$ $(7.9\%)$ in less strict management, leading to a 30% reduction in the relative risk of developing moderately or severely increased albuminuria after 9–12 years, with no clear threshold of $\mathrm{HbA_{1c}}$ and risk observed.
When working with patients with diabetes, a flourishing mindset can be encouraged by starting sessions with questions about improvements since the last visit, guiding the conversation in a positive direction. Patients should be asked to share challenges they've overcome, identifying strengths that can be applied to diabetes management. In reviewing logbooks or discussing nutrition, focus on successes such as in-range blood glucose readings or dietary habits like eating vegetables, and explore how these can be repeated more often. Patients should be given the opportunity to identify their own areas for improvement and set goals, increasing their likelihood of success through ownership. Healthcare providers should be attentive, show genuine interest, and engage patients in a way that demonstrates care, as this fosters better engagement and receptiveness to future recommendations.
Depression is more prevalent in individuals with diabetes, particularly those using insulin therapy, which is associated with a 59% higher risk of developing depression compared to other treatments, and a 42% higher risk when compared specifically to oral antidiabetes agents. Insulin use may not directly cause depressive symptoms but is linked to increased treatment demands and greater disease severity. Self-monitoring of blood glucose, recurrent hypoglycaemia, and elevated HbA1c levels are also risk factors for depression in people with diabetes. There is a bidirectional relationship between diabetes and depression, as individuals with depression are at higher risk for severe hyperglycaemic and hypoglycaemic episodes requiring hospitalization, and those experiencing such episodes are more likely to develop depression. In a 10-year study, people with depression at baseline had a 2.5-fold increased risk of hospitalization for severe hyperglycaemia and an 89% increased risk of severe hypoglycaemia, while those hospitalized for hyperglycaemia or hypoglycaemia were 1.4-fold and 74% more likely to develop depression, respectively.
In type 1 diabetes mellitus (T1DM), hypertension is not universally present but is specifically associated with nephropathy, as individuals with normal urinary albumin excretion (UAE) have a prevalence of hypertension similar to non-diabetic individuals. This indicates that hypertension is an integral component of diabetic nephropathy, likely stemming from shared underlying mechanisms. Blood pressure increases early in the course of nephropathy, with subtle changes often detectable only through 24-hour BP monitoring, such as reduced nocturnal dipping in diastolic BP, particularly in patients with UAE in the high normal range who are at greater risk of progressing to microalbuminuria.
Diabetes risk categorization is based on cardiovascular risk factors, with very high-risk individuals including those with diabetes and established cardiovascular disease or target-organ damage such as left ventricular hypertrophy or chronic kidney disease. Additionally, people with diabetes and three or more major risk factors are classified as very high risk due to increased likelihood of cardiovascular death. High-risk individuals are those with diabetes duration of 10 years or longer without target-organ damage but with additional risk factors. Moderate risk applies to younger individuals, with type 1 diabetes under 35 years or type 2 diabetes under 50 years, having diabetes duration under 10 years and no other risk factors. The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) use similar classification methods to guide therapeutic strategies based on these risk categories.
Insulin sensitivity can be influenced by various factors that are relevant to diabetes. Physical training and increased muscle mass improve insulin sensitivity, whereas increased fat mass, fat distribution, overfeeding, starvation, alcohol consumption, high free fatty acid concentrations, chronic hyperglycemia, hypoglycemia, acidosis, hyperosmolality, hypophosphatemia, excessive secretion of counter-regulatory hormones, hypothyroidism, hyperthyroidism, non-alcoholic fatty liver disease, uremia, and many infections all lead to decreased insulin sensitivity. Certain hormonal conditions such as acromegaly, Cushing disease, pheochromocytoma, and growth hormone deficiency also reduce insulin sensitivity, as do states of physical or mental stress.
Pregabalin is used to treat painful diabetic neuropathy and has been shown to improve subjective sleep and quality of life in individuals with this condition, though it may cause side effects such as somnolence, oedema, and mood disturbance, and sudden discontinuation can lead to seizures, cerebral oedema, and encephalopathy.
Repeated insulin injections at the same site can cause local adipose tissue hypertrophy, leading to slower and irregular insulin absorption, which can be avoided by rotating injection sites. Other factors affecting insulin absorption include local inflammation, edema, exercise, temperature changes, hypoglycemia, and smoking. Exercise increases skin blood flow and can accelerate insulin uptake, especially when injected near active muscles, so injection into the leg may be less favorable during running. Heat increases cutaneous blood flow, potentially causing a rapid insulin surge, while cooler temperatures slow absorption. Hypoglycemia and smoking have also been reported to reduce insulin absorption rates.
CCK-8, a form of the gastrointestinal hormone cholecystokinin, stimulates insulin secretion in vitro and in vivo by acting on specific $\mathrm{G}_{\mathrm{q}}$-coupled receptors on $\beta$ cells, leading to activation of PLC and PKC-dependent pathways. However, its physiological role as an incretin in humans remains uncertain due to the high concentrations required for insulin secretion and its primary involvement in digestion in the duodenum.
Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) refer to glucose levels that are higher than normal but do not meet the diagnostic criteria for diabetes. IGT is identified by elevated glucose levels two hours after a glucose load, while IFG is defined by elevated fasting plasma glucose. Both conditions are associated with a two- to threefold increased risk of progressing to diabetes, and IGT is also linked to cardiovascular risk. IFG is advantageous as it can identify individuals at risk without requiring an oral glucose tolerance test. Collectively, IGT and IFG are sometimes referred to as "pre-diabetes," though this term is considered misleading because not all individuals with these conditions develop diabetes and it overlooks other important risk factors such as family history. The World Health Organization prefers the term "intermediate hyperglycemia." These conditions are more common in older individuals, those who are obese, people from high-risk ethnic groups, and individuals with cardiovascular disease or other components of the metabolic syndrome, including dyslipidemia, hypertension, or visceral adiposity.
Continuous glucose monitoring (CGM) systems, which detect interstitial glucose using enzymatic sensors and integrate with a mobile reader, provide real-time glucose levels (rtCGM) or require scanning (isCGM), and can alert users or care partners to hypoglycaemia or impending hypoglycaemia. In randomized controlled trials, rtCGM reduced hypoglycaemia compared to self-monitoring of blood glucose in type 1 diabetes, including in individuals with impaired awareness. In type 2 diabetes, isCGM reduced hypoglycaemia in open-label trials, and real-world settings showed significant reductions in severe hypoglycaemic events with isCGM, although sensor accuracy in the hypoglycaemic range remains a limitation.
An absent glucagon response is associated with a 25-fold or greater increase in the risk of severe hypoglycaemia in type 1 diabetes. A diminished adrenal epinephrine response serves as a marker for an attenuated autonomic response to hypoglycaemia, leading to reduced neurogenic symptoms and the clinical syndrome of impaired awareness of hypoglycaemia. The impaired catecholamine response to hypoglycaemia in individuals with type 1 diabetes and advanced type 2 diabetes primarily results from an altered sympathetic drive, with a gradual shift of the glycaemic threshold for activation to lower glucose values. There is no structural defect in the adrenal medulla's secretory apparatus, as the catecholamine response to other stimuli like exercise remains intact.
Erectile dysfunction is significantly more prevalent in men with diabetes compared to the general population, with an overall prevalence of 52.5% in men with diabetes, including 37.5% for type 1 diabetes and 66.3% for type 2 diabetes. The prevalence increases with age, rising from 13% among 30-year-olds to 61% in men over 60 years attending a diabetes clinic, and it is even higher at 55% in a general practice population. Erectile dysfunction is considered the most common clinically apparent complication of diabetes in men.
Hyperglycaemia may lead to abnormalities through a mechanism known as glucose toxicity, which is supported by findings of impaired insulin-stimulated glycogen synthesis and glucose-6-phosphate increases in skeletal muscle in individuals with suboptimally managed type 1 diabetes. However, similar impairments are observed in insulin-resistant but normoglycaemic individuals, such as lean relatives of people with obesity or older people with type 2 diabetes, suggesting that mechanisms other than glucose toxicity contribute to insulin resistance in skeletal muscle in these groups.
The National Urban Diabetes Survey conducted in six cities in 2001 found an age-standardized prevalence rate of 12% for diabetes with a slight male predominance, and 5% among individuals under 40 years old. Diabetes was positively and independently associated with increasing age, BMI, waist-to-hip ratio, family history of diabetes, higher monthly income, and physical inactivity. Subsequent studies showed increasing prevalence rates, reaching 14.3% in the Chennai Urban Rural Epidemiology Study (CURES-17) and 18.6% in a more recent study in Chennai. A secular trend indicates a shift toward younger onset of diabetes, particularly in urban areas, where up to 36% of those with diabetes are aged 44 years or younger.
The use of glycemic index (GI) or glycemic load may provide moderate additional benefits for postprandial glycemia and lipid profile beyond considering total carbohydrate alone. Substituting high GI foods such as mashed potatoes, white rice, and sugary drinks with low GI options like legumes, whole grains, and raw fruits is recommended. Fresh fruits are preferable to fruit juices with similar carbohydrate content. However, low GI foods must also align with overall healthy nutrition, as some low GI foods are high in fat and energy, such as chocolate. Certain diabetic products reduce GI by replacing sucrose with sugar alcohols or fructose, but these expensive preparations have not shown substantial benefits, and thus are not recommended. Proper food labeling can assist individuals with diabetes in making healthy food choices.
Sitagliptin, a medication primarily excreted unchanged in the urine, requires dose adjustment based on renal function, with a reduced dose of 50 mg once daily recommended for patients with moderate renal insufficiency (creatinine clearance ≥ 30 to < 50 mL/min) and a further reduced dose of 25 mg once daily for those with severe renal insufficiency (creatinine clearance < 30 mL/min) or end-stage renal disease requiring dialysis; it does not significantly affect P450 isoforms, making it suitable for patients with mild or moderate liver impairment as long as renal function is adequate.
More intense glucose lowering has shown varying benefits in long-term studies on diabetes; for example, the UKPDS study found significant reductions in myocardial infarction over a 10-year post-trial follow-up, while the ADVANCE study did not show benefits for major vascular events, and the VADT study reported reduced macrovascular events at 10 years but not at 15 years.
The cardinal symptoms at diagnosis of diabetes include polyuria, often with nocturia or bed-wetting, polydipsia, weight loss, and fatigue. Diabetic ketoacidosis (DKA) may present with Kussmaul breathing, abdominal pain, vomiting, and impaired neurological status, though this classic presentation affects less than half of cases in high-income countries. Most children today present with milder hyperglycaemia of shorter duration due to increased community recognition, yet 75% of children, with 63% below age 5 years, have symptoms for more than two weeks, indicating potential for earlier diagnosis. Very young children may present with non-specific symptoms such as vomiting or rapid breathing, often alongside an infection. Diabetes should be considered in ill children, and urine or blood testing for glucose and ketones can lead to early diagnosis and prevent DKA and hospitalization. Early recognition of diabetes symptoms is crucial, as many children admitted with severe DKA had previously experienced missed or delayed diagnosis by healthcare providers.
Blood glucose levels are tightly regulated within a normal range of 3.5–8.0 mmol/l (63–144 mg/dl) due to the critical need for glucose by tissues such as the brain, which depends almost exclusively on glucose for energy, utilizing around 100g daily in a 70kg individual. The brain cannot synthesize or store significant amounts of glucose and requires a continuous supply from the bloodstream, with glucose uptake being independent of insulin but reliant on sufficient circulating glucose concentration.
In postmenopausal women with diabetes, estradiol has been reported to improve fasting blood glucose concentration and glycosylated hemoglobin percentage. A larger prospective study of over 15000 women with type 2 diabetes mellitus (T2DM) also reported that hormone replacement therapy (HRT) produced an improvement in HbA1c levels. A recent small randomized trial found that HRT reduced serum fructosamine levels by 5%. However, any potential benefit to glucose tolerance is limited to oral HRT preparations, as transdermal estradiol does not appear to have any effect on glucose tolerance.
Measurement of glucose in urine is not reliable for routinely monitoring diabetes due to its inability to accurately reflect changing levels of hyperglycemia, making interpretation difficult. Although it is rapid, inexpensive, non-invasive, and can provide a quantitative result, its accuracy is limited by individual variations in renal threshold, which also changes during pregnancy and with aging. Additionally, glucose is not excreted renally at blood glucose levels that are significantly elevated above the target needed to minimize diabetic complications.
Standing orders can empower office staff to order overdue laboratory screening and refer patients for eye exams, and may include algorithms for intensifying medication regimens. Effective communication among team members is essential, and incorporating daily clinic "huddles" can help ensure that well-coordinated care is provided to individuals with diabetes.
A range of haemodynamic and metabolic factors contribute to the development and progression of macrovascular disease in diabetes, with the renin-angiotensin-aldosterone system (RAAS) playing a pivotal role in diabetes-associated atherosclerosis. Other vasoactive hormone systems, such as the endothelin and urotensin systems, are also involved in diabetes-related macrovascular disease. Oxidative stress combined with reduced antioxidant defense drives atherogenic processes in diabetes, and immune-inflammatory responses involving factors like TNF-related apoptosis-inducing ligand (TRAIL) and the complement system are implicated. Activation of the inflammasome has also been shown to contribute to cardiovascular disease (CVD) in diabetes.
Premixed insulins combine regular or rapid-acting insulin with NPH insulin in fixed ratios and are beneficial for children who prefer not to use separate vials or face cost limitations, as well as for reducing injection frequency when adherence is a concern, particularly in teenagers. They are available in pen injector devices but offer limited flexibility in adjusting individual insulin doses, which can be a disadvantage when managing variable food intake, illness, or exercise.
Arterial stiffness is a characteristic of people with metabolic syndrome and type 2 diabetes, and increased aortic pulse wave velocity (aPWV) is a marker of arterial stiffness that can independently predict cardiovascular risk and total mortality. A threshold of aPWV >10 m/s is considered indicative of increased arterial stiffness. Early stages of hyperglycaemia and dyslipidaemia can increase arterial stiffness even in individuals with normoglycaemia or impaired glucose metabolism, contributing to early vascular ageing. Arterial stiffness is also a predictor of type 2 diabetes in the general middle-aged population.
Studies indicate that the TLR4 and JNK pathways are involved in connecting the microbiome with insulin resistance, a key factor in diabetes. Evidence from animal models with TLR4 mutations or knockouts, along with a human clinical trial using an anti-CD14 antibody, shows reduced inflammatory responses to LPS exposure, highlighting the role of TLR4/CD14 signaling in inflammation related to diabetes. Additionally, LPS infusion in murine models has been shown to induce changes in insulin sensitivity and glucose metabolism, further linking inflammatory mechanisms to the development of insulin resistance.
Hypoglycemia in individuals with type 1 diabetes (T1DM) can impair cognitive function and driving performance, even at mild levels of 3.4–3.8 mmol/L, leading to issues such as poor road positioning, inappropriate braking, and increased crash risk. Performance deteriorates further as glucose levels drop, yet most individuals do not experience symptoms or recognize their impaired competence, and only one-third treat the hypoglycemia when levels fall below 2.8 mmol/L. In the UK, driving restrictions are based on insulin use rather than diabetes type, as insulin therapy carries a risk of hypoglycemia. This risk also increases with the duration of insulin treatment in type 2 diabetes (T2DM).
In both type 1 and type 2 diabetes, the progression of chronic kidney disease (CKD) is slower in individuals without significant albuminuria compared to those with albuminuria. Additionally, low estimated glomerular filtration rate (eGFR) and albuminuria together increase the risk of end-stage kidney disease (ESKD).
The diagnosis of diabetes is often prompted by symptoms such as thirst, polyuria, weight loss, recurrent infections, and in severe cases, precoma. A single elevated casual plasma glucose value can confirm the diagnosis, with a venous plasma glucose level above 11.1 mmol/L (200 mg/dL) or a capillary plasma level above 12.2 mmol/L (220 mg/dL) being diagnostic. Values between 5.0 and 11.0 mmol/L are considered uncertain by the WHO, necessitating further testing.
Islet autoantibodies are not directly involved in β-cell destruction but serve as biomarkers for identifying individuals at high risk for type 1 diabetes, with their presence detectable years before clinical onset. The number of islet autoantibodies correlates with the likelihood of progressing to diabetes, as demonstrated in longitudinal studies of first-degree relatives: individuals with no islet autoantibodies had a 0.4% risk of progression at 10 years, those with a single islet autoantibody had a 14.5% risk, and those with multiple islet autoantibodies had a 69.7% risk. These findings have enabled the initiation of therapeutic intervention trials aimed at preventing or delaying the onset of type 1 diabetes.
People with diabetes are at an increased risk for several types of cancer, including liver, pancreatic, endometrial, breast, colorectal, bladder, stomach, kidney, and non-Hodgkin's lymphoma, with risk increases ranging from 20-40%. Endometrial cancer risk is doubled in women with diabetes, and there is also elevated risk for gallbladder, lung, ovarian, thyroid cancers, multiple myeloma, and leukaemia. However, diabetes appears to have a protective effect against prostate cancer, reducing the risk by approximately 10-15%, possibly due to lower endogenous testosterone levels in men with type 2 diabetes. Obesity is considered a key factor contributing to the increased cancer risk in people with diabetes. Some associations, particularly with liver and pancreatic cancers, may be influenced by reverse causality, where the cancer itself contributes to the onset of type 2 diabetes.
Poor appetite, reduced meal size, and swallowing difficulties can affect glycaemic levels and may lead to hypoglycaemia in individuals with type 2 diabetes, particularly those on multiple oral anti-diabetes medications, which can be difficult to swallow. In such cases, simplifying treatment regimens and reviewing medications is recommended. Adjustments to diabetes therapy may also be needed to manage hyperglycaemic symptoms, especially if glucose-rich foods are no longer avoided. Dietary restrictions aimed at minimizing weight gain and stabilizing glucose levels can be relaxed, and individuals with diabetes may be offered their preferred foods to encourage eating.
In type 1 diabetes mellitus (T1DM), severe defects in endogenous insulin secretion lead to impaired glycemic control, which can be exacerbated by the normal diurnal variation in plasma cortisol levels. Cortisol contributes to hyperglycemia by increasing endogenous glucose production and reducing tissue glucose uptake. Additionally, the nocturnal rise in cortisol promotes ketone body formation, gluconeogenesis, and lipolysis, further complicating glucose regulation in individuals with T1DM.
Hypoglycaemia is a common and potentially serious adverse effect of sulfonylurea therapy in diabetes treatment, with approximately 20% of sulfonylurea-treated participants in the UKPDS reporting one or more episodes of hypoglycaemic symptoms annually, and around 1% experiencing severe hypoglycaemia requiring third-party assistance each year. Longer-acting sulfonylureas, irregular meals, combination with other glucose-lowering drugs—especially insulin—excessive alcohol consumption, already near-normal fasting glycaemia, old age, and interacting drugs can increase the risk of hypoglycaemia, which, although rarely life-threatening in type 2 diabetes, can impair neural or motor function, endangering the individual and others, and may lead to a poor prognosis after a myocardial infarction, with mortality risk from sulfonylurea-induced hypoglycaemia reported at 0.014–0.033 per 1000 patient-years.
Tolbutamide, phenformin, and insulin were evaluated in the University Group Diabetes Program (UGDP), an early randomized controlled trial for treating maturity-onset diabetes, which controversially found higher mortality rates with oral agents compared to placebo and no significant benefit from insulin use. The UGDP study was criticized for flawed randomization, particularly regarding pre-existing conditions like myocardial infarction, making its conclusions unreliable. These findings led some to question the value of treating maturity-onset diabetes until the UK Prospective Diabetes Study (UKPDS) provided more definitive evidence supporting the importance of treatment. Subsequent cardiovascular outcome trials have further explored the effects of various pharmacological agents in diabetes management.
Individuals with type 2 diabetes mellitus (T2DM) who also have gout may face challenges in managing their condition, as poorly controlled gout can impede exercise and weight loss efforts. These patients must adhere to dietary restrictions not only for glycemic control but also to avoid alcohol and purine-rich foods. Diuretic therapy should be avoided due to its potential to worsen hyperuricemia, unless absolutely necessary. Certain medications like losartan and fenofibrate offer weak urate-lowering effects and may be beneficial for patients with both diabetes and gout when antihypertensive or lipid-lowering treatment is needed.
Improving glucose levels also reduces blood pressure, body weight, uric acid, and the risks of kidney and heart failure. Current clinical guidelines recommend monitoring and optimizing multiple cardiovascular risk factors in people with type 2 diabetes and using GLP-1 RA and SGLT-2 inhibitors alongside metformin. However, many individuals with diabetes still experience cardiovascular and kidney diseases despite treatment with these newer agents, as shown in clinical trials where the risk of cardiovascular outcomes, heart failure hospitalizations, and kidney failure remains high. Part of this suboptimal protection is due to an insufficient response to current drugs; for instance, about 35% of individuals do not show a reduction in HbA₁c with metformin, and a similar percentage show no blood pressure reduction with ACE inhibitors or ARBs. This variability in response extends to other diabetes-related medications as well.
In type 2 diabetes mellitus (T2DM), statins have more modest effects on atherogenic dyslipidemia, reducing triglycerides by up to 15–30% and increasing HDL cholesterol by less than 10%. There is no clear consensus on the benefits of directly targeting hypertriglyceridemia, and since interventions often affect both triglycerides and HDL cholesterol, it is difficult to determine the individual benefits of each.
sRAGE has been shown to have therapeutic value in diabetes-associated atherosclerosis in a streptozotocin diabetic ApoE KO mouse model, where it suppressed atherosclerosis in a dose-dependent manner and reduced plaque complexity independently of glucose or lipid levels. It also suppressed AGE levels in diabetic mice to those comparable to non-diabetic mice, and RAGE blockade with sRAGE reduced inflammatory cell infiltration as well as gene expression of TGF-β, fibronectin, and type IV collagen in the aorta and kidney, leading to a reduction in plaque area, indicating that RAGE activation contributes to both lesion formation and progression of atherosclerosis in diabetes.
Men with diabetes usually require the maximum recommended dose of PDE 5 inhibitors, as these medications only work in conjunction with sexual stimulation and may have varying durations of effectiveness depending on the specific drug used.
In type 2 diabetes, cardiovascular disease risk is increased 2- to 4-fold with moderately increased albuminuria and 9-fold with severely increased albuminuria, and this risk rises exponentially once serum creatinine levels become abnormal, with median survival from initiation of kidney replacement therapy being 2.16 years.
Amylin affects glucose metabolism by causing insulin resistance in rat skeletal muscle when administered in pharmacologic doses, an effect achieved through inhibition of glycogen synthase activity and enhancement of glycogen breakdown, leading to increased lactate release. The role of amylin in insulin secretion remains unclear and is a subject of controversy.
The chromosome 1q21-25 region, particularly a 30Mb stretch adjacent to the centromere, has shown strong replicated evidence for genome-wide linkage to type 2 diabetes mellitus (T2DM) across multiple populations, including European, East Asian, and Native American groups. This region is gene-rich and contains several biologically plausible candidate genes such as USF1, LMNA1, PBX1, ATF6, and DUSP12, some of which are involved in pancreatic development and function. Efforts to identify causal variants in this region include high-density LD mapping and plans for deep resequencing focusing on exons and conserved sequences.
Performing a 75 g oral glucose tolerance test (OGTT) with plasma glucose measurements at fasting, 1 hour, and 2 hours during weeks 24–28 of gestation is recommended for diagnosing gestational diabetes, with the test conducted in the morning after an overnight fast of at least 8 hours.
Type 1 diabetes incidence among children varies significantly across the world, with higher rates observed in Nordic countries and Kuwait, and lower rates in Southeast Asia and parts of South America. Between 1990 and 1999, the age-adjusted incidence rate ranged from 0.11 per 100,000 per year in Zunyi (China) and Caracas (Venezuela) to 37.8 in Sardinia and 40.9 in Finland. More recent data from 2006 indicates the highest recorded incidence of childhood-onset type 1 diabetes was approximately 60 per 100,000 in Finland.
Blood glucose measurement requires careful handling to ensure accuracy, as red blood cells continue glycolysis after collection, a process enhanced by leucocytosis. To minimize glycolysis, samples should ideally be collected on ice, centrifuged rapidly, and analyzed within 30 minutes, though this is often impractical in routine clinical practice. Sodium fluoride in blood collection tubes can inhibit further glucose metabolism, but there is still a potential loss of up to 15% of glucose within the first two hours after collection. Additionally, when an intravenous line is present, blood should be drawn from the opposite arm to prevent contamination from infusions, highlighting important considerations for accurate diabetes diagnosis and management.
Too stringent glycemic control in women with gestational diabetes mellitus (GDM) may be harmful, as a prospective study showed that maintaining mean blood glucose levels below 4.8 mmol/L led to a twofold higher incidence of small for gestational age infants compared to a control group without diabetes, while allowing levels above 5.8 mmol/L resulted in a similar increase in large for gestational age infants, suggesting that targeting a moderate range of 4.8–5.8 mmol/L helps achieve outcomes comparable to those in non-diabetic pregnancies.
In-hospital hypoglycaemia can be caused by various factors including excessive insulin administration, delayed or missed meals, increased physical activity without adequate carbohydrate intake, renal dysfunction leading to reduced insulin clearance, and certain medications that potentiate insulin action or impair glucose metabolism.
Monogenic diabetes is influenced by specific genetic variants, while rare and common variants in pathways related to energy metabolism, such as amylin and mitochondrial pathways, may also play a role in diabetes presentation. These genetic factors can contribute to either type 1 diabetes or type 2 diabetes, depending on the presence of other familial and non-familial factors, leading to a unique individual profile that supports the concept of precision care in diabetes management.
Hypoglycemia in diabetes is defined as blood glucose below 50 mg/dL and may present with neuroglycopenic symptoms such as coma, seizures, disorientation, unstable motor coordination, or dysphasia. Treatment of hypoglycemia may not result in prompt recovery of sensorium, particularly when the condition is severe or prolonged. Situations where hypoglycemia has been treated but a responsible person cannot remain with the patient for the ensuing 12 hours require special attention. Hypoglycemia caused by sulphonylureas or insulin use necessitates careful management due to the risk of recurrent or prolonged low blood glucose levels.
Pioglitazone and rosiglitazone are agents used in the management of diabetes, with dose ranges of 15–45 mg/day and 4–8 mg/day respectively, both having a duration of action of approximately 24 hours. Pioglitazone has active metabolites and is primarily eliminated through bile, while rosiglitazone has inactive metabolites and is mainly excreted in urine.
The incidence of diabetes among 15-29-year-olds in Finland from 1992 to 2001 was reported at 18 per 100,000 per year, while more recent data from Norway during 2006-2010 indicated a stable incidence rate exceeding 30 per 100,000 per year among individuals aged 5-29 years who were new users of insulin and not other anti-diabetes drugs. Challenges in accurately classifying the type of diabetes in adults and potential incomplete ascertainment may affect data reliability, particularly for young adults compared to children, though insulin use data are less likely to suffer from such issues. Incidence differences between countries among young adults should be interpreted cautiously until more standardized data are available.
Women with diabetes, particularly type 1 diabetes, may use oral contraceptive pills (OCPs), though there is a tendency for healthcare providers to prescribe the combined OCP less frequently to these women compared to those without diabetes. Progesterone-only and depot hormonal contraceptives are relatively more popular in women with diabetes. Concerns about the safety of hormonal contraception in women with diabetes include potential adverse effects on glucose metabolism and an increased risk of thromboembolic disease, although these concerns are largely unfounded. Evidence suggests that OCPs, especially those with lower doses of estrogen, have limited effects on carbohydrate tolerance and do not significantly increase cardiovascular risk markers, microvascular complications, or worsen metabolic control in women with type 1 diabetes.
Glucagon plays a critical role in maintaining normal fasting glucose levels, and its absence can lead to hypoglycaemia when insulin is replaced without it. Hepatic glucose production is regulated by both glucagon and insulin, with glucagon promoting glycogenolysis and gluconeogenesis during fasting, while insulin modulates hepatic glucose output. At blood glucose levels of 4.5–5.5 mmol/l, glucagon levels remain low and stable, but insulin secretion adjusts in response to changes in glycaemia, indicating that insulin is more directly involved in fine-tuning glucose homeostasis within this range. The interaction between glucagon and insulin at the hepatic level involves cAMP or other signalling pathways, where glucagon sets a baseline activity that insulin can modulate.
High prevalence rates of diabetes are observed in Polynesian populations, particularly in women, and are closely linked with obesity. In Western Samoa, the prevalence of diabetes in 1991 was 7–9% in rural communities and 16% in Apia, representing a doubling since 1978. In Tonga, the age-standardized prevalence of diabetes was 15.1%, with 80% of cases remaining undiagnosed.
α-glucosidase inhibitors are used in diabetes management and have several beneficial features: they do not cause weight gain or frank hypoglycaemia, and they may reduce inter-prandial episodes of hypoglycaemia. These inhibitors can reduce post-prandial hyperinsulinaemia when combined with other anti-diabetes agents and often lower plasma triglyceride concentrations. They can cause minor alterations in the intestinal absorption of other oral glucose-lowering agents when used in combination therapy but generally provide additive efficacy when used with any other class of glucose-lowering agent. Despite the association between post-prandial hyperglycaemia and cardiovascular risk, a five-year study in individuals with coronary heart disease and impaired glucose tolerance (IGT) found no effect of acarbose, an α-glucosidase inhibitor, on major adverse cardiovascular events.
Blood glucose-lowering agents used in diabetes management are categorized as hypoglycemic or antihyperglycemic. Hypoglycemic agents can lower blood glucose below the normal range, posing a risk of clinical hypoglycemia, and include drugs that inhibit hepatic glucose output, insulin secretagogues active at low glucose concentrations, potent insulin-mimetic drugs, and agents that impair counter-regulatory mechanisms. In contrast, antihyperglycemic agents do not lower blood glucose below the euglycemic range when used alone. Additionally, β-adrenoceptor blockers typically raise glucose levels but can contribute to hypoglycemia by inhibiting the acute counter-regulatory response and reducing hypoglycemia awareness.
Prepregnancy care is particularly important for women with type 1 diabetes, as achieving recommended glycaemic targets can be challenging and many women are unable to meet them. Coordinated prepregnancy and pregnancy care improves outcomes, yet not all women attend, especially younger women without third-level education or those not married or in a relationship. Common reasons for not attending include unplanned pregnancies, fertility concerns, negative interactions with healthcare professionals, complex emotional issues such as fear of disappointment and the desire for a normal pregnancy, and logistical or financial barriers. Awareness of the importance of prepregnancy care has increased even among those who do not attend.
IGT (Impaired Glucose Tolerance), IFG (Impaired Fasting Glucose), and GDM (Gestational Diabetes Mellitus) are conditions related to diabetes. IGT refers to higher than normal blood glucose levels following an oral glucose tolerance test, while IFG indicates elevated blood glucose levels during fasting. GDM is a form of diabetes that develops during pregnancy, typically resolving after childbirth but increasing the risk of developing type 2 diabetes later in life.
The rapid increase in diabetes prevalence in China is likely linked to rising obesity rates, particularly among children and adolescents. National data from 2002 showed that 4.1% of children aged 7–12 years and 5.6% of those aged 12–18 years were overweight, with obesity rates at 2.5% and 1.6%, respectively. In Hong Kong, a study of over 2000 adolescents aged 11–18 years found that 8–10% of those aged 12–13 years were obese. Additionally, a national screening program in Taiwan between 1992 and 1999 reported a rate of newly identified diabetes at 9.0 per 100,000 schoolchildren.
The progression of type 1 diabetes is influenced by the order in which islet autoantibodies appear, with IAA-first and GADA-first presentations showing different risks of progressing to diabetes. In a cohort of over 24,000 individuals, 2172 were autoantibody positive with at least two follow-up visits, and 652 progressed to type 1 diabetes over 15 years. Analysis using continuous-time hidden Markov models identified three distinct trajectories: TR1 (multiple islet autoantibodies at first sample) had only 40% diabetes-free survival after 5 years, TR2 (IAA-first) had 62% diabetes-free survival, and TR3 (GADA-first) had 88% diabetes-free survival. Progression rates within each trajectory can be further refined by age, sex, and HLA-DR, offering a clinically useful prediction of disease onset. These findings suggest that the sequence of autoantibody appearance is linked to disease progression and may be used for individualized risk assessment with the support of machine learning and artificial intelligence.
Individuals with early type 2 diabetes identified through screening often differ from those presenting with symptoms, as they are less likely to have developed microvascular or macrovascular complications. These individuals may have varying attitudes toward health and may not perceive the diagnosis as significant or urgent since it does not necessarily relieve symptoms. They may also be less compliant with lifestyle recommendations such as weight management, diet, and physical activity compared to those with symptomatic diabetes. Due to these factors, a more sensitive and careful approach is needed when discussing the importance of future management, along with appropriate follow-up by the diabetes care team.
Individuals with type 2 diabetes mellitus (T2DM) who carry risk alleles in the genes TCF7L2, PPARG, and KCNJ11 have a significantly increased risk of developing the disease, with a reported 5.71-fold higher odds compared to those without these risk alleles. Additionally, in a separate study conducted in a French population, individuals with at least 18 risk alleles had a notable association with T2DM, even after adjusting for age, BMI, and gender.
Diabetes is a spectrum of disorders that includes type 1 diabetes and type 2 diabetes, with other forms such as maturity onset diabetes of the young (MODY) and latent autoimmune diabetes in adults (LADA) existing as intermediates. Type 2 diabetes, a complex disease, is characterized by impaired insulin secretion, insulin resistance, or both, and arises from the interaction of genetic, epigenetic, and environmental factors. The genetic architecture of type 2 diabetes involves a combination of common single-nucleotide polymorphisms (SNPs), protective and rare variants, parent of-origin effects, structural polymorphisms, and microRNAs, further influenced by gene-gene and gene-environment interactions as well as epigenetic mechanisms. Genome-wide association studies (GWAS) and next-generation sequencing have identified over 1000 genetic variants related to type 2 diabetes risk and diabetes-related traits, though the SNPs currently reported account for less than 20% of the disease's heritability. The CAPN10 gene on chromosome 10, encoding calpain 10, was the first type 2 diabetes susceptibility gene identified through linkage studies, while variants in TCF7L2 have been successfully linked to type 2 diabetes, although they do not account for the entire genetic linkage signal.
Insulin secretion by $\beta$-cells is primarily determined by circulating levels of glucose and other nutrients such as amino acids and fatty acids, which initiate an insulin secretory response to enable nutrient uptake and metabolism by target tissues. After nutrient absorption, $\beta$-cells detect the resulting decrease in circulating nutrients and reduce insulin secretion to prevent hypoglycemia. This process is regulated by mechanisms that coordinate afferent information and ensure appropriate insulin release. In normoglycemic conditions, hormones and neurotransmitters have little effect on insulin secretion, helping to maintain stable blood glucose levels.
Patients with diabetes who have late complications such as nephropathy are at increased risk of foot ulcers, particularly those who have recently started dialysis for end-stage renal disease. Additionally, patients with renal transplants, and especially those with combined pancreas-renal transplants, remain at high risk of ulceration even if they are normoglycemic due to the pancreas transplant.
Chronic high consumption of alcohol can lead to secondary diabetes due to its toxic effect on the pancreas, causing acute and chronic pancreatitis. Approximately 45% of chronic pancreatitis cases are complicated by diabetes. Insulin treatment is typically needed to manage hyperglycemia in these patients, although diabetic ketoacidosis is rare, possibly because pancreatic damage also affects glucagon-secreting α-cells, which play a key role in ketogenesis. However, a heavy alcoholic binge combined with low food intake can result in alcoholic ketoacidosis.
Patients with diabetes may experience various bone and joint disorders, which can lead to complications such as diabetic arthropathy, osteoporosis, and Charcot joint, often resulting from neuropathy, vascular disease, and metabolic disturbances associated with diabetes.
Gaps in diabetes care or loss to follow-up lead to elevated HbA1c and glucose variability, increasing the risk of short-term complications such as severe hypoglycaemia or hyperglycaemia, which can result in emergency room visits or hospitalization. Persistent hyperglycaemia also raises the risk of long-term microvascular and macrovascular complications. Transition from paediatric to adult care should involve discussions about chronic diabetes complications, pregnancy planning, and routine screening for early signs of kidney and eye issues, as well as risk factors for macrovascular complications, to prevent young adults from avoiding follow-up care due to being unprepared for such discussions.
Improving diabetes care requires attention to the well-being of healthcare providers, as emphasized by nurses in a Cape Town informal settlement who highlighted the importance of "caring for the carers." Effective diabetes management is influenced by the relationship between health workers and managers, as well as the organizational culture, which should align with values of empowerment and support. When healthcare systems operate in a mechanistic and bureaucratic manner, treating staff as replaceable resources, it undermines the ability of health workers to motivate patients and provide compassionate care. For health workers to effectively support patients in healthy living and behavior change, the organization must reflect congruence between individual values and its culture and structures. A supportive organizational environment that nurtures staff enables them to better care for patients with diabetes.
Dexamethasone, commonly used in the treatment of cancer and Covid-19, can cause hyperglycaemia in individuals throughout the 24-hour period.
Insulin resistance impairs nitric oxide (NO) production through the PI3K signaling pathway, which in turn reduces the protective effects of NO against LDL oxidation and vascular smooth muscle cell (VSMC) proliferation. In contrast, hyperinsulinemia enhances VSMC proliferation and migration via the Ras/Raf/MEKK/MAPK pathway, contributing to a pro-atherogenic effect of insulin. IL-6 decreases insulin-stimulated NO production in endothelial cells by reducing insulin signaling activity through increased TNF-α production, while it enhances insulin-stimulated glucose uptake in skeletal muscle and adipose tissue without increasing TNF-α expression in these tissues.
Tight blood pressure control, with an achieved blood pressure of approximately 140/80 mmHg, reduces the risk of microalbuminuria in type 2 diabetes mellitus (T2DM), and many guidelines recommend a blood pressure target of 130/80 mmHg for individuals with T2DM to prevent cardiovascular events, although renal outcome studies have shown benefits at around 140/80 mmHg. While first-line therapy with RAS inhibitors may be most effective, achieving sufficient blood pressure reduction is more important than the specific class of first-line agent used.
GLP-1 receptor agonists (GLP-1RAs) have been shown to reduce the risk of hospitalization for heart failure and demonstrate a significant effect on individual components of major adverse cardiovascular events, including cardiovascular death, fatal or non-fatal myocardial infarction, and fatal or non-fatal stroke, as revealed by a meta-analysis of cardiovascular outcome trials involving over 60,000 individuals.
Glucose at concentrations as low as 1–6 mmol/L can stimulate insulin secretion even when $\mathrm{K_{ATP}}$ channels are maintained in the open state by diazoxide, indicating a $\mathrm{K_{ATP}}$-independent mechanism. While the exact mechanisms are not fully established, it is known that glucose must be metabolized and changes in adenine nucleotides are involved in this pathway. Activation of PKA and PKC is not required for this process. The $\mathrm{K_{ATP}}$-independent amplifying pathway has been suggested to be impaired in type 2 diabetes, and targeting this pathway with novel therapeutic strategies may help restore β-cell function in patients with the condition.
Thiazide diuretics can cause altered carbohydrate and lipid metabolism, hyperinsulinemia, hypokalemia, hypomagnesemia, hyperuricemia, and ventricular ectopics, although these side effects are minimal at usual doses. These medications reduce plasma volume, which is relevant in diabetes as plasma volume expansion is a pathogenic mechanism in hypertension associated with diabetes. Excessive reduction in plasma volume may lead to postural hypotension.
Innovative strategies for diabetes care, such as technology-mediated communication between patients and the diabetes care team, are being introduced in high-resource settings, though their cost-effectiveness and patient willingness to pay remain key considerations. Factors such as a patient's age and educational background may influence their ability to use such IT-based systems. In low-resource settings, the application of IT in diabetes management is limited due to lack of Internet access, unfamiliarity with computers among healthcare workers, and insufficient infrastructure in primary care settings. Patients from poorer backgrounds are also unlikely to have Internet access, further restricting the reach of technology-based diabetes care solutions.
In diabetic vascular cells, glucose is not the preferred substrate for aldose reductase due to the enzyme's high Michaelis constant (Km) for glucose, which is 100 mmol/L, whereas the intracellular concentration of glucose in the diabetic retina is only 0.15 mmol/L. Instead, glycolytic metabolites of glucose such as glyceraldehyde-3-phosphate, which have a higher affinity for aldose reductase, may serve as the physiologically relevant substrate in this context.
Hyperinsulinaemia has been identified as a potential predictor of future type 2 diabetes development despite being associated with normal glucose tolerance and normal insulin sensitivity. The presence of hyperinsulinaemia in these individuals suggests it may serve as a biomarker for reduced glucose effectiveness, a condition linked to the future onset of type 2 diabetes. This paradoxical relationship raises questions about the underlying mechanisms, particularly whether hyperinsulinaemia indicates impaired glucose effectiveness. Additionally, considering the brain's role in regulating glucose effectiveness, it is proposed that a brain-related defect might contribute to reduced glucose effectiveness and the accompanying hyperinsulinaemia in the progression of type 2 diabetes. Further research is needed to determine if hyperinsulinaemia is indeed a reliable biomarker for reduced glucose effectiveness and to explore the potential involvement of brain dysfunction in the pathogenesis of type 2 diabetes.
Acute painful neuropathy occurs in both type 1 and type 2 diabetes and is characterized by continuous burning pain, often described as walking on burning sand, with nocturnal exacerbation. It typically presents with positive sensory symptoms such as allodynia and hyperalgesia, and is commonly associated with erectile dysfunction and depression. Motor function is generally preserved, and there is little sensory loss. Severe weight loss, known as diabetic cachexia, may precede its onset, and this weight loss improves with better glycemic control. Severe manifestations usually subside within 10–12 months without recurrence over six years of follow-up.
Diabetic gastroparesis diagnosis is complicated by the frequent use of opioids for abdominal pain, with studies showing that among individuals with gastroparesis, those using opioids—particularly potent ones like morphine—experience worse symptoms, greater gastric retention, lower quality of life, and higher hospitalization rates compared to non-users or those on weaker opioids. Opioids contribute to delayed gastric emptying through mechanisms such as antral hypomotility and pylorospasm, and it has been suggested that a trial with a peripherally active mu-opioid receptor antagonist may help distinguish the effects of opioids from those of the underlying disease.
Agents that activate glucokinase (GK) are being studied for their potential to stimulate insulin secretion by increasing glucose metabolism in pancreatic β-cells, but this approach can cause hypoglycaemia and often loses effectiveness over time in type 2 diabetes. Glucokinase is also present in the liver, where it is regulated differently, and hepato-selective GK activators are being explored to enhance post-prandial glucose uptake without inducing hypoglycaemia; however, this strategy may lead to excessive glycogen storage and increased lipogenesis in the liver.
Exercise interventions, including aerobic, resistance, and combined exercise training, improve glycemic control in individuals with type 2 diabetes mellitus (T2DM), with combined exercise showing significantly greater benefits compared to either aerobic or resistance exercise alone when performed three times per week under supervised conditions. However, smaller studies with less controlled dietary and medication variables and lower statistical power may not show significant differences between exercise types.
A foot lesion can be a presenting sign of diabetes, with the lifetime risk of developing a foot ulcer in people with diabetes estimated to be as high as 25%. Presentation with a black toe is particularly associated with type 2 diabetes mellitus (T2DM). Peripheral neuropathy in diabetes leads to sensory, motor, and autonomic dysfunction, resulting in loss of protective pain sensation, dry skin, and callus formation. The loss of pain sensation in the feet often goes unnoticed, and injuries may not be recognized until significant damage occurs. Approximately half of patients with foot ulcers also have concomitant peripheral arterial disease (PAD). Foot ulcers accompanied by PAD are associated with lower healing rates, higher major amputation rates, and increased mortality, as observed in the EURODIALE study.
Aggressive management of modifiable cardiovascular disease (CVD) risk factors in patients with type 2 diabetes mellitus (T2DM) and microalbuminuria, as demonstrated in the Steno-2 study, leads to a significant reduction in CVD events and a lower risk of developing proteinuria (relative risk 0.39 [0.17–0.87]). While individual interventions such as smoking cessation, lipid control, and aspirin use have not been well studied in diabetic kidney disease, the combined approach to risk factor modification shows clear benefits despite challenges in achieving strict treatment targets.
In women with diabetes, intrauterine contraceptive devices (IUDs) are considered safe and effective. Initial concerns regarding an increased risk of pelvic inflammatory disease (PID) in women with diabetes have been largely disproven, with studies showing no elevated risk of PID in those with type 1 or type 2 diabetes. Additionally, earlier claims of higher IUD failure rates in diabetic women have not been supported by research.
Antibodies against exogenous insulin are distinct from IAA levels at the clinical onset of T1DM and are not linked to autoimmunity, yet they share some binding characteristics. These antibodies have higher specificity compared to IAA and can be detected using the ELISA test, which is not predictive for T1DM. In contrast, the IAA fluid-phase radioimmunoassay offers high sensitivity and specificity for detecting T1DM and has been adapted to require a smaller serum volume, using 25μL instead of 600μL.
Growth factors such as platelet-derived growth factor (PDGF) and epidermal growth factor have been explored for their potential to modify biochemical abnormalities in wound healing, particularly in neuropathic ulcers associated with diabetes. While some randomized clinical studies suggest support for their use, the high cost and the observation that most neuropathic ulcers can heal with appropriate offloading limit the routine application of these agents. The evidence for their effectiveness in daily clinical practice remains insufficient.
Health care providers play a key role in equipping individuals with diabetes with self-management knowledge and skills, individualizing medical and behavioral regimens, supporting informed decision-making, and offering social and emotional support through a collaborative relationship. Physician inertia, or the failure to adjust patient management in response to abnormal clinical results, is a significant issue in diabetes care. Studies have shown delays in treatment escalation for patients with elevated HbA1c levels, such as an average delay of 15 months for those on metformin and 21 months for those on sulfonylurea monotherapy. Despite the complexity and rapid advancements in diabetes management, many generalists do not perceive the need for additional training in diabetes care, and the involvement of non-medical healthcare professionals is sometimes not accepted in traditional settings.
Type 2 diabetes mellitus (T2DM) is a global epidemic with a prevalence of 285 million people in 2009, projected to rise to 435 million by 2030. In the USA, nearly 24 million people had diabetes in 2007, mostly cases of T2DM, with at least 57 million individuals having pre-diabetes, a condition marked by impaired fasting glucose or impaired glucose tolerance. The prevalence of diabetes has increased by 90% over the last decade, with even faster growth observed in many regions worldwide. The rising incidence is linked to both environmental and genetic factors that affect insulin sensitivity and insulin secretion. Insulin resistance, often initiated in early life, is exacerbated by obesity and sedentary lifestyles, leading to disruptions in glucose homeostasis and abnormalities in lipid and protein metabolism, with relative insulin deficiency being the key metabolic distinction between obesity and the onset of hyperglycemia.
Some screening tools for eating disorders have not been validated for use with people with diabetes and may include items influenced by diabetes management, such as avoiding foods with sugar, which can lead to inaccurate assessments. Direct and sensitive questions about eating habits, attitudes toward food, concerns about body weight, and methods of weight control are important when evaluating individuals with diabetes for potential eating disorders.
Raised insulin levels may act on insulin-like growth factor I (IGF-I) receptors in the skin to cause epidermal overgrowth, suggesting a link between insulin resistance and hyperinsulinaemia with acanthosis nigricans, while similar effects in the ovary could contribute to polycystic ovary disease, which is associated with insulin-resistant states.
Tight glycaemic management may prevent the progression of diabetic neuropathy, but improved glycaemic levels do not necessarily relieve pain in diabetic sensorimotor polyneuropathy. Pain relief outcomes are categorized such that 30–50% relief is considered moderately effective, while over 50% is considered a good outcome. Certain medications including duloxetine, venlafaxine, pregabalin, oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin have been found to be more effective than placebo in relieving neuropathic pain.
Excessive insulin administration can occur due to errors by a person with diabetes, a doctor, or a pharmacist, or may result from a deliberate overdose during a suicide or parasuicide attempt, and excessive sulfonylurea administration can also contribute to hypoglycemia. Unpredictable insulin absorption, which can lead to hypoglycemia, may occur because insulin is absorbed more rapidly from the abdomen, or due to lipohypertrophy, which alters insulin absorption. Altered clearance of insulin, such as decreased insulin clearance in renal failure, can further contribute to hypoglycemia, as can decreased insulin requirement due to missed, small, or delayed meals, alcohol consumption—which inhibits hepatic glucose output—or vomiting, which may occur with gastroparesis, a long-term complication of diabetes. Exercise promotes glucose uptake into muscle and increases the rate of insulin absorption, which can also lead to hypoglycemia, and recurrent hypoglycemia may lead to hypoglycemic unawareness.
Personality traits and psychological factors influence glycaemic control in diabetes, with certain characteristics such as a strong need for achievement and high responsivity to social demands associated with better glycaemia, while opportunism, alienation, poor impulse control, self-destructive tendencies, and interpersonal difficulties are linked to worse glycaemia. Depression, lethargy, distress, disordered eating, anxiety, and family conflict are associated with higher HbA1c levels in type 1 diabetes, and higher neuroticism in type 2 diabetes correlates with improved glycaemic control, possibly due to increased motivation for management. Type D personality, characterized by high negative affect and social inhibition, in type 2 diabetes is associated with more barriers to medication use and less healthy eating and healthcare consultation.
Worldwide, chronic kidney disease (CKD) is a common complication of diabetes, with diabetes being a leading cause of end-stage kidney disease (ESKD). The proportion of individuals starting kidney replacement therapy due to diabetes varies significantly by region, from 13% in China to 66% in Singapore. In the USA, the incidence of ESKD in people with diabetes increased by 50% between 1996 and 2006 but has since stabilized, reaching approximately 180 per million per year in 2018. Over the past decade, the incidence of ESKD has remained stable or declined in those with type 1 diabetes but increased in those with type 2 diabetes, with the majority of diabetic individuals on kidney replacement therapy having type 2 diabetes.
Psychological therapies, particularly cognitive behavioral therapy (CBT), have been studied in individuals with diabetes primarily focusing on anxiety symptoms rather than diagnosed anxiety disorders. These symptoms are often addressed as part of depressive disorders or common mental disorders. A systematic review found that CBT led to a reduction in anxiety symptoms at 3 and 6 months, but not at 12 months, and also resulted in a significant short- and medium-term reduction in HbA1c levels. However, the studies reviewed did not specifically target individuals with diagnosed anxiety disorders or elevated anxiety symptoms.
Anti-diabetes therapy selection is guided by comorbidities and cardiovascular risk in people with type 2 diabetes. SGLT-2 inhibitors are preferred for those with chronic kidney disease due to kidney and cardiovascular protection, and are also prioritized in individuals with heart failure. For those who cannot take SGLT-2 inhibitors, long-acting GLP-1RAs are recommended. Specific GLP-1RAs and SGLT-2 inhibitors are advised for people with established atherosclerotic disease or multiple cardiovascular risk factors, which often include dyslipidaemia, obesity, smoking, age, or hypertension. The cardiovascular benefits of these medications appear independent of their glucose-lowering effect and prior metformin use, making them suitable regardless of baseline HbA1c or metformin therapy status.
The Look AHEAD (Action for Health in Diabetes) study involved 5145 obese individuals with type 2 diabetes and found that an intensive lifestyle intervention did not significantly affect cardiovascular disease (CVD) outcomes over 9.6 years, despite improvements in surrogate markers such as glucose levels, lipids, blood pressure, sleep apnoea, liver fat, kidney disease, and retinopathy, along with a reduced need for diabetes medications. Weight loss trials have also been shown to improve lipids by reducing hepatic steatosis and the production of triglyceride-rich lipoproteins.
Insulin's amino acid sequence was identified in 1955 and its three-dimensional structure in 1969, both discoveries being significant in diabetes research. The complete insulin molecule was synthesized from amino acids in 1965, contributing to diabetes treatment advancements. The insulin precursor, proinsulin, was identified in 1967. In 1950, a bioassay for insulin was developed based on its ability to lower blood glucose in alloxan-diabetic rats, a method later replaced in 1956 by a new approach.
Diabetic pregnancies are associated with an increased rate of preterm birth, with studies showing a significant difference compared to the general maternity population. In one study, 35.8% of births among diabetic women were preterm versus 7.4% overall, and 9.4% were spontaneous preterm births. Another study found 32.2% preterm births among women with type 1 diabetes. Risk factors for spontaneous preterm delivery in diabetic women include preeclampsia, nephropathy, poor glycemic control, and obesity. Steroids like betamethasone or dexamethasone are commonly used to promote fetal lung maturity in at-risk pregnancies, but in women with diabetes, these medications can worsen glycemic control, necessitating increased insulin doses or insulin infusion as part of management.
Thiazolidinediones, DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists are classes of medications used in diabetes management that are unlikely to cause hypoglycaemia due to their mechanisms of action, unless combined with insulin or sulfonylureas. Hypoglycaemia should be considered in any person with diabetes who presents with acute illness, drowsiness, unconsciousness, confusion, aggression, or seizures. In-hospital hypoglycaemia is defined as a blood glucose level of ≤3.9 mmol/L (70 mg/dL) and is a common occurrence, often linked to inadequate awareness and management among healthcare providers.
Several continuous-acting GLP-1RAs, such as liraglutide and semaglutide, have demonstrated effectiveness in reducing major adverse cardiovascular events in individuals with type 2 diabetes and established or high-risk cardiovascular disease, as shown in cardiovascular outcome trials like the LEADER trial and the SUSTAIN 6 trial.
Guidelines for targets related to glycated hemoglobin (HbA₁c) and self-monitoring of blood glucose (SMBG) have been proposed by organizations such as ISPAD and the American Diabetes Association (ADA), as summarized in Table 69.4.
Metabolic memory suggests that hyperglycaemia can harm people with diabetes years before a type 2 diabetes diagnosis, with 25% showing complications at diagnosis, indicating that early detection and strict glycaemic control may help prevent long-term vascular complications. Additionally, glycaemic fluctuations, not captured by HbA1c levels, may influence growth factor and cytokine expression and cause epigenetic changes through mechanisms like histone modification, DNA methylation, and non-protein coding RNAs, which respond to environmental factors such as high blood glucose.
These drugs—rosiglitazone, pioglitazone, and troglitazone—are thiazolidinediones, a class of medications used in the management of type 2 diabetes mellitus. They function primarily by increasing insulin sensitivity in peripheral tissues, particularly in adipose and muscle tissue, thereby improving glucose uptake and reducing hepatic glucose production. These agents are often used as adjuncts to diet and exercise to help control blood glucose levels in patients with type 2 diabetes.
An increase in dietary fibre may help reduce intestinal transit time but should be introduced gradually to avoid excessive flatulence and bloating, which may already be present in people with diabetes. Lactulose can decrease colonic pH and increase osmotic activity to stimulate colonic propulsive activity. Chronic use of anthraquinone laxatives, such as senna, cascara, and aloes, may worsen existing autonomic neuropathy. For severe constipation or obstipation unresponsive to conventional treatment, drugs like bethanechol (a cholinergic agonist) or pyridostigmine (a cholinesterase inhibitor) may be considered to stimulate colonic smooth muscle.
Increased aldose reductase enzyme activity leads to the accumulation of sorbitol and fructose, contributing to diabetic complications, and aldose reductase inhibitors aim to block this polyol pathway. Although these inhibitors have undergone phase III clinical trials, they have not received FDA approval due to concerns over efficacy or toxicity. However, epalrestat is available in Japan and India following the Aldose Reductase Inhibitor-Diabetes Complications Trial, which demonstrated a delay in the progression of diabetic neuropathy over three years in Japanese individuals with mild neuropathy, and ranirestat has also shown significant improvement in similar contexts.
Regular anaerobic exercise training in individuals with type 1 diabetes mellitus (T1DM) may lead to worsening glycemic control, potentially due to irregular schedules of very vigorous exercise, reduced insulin doses, and high carbohydrate intake. Despite improvements in physical fitness and $\dot{V}\mathrm{O}_{2\mathrm{max}}$, individuals with T1DM may not experience increased insulin sensitivity but instead may show enhanced use of non-esterified fatty acids as a fuel source.
Improving glycaemic control before pregnancy and early in the first trimester reduces the risk of congenital anomalies and lowers perinatal mortality. Pre-pregnancy care has been shown to significantly decrease the risk of congenital malformations with a relative risk (RR) of 0.25 and a number needed to treat (NNT) of 19, as well as reduce perinatal mortality with an RR of 0.34 and an NNT of 46. Benefits are associated with any improvement in HbA1c levels, though achieving an average reduction of 13 mmol/mol (1.2%) in HbA1c increases the risk of hypoglycaemia during the first trimester, with an RR of 1.51.
Sulfonylureas are medications used to lower blood glucose levels in diabetes, and their hypoglycemic effect can be enhanced by drugs such as azaproprazone, phenylbutazone, salicylates, probenecid, sulfonamides, clarithromycin, nicoumalone, and antifungal agents like fluconazole, ketoconazole, miconazole, and voriconazole. Conversely, the hypoglycemic effect of sulfonylureas may be reduced by rifampicin and chlorpromazine.
Diabetes is strongly related to family functioning, particularly in children and adolescents, with low family conflict, good communication, cohesion, and marital satisfaction associated with better diabetes control. Adherence or self-care behaviors such as taking medication, following a diet, monitoring glucose, and engaging in exercise are only weakly linked to diabetic control, which may be due to inaccuracies in self-reported behavior. For individuals who are seriously non-compliant, psychological interventions like psychotherapy, family therapy, and patient empowerment programs can help improve goal-setting, problem-solving, coping, stress management, and self-motivation. Mental health professionals, including psychologists, should be part of the diabetes care team.
Acute metabolic complications, such as diabetic ketoacidosis and severe hypoglycaemia, are the most common causes of death in adults with type 1 diabetes under the age of 30 years, with diabetic ketoacidosis being more prevalent. Drug abuse is a significant risk factor, increasing the likelihood of death from acute complications nearly sixfold, and more than 50% of young adults presenting with diabetic ketoacidosis report recreational drug use, although only 20% disclose it initially. Substance abuse, particularly when co-occurring with mental illness, is associated with high mortality in young people with type 1 diabetes, and there is limited data on the effects of new psychoactive drugs on diabetes.
In individuals with diabetes and lower-extremity arterial disease, the combination of low-dose aspirin (100 mg daily) and low-dose rivaroxaban (2.5 mg twice daily) significantly reduces major limb events, as demonstrated in a subgroup analysis of the COMPASS trial.
Sulfonylureas, specifically glibenclamide, cross the placenta and reach concentrations in umbilical cord plasma that are 50–70% of maternal levels. Glibenclamide use during pregnancy has been associated with higher rates of neonatal hypoglycaemia and macrosomia compared to insulin or metformin, and it has also failed a non-inferiority test against insulin based on a composite outcome including neonatal hypoglycaemia, macrosomia, and hyperbilirubinaemia. Additionally, glibenclamide failed to provide adequate glycaemic control in 23% of women with gestational diabetes mellitus (GDM), and there are no long-term safety data available for offspring exposed to glibenclamide in utero. No international regulatory body currently approves glibenclamide for use during pregnancy.
The prevalence of type 2 diabetes is increasing worldwide, with approximately 285 million people affected globally in 2010, making it one of the most common non-communicable diseases. This rise is particularly notable in regions experiencing rapid economic development and urbanization, which are linked to a westernized lifestyle that contributes to the disease. Additionally, the aging population, especially the growing proportion of individuals over 65 years old, has significantly increased diabetes prevalence. The age of onset is also decreasing, leading to a higher number of young, working-age individuals developing the condition. Multiple risk factors associated with type 2 diabetes, including those tied to urbanization and lifestyle changes, play a key role in this growing health concern.
Global initiatives such as the United Nations’ Sustainable Development Goals and the WHO’s Global Action Plan for non-communicable diseases (NCDs) incorporate diabetes into broader health agendas, linking it with conditions like cardiovascular diseases, cancers, and chronic respiratory diseases. These initiatives aim to improve access to medicines, achieve universal health coverage, and reduce premature mortality, but they often overlook weaknesses in diabetes care delivery systems. Low- and middle-income countries (LMICs) face particular challenges as their health systems are typically structured to manage acute rather than chronic conditions, complicating efforts to address the rising burden of NCDs alongside existing diabetes populations. The double burden of disease in these regions—where NCDs coexist with communicable diseases—requires tailored health system approaches, though some synergies exist, as certain infectious diseases like HIV/AIDS also require chronic disease management strategies.
Traditional risk factors for diabetes include increasing age, adiposity, physical inactivity, dietary factors, a positive family history, and the presence of other cardiometabolic risk factors, many of which are considered causally linked to the development of the disease. Prevention strategies primarily target modifiable factors such as unhealthy diet and physical inactivity. Research from the Whitehall II study indicates that these traditional modifiable risk factors, when measured over time, account for about half of the social inequalities in the incidence of type 2 diabetes.
Erectile dysfunction is more prevalent in older adults and occurs earlier and more frequently in men with diabetes over 60 years of age, affecting 55–95% of men with diabetes compared to 50% of those without diabetes. It is often overlooked or mistakenly attributed to reduced quality of life or depression. Contributing factors include vasculopathy, autonomic neuropathy, hormonal dysregulation, endothelial dysfunction, psychogenic elements, certain medications such as cimetidine, beta-blockers, and spironolactone, as well as high alcohol consumption.
Aspects of bone strength and quality not measured by DEXA scans may be impaired in individuals with diabetes, potentially contributing to greater bone fragility, though current methods to assess these factors are not well validated. Some studies using high-resolution computed tomography in people with type 2 diabetes have found no significant differences in bone microarchitecture compared to those without diabetes, while one study noted increased cortical bone porosity at the radius. Additionally, microindentation analysis in one study suggested reduced bone mechanical strength in those with type 2 diabetes, but it remains uncertain whether structural or quality-related bone abnormalities are consistently present in diabetes.
Diabetic hand syndrome typically affects individuals over 60 years of age and is characterized by thickening of the skin over the dorsa of the hands and digits, particularly around the proximal interphalangeal joints, known as sclerodactyly. In more severe cases, the skin takes on a tight, waxy appearance with pebbly pads over the knuckles and distal fingers. The interphalangeal joints are especially vulnerable, and involvement of the periarticular connective tissue can lead to painful, stiff fingers. In some instances, the condition progresses to fixed flexion deformities of the fingers and Dupuytren contracture, while thickening of the wrist's soft tissues may compress the median nerve, resulting in carpal tunnel syndrome.
In individuals without diabetes, falling plasma glucose concentrations trigger a series of physiological responses. As glucose levels decline within the postabsorptive range, insulin secretion decreases. When glucose levels drop just below the normal physiologic range, secretion of counter-regulatory hormones such as glucagon and epinephrine increases. Further decreases in plasma glucose provoke a stronger sympathoadrenal response, leading to noticeable symptoms. If glucose levels continue to fall, they can result in functional brain failure.
When initiating continuous subcutaneous insulin infusion (CSII), a flat basal rate of 50% of the total daily dose divided equally over 24 hours is a simple starting point, though it does not account for fluctuating insulin needs. Most individuals with type 1 diabetes require multiple basal rates throughout the day due to variations in insulin requirements, particularly showing increased needs late in the evening and in the early morning, known as the dusk and dawn phenomena. Expert groups recommend using a modified circadian basal profile with 4–5 basal rate segments, adjusting insulin delivery to be higher during early morning and late evening and lower during late night and early afternoon.
Intraperitoneal insulin administration is absorbed more quickly than the subcutaneous route and delivers a major portion of insulin directly into the portal circulation, potentially reducing the risks of high peripheral insulin levels that may contribute to vascular complications of diabetes and the development of obesity. Early studies suggest that intraperitoneal insulin delivery via implantable pumps may achieve better glucose control with less hypoglycemia compared to the subcutaneous route. Experience with intraperitoneal insulin has also been documented in patients undergoing continuous ambulatory peritoneal dialysis, where insulin is administered with dialysis fluid, showing more consistent absorption and lower peripheral insulin levels, although no robust trials have confirmed the superiority of any specific route.
Diabetes care has significantly advanced since the discovery of insulin a century ago, shifting from life-saving measures to optimizing treatment for people with diabetes. Intensive glycaemic management has been shown to reduce the progression of diabetes-related complications in both type 1 diabetes, as demonstrated by the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications studies, and type 2 diabetes, as shown by the UK Prospective Diabetes Study. This evidence has led to the establishment of rigorous glycaemic targets, such as glycated haemoglobin (HbA1c) levels ≤ 7% (53 mmol/mol), which are now recommended for most non-pregnant adults with diabetes. Although the effectiveness of these targets, particularly regarding outcomes like end-stage renal disease, remains debated, optimal glycaemic control is still a key principle in diabetes care. These advancements have altered the disease's natural history and epidemiology, with chronic complications such as nephropathy, neuropathy, and vascular disease becoming more prevalent and prominent in clinical guidelines.
Islet transplantation can correct glycemic lability and recurrent hypoglycemia, offering a technically easier option especially suitable for individuals with glycemic control issues and no major complications, while whole pancreas transplantation, though more technically challenging, provides stable glucose control.
Hyperglycemia in type 2 diabetes is associated with reduced brain glucose uptake, suggesting that metabolic dysfunction in humans may lead to changes in the blood-brain barrier similar to those observed in mice with obesity, where GLUT1 expression is reduced. This implies that impaired glucose transport into the brain via GLUT1 may contribute to altered cerebral glucose metabolism in diabetes.
Osteoprotegerin appears to be a survival factor for endothelial cells and has been associated with vascular calcifications and a pro-atherosclerotic role in the vasculature, particularly in diabetes. Increased circulating osteoprotegerin levels have been observed in experimental diabetes, and microarray studies in human diabetes specimens have shown upregulation of osteoprotegerin mRNA levels in kidney samples. Plasma osteoprotegerin levels correlate with renal dysfunction and cardiovascular disease in both type 1 and type 2 diabetes, and are linked to vascular endothelial dysfunction. In individuals with type 1 diabetes and nephropathy, plasma osteoprotegerin is a strong independent predictor of progression to end-stage renal disease, cardiovascular events, and all-cause mortality.
In individuals with type 2 diabetes mellitus (T2DM), an amlodipine-based antihypertensive regimen demonstrated significant benefits in reducing mortality and cardiovascular events compared to an atenolol-based regimen. This included a 25% reduction in fatal and non-fatal strokes, a 48% decrease in peripheral vascular disease (PVD), and a 57% reduction in non-coronary revascularization procedures.
In women with type 1 diabetes, sexual dysfunction is associated with increased odds of developing cardiovascular autonomic neuropathy, as indicated by a study with an odds ratio of 1.52 (95% CI 0.89 to 2.61), based on a long-term follow-up of the DCCT/EDIC cohort.
Restoration of hypoglycaemia awareness in individuals with diabetes can lead to increased blood flow in neural pathways involved in self-awareness and decision-making, specifically the anterior cingulate cortex, indicating a degree of reversibility in brain responses affected by impaired awareness of hypoglycaemia. However, brain regions responsible for arousal and emotional processing, such as the fronto-thalamic networks, show reduced responsiveness to this restoration. This difference in neural response may explain why some individuals with impaired hypoglycaemia awareness do not fully regain awareness even with interventions like structured education and diabetes technology.
Transfer of the insulin gene can be used to engineer a glucose sensor in skeletal muscle, enhancing glucose uptake in a glucose-dependent manner to lower hyperglycaemia. Skeletal muscle is a suitable target for this strategy because it can efficiently secrete proteins into the bloodstream and has a metabolism highly dependent on glucose consumption, accounting for approximately 70% of glucose disposal after a meal. Additionally, gene transfer to muscle using AAV vectors results in minimal systemic biodistribution, limiting effects to the target organ, and is not hindered by pre-existing neutralizing antibodies against AAV, which are relatively common in the general population.
For an oral glucose tolerance test (OGTT), individuals should consume at least 250g of carbohydrate over 3 days before the test to ensure accurate results, yet this preparation is often not followed. This oversight may lead to a higher number of older individuals showing normal fasting glucose but elevated 2-hour glucose values, potentially indicating "starvation" diabetes rather than true diabetes.
Glucose in diabetes can be monitored using transcutaneous needle sensors that employ an enzymatic method, such as glucose oxidase, to measure glucose levels in the interstitial fluid of subcutaneous fatty tissue. These sensors generate an electrical current proportional to the glucose concentration, with a small background current that can be adjusted as a signal offset. Continuous glucose monitoring (rtCGM) systems typically function for up to 10 days before requiring sensor replacement and transmit average glucose values every five minutes. Some systems are factory calibrated, while others require daily calibration using capillary blood glucose measurements to correct for sensor drift. Certain medications, like paracetamol, may interfere with the accuracy of these glucose measurements.
Person-centred diabetes self-management education and support (DSMES) aims to empower individuals with diabetes to manage glycaemic, lipid, and blood pressure levels to prevent complications, requiring motivation and sustained engagement in challenging behaviours. Healthcare professionals are encouraged to shift from an educator role to a collaborative one, emphasizing autonomy, collaboration, and empowerment. Competencies of diabetes educators involve establishing change-based relationships with patients, where their roles in the relationship define DSMES effectiveness. However, uptake of DSMES is limited, as only 30% of educators in a survey reported self-management education as effective, citing barriers such as time constraints, lack of behaviour change skills among professionals, and perceived disinterest from patients. Effective change-based relationships are key to promoting behaviour change interventions, which can be supported by appropriate tools.
Gestational diabetes (GDM) is a condition in which women without a prior diagnosis of diabetes develop glucose intolerance during pregnancy, with a prevalence ranging from 1% to 14% depending on diagnostic criteria and population. GDM is associated with adverse maternal and fetal outcomes, and women with GDM have an increased risk of developing the condition in subsequent pregnancies and type 2 diabetes. Offspring of mothers with GDM are at high risk of macrosomia and, as adults, are more likely to develop obesity and type 2 diabetes, highlighting the importance of preventing GDM as a clinical priority.
Metformin, a medication used in the management of diabetes, is primarily cleared by the kidneys. Cimetidine can reduce its renal clearance, leading to accumulation. Other drugs that impair renal function, such as non-steroidal anti-inflammatory agents and aminoglycosides, may also increase metformin levels, raising the risk of lactic acidosis. Metformin should be discontinued 24 hours before prolonged fasting, such as before surgery, and 48 hours before procedures involving intravenous radiocontrast media. Patients taking metformin should avoid alcohol or consume it in moderation due to the risk of hepatic damage, which can contribute to hypoglycemia and lactic acidosis.
GLP-1 receptor agonists, such as exendin-4, may have cardioprotective effects by reducing infarct size in models of ischemia-reperfusion injury.
Insulin therapy has evolved over the past century, with insulin analogues largely replacing traditional basal-bolus regimens using human insulins and NPH. These analogues offer better glycemic control, reduced day-to-day variability, and lower risk of hypoglycemia in individuals with type 1 diabetes compared to human insulin preparations, which are associated with greater fluctuations in glycemic levels due to their pharmacodynamic properties. Despite significant improvements in type 1 diabetes management through basal-bolus regimens with newer insulins, research continues to develop more physiological insulin delivery methods.
Several oral hypoglycemic agents used in diabetes management, such as glimepiride, glipizide, glibenclamide, tolbutamide, and nateglinide, are metabolized by the enzyme CYP2C9, and individuals with genetically determined low CYP2C9 activity have an increased risk of experiencing severe hypoglycemia associated with sulfonylurea use.
Rapid-acting secretagogues, such as the meglitinide repaglinide and the phenylalanine derivative nateglinide, are designed to facilitate prandial insulin release, potentially mimicking normal physiology. These agents may offer benefits in early insulin secretion compared to sulfonylureas, though this effect has not been consistently observed across studies. They are considered suitable for sulfonylurea-intolerant patients, those with irregular food intake, and individuals showing a specific response to the medication. However, their broader use is limited by a lack of evidence for improved clinical outcomes, higher cost, more frequent dosing, and no significant advantage in HbA1c reduction compared to other treatments like glipizide. Nateglinide's rapid kinetics may contribute to its lower overall antihyperglycemic efficacy. Secretagogues remain relevant in addressing insulin secretory deficits, particularly in lean individuals, either as monotherapy or in combination with other therapies.
Agents targeting defects in insulin receptor signaling or early post-receptor lesions may offer broader therapeutic benefits, but their effectiveness is limited if the primary defects occur at more distal locations in the signaling pathway. Potential target sites for improving cellular defects in insulin action are illustrated in Figure 60.13.
α-lipoic acid is used in some countries to treat diabetic neuropathy and has been shown to increase insulin sensitivity and improve glycemic control, potentially through its role as a cofactor for dehydrogenases in glycolysis and the Krebs cycle. It also enhances insulin signaling by increasing insulin receptor TKA and IRS1 tyrosine phosphorylation, leading to greater activation of PI3K and increased translocation of GLUT-4 to the plasma membrane. Isoferulic acid, another compound, improves glucose metabolism by increasing GLUT-4 expression and reducing gluconeogenesis via decreased phosphoenolpyruvate carboxykinase (PEPCK) activity.
Gestational diabetes originated from the recognition of the relationship between fetal survival, birth weight, and hyperglycemia during pregnancy, with the term being used by Pedersen and others in the late 1960s; one of the earliest documented cases involved a pregnant woman in 1823 presenting with new-onset thirst and glycosuria, resulting in the delivery of a dead macrosomic baby.
The table provides information on DPP4 inhibitors used in diabetes management, including Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, and Alogliptin. These agents are administered either once daily (od) or twice daily (bd), with varying doses, half-lives, and selectivity for DPP4. Sitagliptin is taken once daily at a dose of 100 mg, has a half-life of 8–24 hours, and is primarily excreted unchanged in urine. Vildagliptin is taken twice daily at 50 mg, has a shorter half-life of 1.5–4.5 hours, and is metabolized into inactive metabolites before excretion in urine. Saxagliptin, at a once-daily dose of 5 mg, has a half-life of 2–7 hours and is metabolized into active metabolites, with approximately 60% excreted in urine. Linagliptin is administered once daily at 5 mg, exhibits a half-life of 10–40 hours, has the highest selectivity for DPP4, and is primarily excreted via bile unchanged. Alogliptin is taken once daily at 25 mg, has a half-life of 12–21 hours, remains mostly unchanged during excretion, and is primarily eliminated through urine.
In diabetes, blood glucose concentrations may remain elevated despite administration of extra insulin, while in other cases, blood glucose can drop below 3.5 mmol/L (70 mg/dL). Elevated blood ketones above 1.5 mmol/L or significant ketonuria may occur, particularly in severe or persistent cases. These metabolic disturbances can lead to symptoms such as exhaustion, confusion, dehydration, difficulty breathing, severe abdominal pain, or a severe hypoglycemic reaction, especially in children.
Certain medications have been shown to reduce the risk of developing diabetes. For example, treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors, such as dapagliflozin, is associated with a 33% reduction in the development of type 2 diabetes over a median follow-up of 21.2 months. Additionally, while angiotensin-converting enzyme (ACE) inhibitors like ramipril do not significantly reduce incident diabetes in individuals with impaired glucose tolerance or impaired fasting glycaemia over three years, they are linked to increased regression to normoglycaemia. Some clinical trials also suggest that ACE inhibitors and angiotensin receptor blockers may lower diabetes risk in high-risk individuals with hypertension.
Devices used for self-monitoring of blood glucose must meet ISO 15197:2013 standards, though national or local guidelines may impose additional requirements; people with diabetes often believe their devices are accurate due to compliance with these standards or approval from regulatory bodies like the FDA or CE mark, but this assumption can be incorrect, highlighting the importance of education in helping individuals recognize inaccurate readings. Blood glucose meters are particularly useful at higher glucose levels, such as distinguishing between 11 mmol/l (198 mg/dl) and 14 mmol/l (252 mg/dl), where the primary goal is achieving a significant reduction in plasma glucose, whereas inaccuracies of 15% have more serious implications at lower glucose levels.
Gastrointestinal manifestations are common in diabetes, though diabetes may not always be the direct cause of these symptoms. Fluctuations in glycemia can influence the development of neuropathy and lead to acute changes in gastric emptying, with extrinsic and enteric neuropathies playing a central role in diabetic gastroenteropathy. Motor dysfunctions in diabetes can affect any part of the gastrointestinal tract, resulting in either accelerated or delayed transit, and incontinence, often underreported, may stem from sphincter dysfunction or impaired sensation.
Jobs that restrict the employment of workers with insulin-treated diabetes are listed in Table 66.3, and people treated with insulin are typically not permitted to work in certain occupations where the risk of hypoglycaemia is considered unacceptable, such as train driving.
Hypoglycaemia is a neglected complication of diabetes, and the 2021 American Diabetes Association's Standards of Care now include a time in range of >70% and below range of <4% when using ambulatory glucose profiles as a key glycemic goal, aiming to address glycaemic variability. Problematic hypoglycaemia, defined as ≥2 episodes of severe hypoglycaemia per year or 1 episode plus hypoglycaemia unawareness, extreme glycaemic lability, or maladaptive behaviour, requires more individualized management, and current recommendations propose a four-stage tiered algorithm for its management.
As early, individualized, and intensified interventional approaches to manage hyperglycaemia in type 2 diabetes have gained acceptance, the use of combinations of two or more oral agents with different mechanisms of action has become commonplace. Guidelines suggest that individuals presenting with moderate to severe hyperglycaemia may be considered for initial pharmacotherapy with a combination of glucose-lowering agents. Fixed-dose, single-tablet dual combinations are available to facilitate combination therapy, designed to provide bioequivalence and similar efficacy, with minor adjustments potentially allowing extra blood glucose-lowering effects.
Marked oscillations in maternal glycaemic levels may lead to accelerated fetal growth and fetal compromise even in pregnancies with apparently good diabetes management. Fetal death, when it occurs, is typically after 32 weeks and often associated with hyperglycaemia, polyhydramnios, or accelerated fetal growth. Women with diabetes and additional complications such as vasculopathy or pre-eclampsia may experience intrauterine growth restriction and fetal demise as early as the second trimester, likely due to placental vascular disease. Amniotic erythropoietin, which indicates chronic fetal hypoxia in late pregnancy, is elevated in diabetic pregnancies compared to non-diabetic ones and, in some cases, correlates inversely with cord blood pH and partial pressure of oxygen at birth.
The deficiency or absence of insulin prevents glucose uptake into tissues like muscle, fat, and liver, leading to high blood glucose levels. Dysregulated secretion of counter-regulatory hormones such as glucagon, growth hormone, and catecholamines contributes to increased gluconeogenesis and breakdown of triglycerides into free fatty acids. Beta-oxidation of these free fatty acids results in the formation of ketone bodies—specifically β-hydroxybutyrate, acetoacetate, and acetone. Acetone, being volatile, is exhaled through the lungs, causing a sweet-smelling breath. The release of ketone bodies into circulation leads to metabolic acidosis by depleting acid buffers.
The first orally active glucose-lowering drug, synthalin, a guanidine derivative, was developed in 1926 but was withdrawn due to toxicity, which has been a recurring issue for oral anti-diabetes drugs; this was followed by the development of sulfonylureas, originating from the work of Auguste Loubatières in France.
The UKPDS provided longitudinal data that helped define the natural history of cardiovascular complications in type 2 diabetes mellitus (T2DM), leading to the development of mathematical models to identify predictors for cardiovascular disease. The Framingham Heart Study, while primarily focused on the general population, also contributed to understanding factors contributing to cardiovascular disease and developed risk prediction models, though it included only a few hundred individuals with diabetes. Risk equations from both studies show moderate effectiveness in the UK and USA but vary in performance across different countries and ethnic groups, limiting their applicability to broader diabetes populations in Europe, the USA, and elsewhere.
The incidence of end-stage renal disease (ESRD) in individuals with type 1 diabetes mellitus (T1DM) appears to be declining in some regions. In Sweden, among 12,032 cases of childhood-onset diabetes, only 33 individuals developed ESRD after a diabetes duration of more than 15 years, resulting in a cumulative incidence of 0.7%. Data from the Pittsburgh Epidemiology of Diabetes Complications Study also indicate a declining trend, although after 30 years of diabetes duration, the cumulative incidence of ESRD remained higher at 18% for those diagnosed between 1965 and 1969. Combined registry data show that between 1991 and 2000, the number of people with T1DM starting renal replacement therapy (RRT) either remained stable or slightly decreased, despite an overall rise in T1DM incidence. Additionally, survival rates after the onset of ESRD may have improved during this period.
Extra precautions are needed after an episode of self-treated hypoglycaemia within the previous 24 hours, including more frequent glucose testing, exercising with an informed partner, and possibly incorporating an anaerobic component into training to help raise blood glucose levels.
The discovery of insulin significantly improved outcomes for patients with type 1 diabetes mellitus (T1DM), allowing effective treatment of acute complications like diabetic ketoacidosis. However, increased survival led to the development of secondary complications such as retinopathy, nephropathy, neuropathy, and vascular disease. The Diabetes Control and Complications Trial (DCCT) in 1993 demonstrated that microvascular complications could be delayed or avoided through good glycemic control, achieved via intensive insulin therapy resulting in a hemoglobin A1c (HbA1c) level 1% (11 mmol/mol) lower than the control group, though not fully normalized. Similarly, the UK Prospective Diabetes Study (UKPDS) showed that a 1% (11 mmol/mol) reduction in HbA1c in type 2 diabetes mellitus (T2DM) led to significant improvements in microvascular outcomes, reinforcing the importance of glycemic control in preventing diabetes-related complications.
For diabetes, integration across policy, health system, and community levels is necessary, with the involvement of various sectors including the private sector, particularly in improving access to medicines and technologies. The private sector has played an active role in addressing other diseases in low- and middle-income countries and could similarly contribute to diabetes care. Additionally, private healthcare providers may support the delivery of universal health coverage in the context of diabetes management.
Insulin resistance, a condition related to diabetes, has shown conflicting evidence regarding its association with stroke. The ARIC study found that in individuals without diabetes, each increase of 50 pmol/L of fasting insulin was associated with a mild increase in stroke risk (risk ratio of 1.19), although this association became less clear after adjusting for other risk factors such as age, systolic blood pressure, and smoking.
Transient hyperglycemia contributes to metabolic memory in diabetes through various molecular mechanisms, including glycotoxicity, the formation of advanced glycation end products (AGEs), glycation of DNA, increased glucose metabolism flux, oxidative damage, and overproduction of PKC-β and mitochondrial stress. Additionally, transient hyperglycemia can induce long-lasting epigenetic changes in the promoter region of the NFκB subunit p65 in aortic endothelial cells, which can be prevented by reducing mitochondrial superoxide production or the generation of α-oxoaldehydes like methylglyoxal.
Continuous glucose monitoring (CGM) in pregnant women with type 1 or type 2 diabetes showed improvement in mean HbA1c levels in late pregnancy (5.8% vs 6.4% or 40 mmol/mol vs 48 mmol/mol, p=0.0007) and lower large-for-gestational-age (LGA) rates (35% vs 60%) compared to conventional glucose monitoring. However, a separate Danish RCT found no improvement in glycemic control or pregnancy outcomes with intermittent real-time CGM (RT-CGM) compared to seven daily self-monitored plasma glucose tests, particularly in women who already had low HbA1c at conception (6.6% vs 6.8% or 49 vs 51 mmol/mol) and used RT-CGM intermittently in 60% of cases.
Raised insulin levels may act on insulin-like growth factor I (IGF-I) receptors in the skin to cause epidermal overgrowth, which is related to acanthosis nigricans, and similar events in the ovary could lead to polycystic ovary disease, both of which are associated with insulin-resistant states.
Infections can influence diabetes by contributing to its etiology and pathogenesis, worsening hyperglycemia in individuals with established diabetes, and exacerbating diabetes complications; notably, infections are a significant predisposing factor for both diabetic ketoacidosis and hyperosmolar hyperglycemia syndrome.
NAFLD is discussed in the context of type 2 diabetes, including its definition, diagnosis, epidemiology, aetiology, pathogenesis, and treatment, particularly in individuals with or without coexisting cardiovascular disease; NAFL is characterized by macrovesicular steatosis in ≥5% of hepatocytes in individuals who consume little or no alcohol without hepatocyte ballooning, while NASH includes steatosis, inflammation, and hepatocyte injury with or without fibrosis; liver fibrosis in NAFLD is classified into five stages ranging from F0 (no fibrosis) to F4 (cirrhosis).
GAD65 prevents autoimmune destruction of pancreatic beta cells and type 1 diabetes mellitus (T1DM), as indicated by studies on NOD mice.
Gestational diabetes mellitus (GDM) can be diagnosed using different glucose tolerance test protocols, including varying glucose loads, numbers of elevated OGTT results, and glycaemic thresholds, as seen in previous large randomized controlled trials. Different thresholds for initiating insulin treatment have also been used. More recent studies comparing the IADPSG diagnostic criteria with traditional thresholds have not consistently shown better treatment outcomes, with some focusing on comparing one-step versus two-step diagnostic approaches rather than evaluating the cost-effectiveness of the IADPSG thresholds.
Type 1 diabetes, previously known as insulin-dependent or juvenile-onset diabetes, is associated with insulitis and islet autoimmunity, including the presence of islet cell autoantibodies (ICAs), and is strongly linked to human leucocyte antigen (HLA). It has been studied through genetic research and long-term follow-up of children from birth, contributing to a better understanding of its aetiology and pathogenesis. A subset of adults initially diagnosed with type 2 diabetes, particularly those with secondary failure to sulfonylurea treatment, may also test positive for ICAs, a condition known as latent autoimmune diabetes of adults (LADA). While LADA shares some genetic and autoimmune features with childhood type 1 diabetes, there are differences in their genetic background, autoimmune processes, and clinical presentation. Research continues to identify triggers of beta-cell autoimmunity and factors influencing the progression to clinical diabetes in individuals with beta-cell autoantibodies.
Glucagon-like peptide-1 receptor agonists, including liraglutide, semaglutide, albiglutide, and dulaglutide, have been shown to significantly reduce the risk of a composite cardiovascular endpoint in patients with type 2 diabetes, which includes death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke. Studies such as LEADER, SUSTAIN-6, Harmony Outcomes, and REwIND support these findings, whereas other agents in the same class, like lixisenatide, exenatide once weekly, and oral semaglutide, have shown less consistent cardiovascular benefits in trials such as ELIXA and EXsCEL.
Gene therapy approaches targeting adipose tissue or the liver in obese diabetic mice have demonstrated improvements in glucose tolerance and insulin sensitivity. AAV-mediated delivery of mitoNEET or BMP7 to white adipocytes leads to benign expansion of white adipose tissue, reduced inflammation, and preserved insulin sensitivity. Similarly, adenoviral-mediated gene transfer of Sfrp5, an antiinflammatory adipokine linked to the Wnt signaling pathway, reduces adiposity and adipose tissue inflammation in models of obesity and diabetes. Additionally, intravascular delivery of adenoviral vectors encoding GLP-1 in obese diabetic mice inhibits macrophage infiltration and inflammation in adipose tissue, suggesting that the anti-inflammatory effects of GLP-1 contribute to improved insulin sensitivity.
Low birth weight is associated with an increased risk of developing type 2 diabetes later in life, and this may be influenced by intrauterine effects such as growth retardation observed in monochorionic monozygotic twins compared to dizygotic twins. The role of heritability in diabetes is complex, as current estimates are based on the most recent generations, while many studied genetic variants are ancestral, having modest effects and escaping purifying selection. It remains uncertain whether these ancestral variants can fully account for the recent diabetes epidemic or if rare variants with stronger effects may play a more significant role.
GDM is diagnosed for the first time during pregnancy and may occur at any time, most commonly after 24 weeks, while diabetes in pregnancy applies to women who have previously diagnosed diabetes or hyperglycaemia that meets WHO criteria for diabetes in the non-pregnant state. Most women with overt diabetes in pregnancy have previously unrecognized type 2 diabetes, though between 3% and 10% of those with newly recognized diabetes during pregnancy have type 1 diabetes. Type 1 diabetes may be suspected when blood glucose levels are unusually high and in the absence of obesity, and some of these women may stop insulin postnatally but typically experience relapse. Serological tests for islet cell autoimmunity are usually strongly positive in such cases, and approximately 75-90% of hyperglycaemia cases in pregnancy are GDM.
Individuals with early type 2 diabetes mellitus (T2DM) identified through screening often differ from those presenting with symptoms, as they are less likely to have developed microvascular or macrovascular complications. These individuals may have different attitudes toward health, and the diagnosis may be less welcomed since it does not immediately relieve discomfort or seem relevant to future health. This can lead to lower compliance with lifestyle advice such as weight management, diet, and physical activity. Therefore, a sensitive and careful approach is needed when discussing the need for future actions, along with appropriate follow-up by the diabetes team.
Freedom from hyperglycemic symptoms, preventing undesirable weight loss, avoiding hypoglycemia and other adverse drug reactions, screening for and preventing vascular complications, detecting cognitive impairment and depression at an early stage, and achieving a normal life expectancy for patients where possible are medical goals in diabetes management. Patient-oriented aspects include maintaining general well-being and good quality of life, acquiring skills and knowledge to adapt to lifestyle changes, and encouraging diabetes self-care.
Pregnancies in women with diabetes still have congenital malformation and perinatal mortality rates 2–5-fold higher than in women without diabetes, despite medical advances. Optimizing glycaemic levels is challenging and must be balanced against the risk of maternal hypoglycaemia. Improved obstetric surveillance and better management of maternal hyperglycaemia have contributed to successful pregnancy outcomes for most women. Recent advances in continuous subcutaneous insulin infusion (CSII), continuous glucose monitoring (CGM), and hybrid closed-loop systems show promise, though their specific roles and impact on perinatal outcomes and patient satisfaction remain uncertain. The high cost of these technologies is likely to limit their use to select, well-supported patients.
When β cells decompensate and diabetes develops with marked hyperglycaemia, treatment becomes difficult, often requiring insulin therapy as β-cell function declines, though insulin sensitizers like metformin and thiazolidinediones may have limited effectiveness. High glucose levels can persist despite large insulin doses, sometimes exceeding 500 units/day, and U500 insulin can help reduce the required insulin volumes. Insulin pumps are an option for managing very high insulin requirements.
Simpler tests like homeostasis model assessment (HOMA-IR, HOMA-B) and QUICKI have been developed to assess insulin sensitivity in epidemiological studies using fasting plasma glucose and insulin or C-peptide concentrations. However, these indices have limitations because the liver provides fasting plasma glucose, and under fasting conditions, a significant portion of glucose is utilized by non-insulin-dependent tissues like the brain, as well as insulin-sensitive tissues such as muscle and liver. As a result, insulin resistance indices measured during fasting do not strongly correlate with clamp-derived glucose disposal rates.
Cardioselective β₁-adrenoceptor antagonists are less likely to interfere with the awareness of or recovery from hypoglycemia, making them preferable for patients treated with insulin or sulfonylureas. While even low doses of these antagonists may modify certain symptoms of hypoglycemia like tachycardia, other symptoms such as sweating remain unchanged or may become more pronounced during β₁-blockade. Overall, cardioselective β-adrenoceptor antagonists rarely impair the recognition of hypoglycemia, and they do not increase the incidence of hypoglycemia, even in patients prone to it. In contrast, non-selective drugs can impair recovery from hypoglycemia.
GLP-1RAs as a drug class reduce MACE by 14% compared to placebo, with a number needed to treat of 65 over three years, and consistently show cardiovascular benefits across trials except for lixisenatide in the ELIXA trial, possibly due to its shorter half-life. Excluding ELIXA from analysis reduces heterogeneity and elevates evidence certainty to high according to GRADE criteria. GLP-1RAs also significantly reduce the risk of cardiovascular mortality, myocardial infarction, and stroke by 13%, 10%, and 17% respectively, lower all-cause mortality with an NNT of 114 over three years, and decrease hospitalization for heart failure by 11% and a composite kidney outcome by 21%.
Thiazolidinediones can be used as monotherapy in individuals with type 2 diabetes, with or without obesity, when lifestyle modifications do not achieve adequate glycemic control. These medications are typically positioned in treatment algorithms either as an alternative to metformin when it is inappropriate or not tolerated, or as an add-on to metformin therapy when weight gain is not a concern and insulin secretagogues are not preferred. Due to their slow onset of action, substituting a thiazolidinedione for another glucose-lowering agent can lead to a temporary decline in glycemic control. Additionally, thiazolidinediones can be combined with insulin to improve glycemic management.
PTSD is associated with common biological and behavioural factors that may also contribute to diabetes, including chronic hyperarousal of the sympathetic nervous system and renin-angiotensin-aldosterone system, which are linked to neurometabolic changes, inflammation, and oxidative stress. Additionally, abnormalities in limbic-neuronal structure and function observed in PTSD may influence central regulation of body weight, potentially impacting metabolic health.
In type 2 diabetes, the β-cell mass in the pancreas is on average about 40% lower compared to individuals without diabetes, though there is some overlap between the two groups as shown in scatterplot data with mean values and standard deviation.
Thiazolidinediones improve glucose metabolism by reducing circulating free fatty acids, which rebalances the glucose-fatty acid (Randle) cycle, facilitates glucose utilization, and restricts fatty acid availability for hepatic gluconeogenesis, while also decreasing ectopic lipid deposition in muscle and liver; however, they may reduce mitochondrial respiratory function despite increasing mitochondrial biogenesis.
High levels of stress may trigger the appearance of diabetes in genetically susceptible individuals, with evidence showing that children with diabetes experienced greater stress, particularly actual or threatened family losses, prior to diagnosis compared to healthy controls. However, no such relationship has been found in young adults newly diagnosed with type 1 diabetes mellitus (T1DM). Major stressful life events or pre-existing depression increase the risk of type 2 diabetes mellitus (T2DM) by up to 37%. The physiological basis for this effect is not fully understood but is thought to involve stress-induced dysregulation of glucose metabolism or disruption of insulin signaling processes within the central nervous system in individuals who are genetically and constitutionally predisposed to diabetes.
SGLT-2 inhibitors and GLP-1 receptor agonists may reduce the risk of macrovascular complications in diabetes, particularly in high-risk individuals, though some agents may be more effective than others; it is uncertain whether these vasculoprotective effects extend to individuals with early atherosclerotic disease or for primary prevention, and the glucose-independent mechanisms underlying their cardiovascular benefits have not been fully elucidated. Current clinical trials are investigating the combined use of SGLT-2 inhibitors and GLP-1 receptor agonists to assess potential synergistic macrovascular protection in diabetes and cardiovascular disease.
Hypoglycaemia can occur not only with insulin treatment but also with other glucose-lowering drugs, particularly sulfonylureas, and may lead to increased risk of motor vehicle incidents in individuals with type 2 diabetes. Studies have shown that drivers with type 2 diabetes treated with sulfonylureas have a higher crash risk, likely due to unsuspected hypoglycaemia, and those with a history of hypoglycaemia-related insurance claims have greater rates of accidents requiring hospital treatment, even when not using insulin.
Some commonly used medications are associated with adverse metabolic effects and an increased risk of diabetes. High-dose thiazide diuretics worsen insulin resistance, while beta-blockers impair insulin secretion. Second-generation antipsychotics have been linked to hyperglycemia and diabetes. Additionally, protease inhibitors and nucleoside reverse transcriptase inhibitors, used in highly active antiretroviral therapy (HAART) for HIV, are associated with insulin resistance, abnormal glucose and lipid metabolism, and an increased risk of type 2 diabetes mellitus (T2DM). The increasing use of these medications may significantly impact diabetes prevalence.
Insulin administration is crucial in managing diabetic ketoacidosis (DKA), as it enhances peripheral glucose utilization, reduces hepatic glucose production, inhibits free fatty acid release from adipose tissue, and decreases ketogenesis. A typical approach involves an initial intravenous or intramuscular bolus of rapid-acting insulin at 0.1 units/kg, followed by a continuous intravenous infusion of regular insulin at 0.1 units/kg/h, though evidence suggests the bolus may be unnecessary if prompt intravenous access and continuous infusion can be established. DKA can also be associated with COVID-19 infection.
Type 2 diabetes is a strong predictor of worse clinical outcomes in individuals with end-stage liver disease and is closely associated with the severity of liver disease, including cirrhosis, as indicated by the Child-Pugh class and MELD score. It is also linked to more severe hepatic encephalopathy in people with established cirrhosis, independent of liver disease severity and cause. Additionally, individuals with type 2 diabetes have approximately a two-fold increased risk of developing hepatocellular carcinoma (HCC) and HCC-specific mortality compared to those without type 2 diabetes. Those with both type 2 diabetes and HCC also face a 40% higher risk of all-cause mortality and a 90% increased risk of decompensated cirrhosis.
Pharmacotherapy for type 2 diabetes has evolved beyond managing hyperglycaemia to include reducing cardiovascular risk, influenced by findings from cardiovascular outcomes trials showing that certain anti-diabetes agents—specifically sodium-glucose cotransporter 2 inhibitors (SGLT-2) and glucagon-like peptide 1 receptor agonists (GLP-1RAs)—have beneficial effects on hard clinical endpoints. Clinicians are encouraged to consider indicators of high risk or established atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure when selecting optimal treatments, and this chapter reviews the main glucose-lowering drug classes in terms of their benefits, harms, and current role in managing type 2 diabetes.
Thiazolidinediones enhance glucose uptake in adipose tissue and skeletal muscle by increasing the availability of GLUT4 glucose transporters, contributing to improved insulin sensitivity, partly through reduced production of proinflammatory cytokines like TNF-α, which is involved in muscle insulin resistance. These drugs also boost adiponectin production, which enhances insulin action and may positively influence vascular reactivity. Due to the expression of PPAR-γ in various tissues, thiazolidinediones can exert pleiotropic effects by influencing responsive genes across multiple organs.
Adults with type 1 diabetes mellitus (T1DM) exhibit a specific pattern of mild cognitive dysfunction, particularly in domains such as intelligence, attention, psychomotor speed, cognitive flexibility, and visual perception, as shown by a meta-analysis of 31 studies comparing individuals with and without diabetes. Despite these differences, performance on measures of language, learning, and memory remained largely unaffected, with the latter being notably preserved even after an average of 20 years of living with the condition. The observed cognitive differences were modest, with effect sizes ranging from 0.3 to 0.8 standard deviation units, indicating that not all cognitive functions are equally impacted by T1DM.
Hyperglycemia is a common issue in hospitals, affecting around 25% of inpatients, and poor glycemic control is particularly prevalent among patients with diabetes. Many diabetic patients are not admitted specifically for complications related to their condition, and as a result, blood glucose management often becomes secondary to treating the primary reason for admission. Additionally, in patients without diabetes who develop hyperglycemia during acute illness, high glucose levels are frequently overlooked or managed inappropriately.
The LEADER trial evaluated 9340 participants with type 2 diabetes who were randomized to receive either once-daily 1.8 mg liraglutide or placebo in addition to standard care, with a median follow-up of 3.8 years; all participants were at increased cardiovascular risk due to factors such as age over 50 years with a history of cardiovascular conditions like coronary heart disease, cerebrovascular disease, peripheral vascular disease, chronic kidney disease, or heart failure, or age over 60 years with at least one cardiovascular risk factor such as microalbuminuria, hypertension, left ventricular dysfunction, or an ankle-brachial index below 0.9; most participants (81.3%) had established cardiovascular disease, chronic kidney disease stage 3 or higher, or both; liraglutide treatment reduced the incidence of the primary outcome, which was a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (three-component MACE), with a hazard ratio of 0.87 and a 95% confidence interval.
Islet cell transplantation has been shown to substantially improve health-related quality of life, with a five-year survival rate of 98.4% according to the Collaborative Islet Transplant Registry. Mortality rates from single-center studies range from 0.3–1.0% per 100 person-years, and there has been a decrease in serious transplant-related adverse events from approximately 20% in 1999–2002 to around 7% in 2011–2014. Simultaneous islet-kidney transplantation (SIK) appears to offer a survival benefit compared to kidney transplantation alone or being on the waiting list. However, most studies have had small sample sizes, and more research with appropriate control groups and longer follow-up is needed.
Hyperglycemia, which is clinically relevant, commonly occurs with high doses of glucocorticoids, and its occurrence during thiazide treatment should prompt reassessment of the drug's necessity, with consideration of substituting the diuretic with a small dose of furosemide or bumetanide or adjusting the antihypertensive regimen to reduce or replace bendroflumethiazide.
Metformin has been found to be safe and effective in managing gestational diabetes mellitus (GDM), with some studies showing it leads to less maternal weight gain and lower birth weights compared to insulin. It is also associated with a lower risk of neonatal hypoglycemia than insulin. However, about half of the women treated with metformin required additional insulin therapy, particularly those who were older, had higher baseline BMI, more severe and earlier hyperglycemia, and earlier diagnosis and treatment of GDM. Comparisons with glibenclamide showed similar differences in maternal and neonatal outcomes.
Combination therapy for diabetes, whether involving oral agents alone, oral agents and insulin, or oral agents with other injectable medications like incretin mimetics, is supported by its superior efficacy compared to switching from one medication to another. Clinical trials have shown that adding therapies together is more effective than monotherapy. For example, patients with poor glycemic control on glyburide showed no improvement when switched to metformin monotherapy but experienced significant reductions in fasting plasma glucose when glyburide was combined with metformin. This principle extends to other combinations, where pairing agents with different mechanisms enhances glucose-lowering effects. Additionally, combination treatment can target both preprandial and postprandial hyperglycemia, similar to the balanced use of basal and bolus insulin.
Dietary fat's role in diabetes management has been studied since the 1950s, with findings indicating that it can influence insulin signaling and that saturated fat is linked to cardiovascular disease. However, total dietary fat does not appear to be significantly associated with diabetes risk. While some diabetes prevention programs have aimed to limit total fat, the primary factor in reducing diabetes risk seems to be weight reduction rather than the specific macronutrient composition of the diet. There is no clear consensus on the percentage of calories from fat in relation to diabetes management, but the types and sources of fat, along with the overall quality of the diet, are considered more important.
Maturity-onset diabetes of the young (MODY) refers to monogenic forms of diabetes caused by high-penetrance mutations in more than 10 different genes, with early onset typically before 25 years of age and varying degrees of β-cell dysfunction. MODY is inherited in an autosomal dominant manner and exhibits extreme allelic heterogeneity, meaning that most mutations are unique to specific families. Some MODY genes, such as HNF1A, HNF4A, HNF1B, GCK, and PDX1, are also associated with common, less-penetrant variants that increase the risk of type 2 diabetes.
Injected liquid silicone under high pressure areas of the diabetic foot has been used in the USA and is supported by a randomized controlled trial showing that it reduces foot pressures and increases subcutaneous tissue in the forefoot. The therapy, known as an "injectable orthosis," is now available in certain European countries, and a follow-up study confirmed its effects last up to 2 years, though booster injections may be needed periodically.
Hyperglycemia in diabetes leads to osmotic diuresis, which depletes electrolytes such as sodium, potassium, and phosphates, along with water, causing significant dehydration and reduced total body potassium. Despite overall potassium depletion, serum potassium levels may appear normal or elevated due to an extracellular shift caused by severe acidosis. Close monitoring of serum potassium is essential during insulin treatment, as levels can drop rapidly once therapy begins.
In some individuals with type 2 diabetes, particularly those with poor metabolic control and high blood glucose levels, symptoms resembling counter-regulatory responses occur even at normal glucose levels, and experimental evidence suggests that the threshold for hypoglycemic counter-regulation may be reset to normal glucose values in these individuals. A diminished glucagon response in diabetes leads to reduced glycogenolysis and gluconeogenesis, increasing the risk of severe hypoglycemia. The mechanisms behind the loss of $\alpha$-cell glucagon release in diabetes are not fully understood, and while animal studies provide some insights, they may not directly translate to humans due to differences in pancreatic physiology. In type 1 diabetes, the $\alpha$-cell defect appears specific to hypoglycemia, as glucagon release in response to stimuli like amino acids remains intact.
Liraglutide, a GLP-1 receptor agonist, in combination with metformin, has been found to be effective in improving glycemic levels in children aged 10–16 years with type 2 diabetes and is now FDA approved for use in children aged 10 years or older. Ongoing clinical trials are assessing the safety and efficacy of adult-approved therapies, including SGLT-2 inhibitors and DPP-4 inhibitors, for treating type 2 diabetes in children.
Plasma concentrations of ET-1 are elevated in patients with type 2 diabetes mellitus (T2DM) complicated by atherosclerosis compared to those without diabetes and healthy individuals. Increased ET-1 levels are also observed in subjects with diabetes and carotid atherosclerosis. ET-1 promotes the production and release of inflammatory cytokines from monocytes, enhances LDL cholesterol uptake by these cells, and contributes to their transformation into foam cells. Additionally, cytokines released from monocytes-macrophages stimulate further ET-1 production, creating a positive feedback loop that amplifies cytokine production.
Individuals with impaired glucose tolerance (IGT) who participated in a 6-12 month intervention involving supervised exercise programs and dietary counseling showed a reduced risk of developing diabetes compared to those who declined the intervention, with 11% of the intervention group developing diabetes versus 21% of the control group after 5 years; additionally, over 12 years, the mortality rate was lower in the intervention group (6.5 per 1000 person-years) compared to the control group (14.0 per 1000 person-years).
Diabetes can lead to a decrease in HDL cholesterol levels due to several factors, including the acceleration of CETP-mediated exchange of VLDL triglycerides for HDL cholesteryl esters in the presence of hypertriglyceridemia. This process results in HDL triglycerides becoming a substrate for plasma lipases, particularly hepatic lipase, which converts HDL into smaller particles that are cleared more rapidly from the plasma. Additionally, precursors of advanced glycation end-products can impair HDL's role in reverse cholesterol transport.
Both type 1 and type 2 diabetes mellitus (T1DM and T2DM) result from environmental factors acting on genetically susceptible individuals, and diabetes during pregnancy can increase the risk of obesity and diabetes in offspring. Maternal hyperglycemia during pregnancy predisposes the child to an earlier onset of T2DM compared to when diabetes develops in the mother after pregnancy. Children and young adults of mothers with T1DM exhibit greater insulin resistance and glucose intolerance than those of mothers without diabetes, while similar metabolic abnormalities are not observed in offspring of fathers with T1DM. The intrauterine environment's influence on T2DM susceptibility is further supported by the observation that a family history of diabetes is more frequently reported on the maternal side than the paternal side.
Several studies have demonstrated the effectiveness of interventions in preventing or delaying the onset of type 2 diabetes in individuals with impaired glucose tolerance (IGT). The Da Qing study showed a 38% relative risk reduction (RRR) in diabetes incidence over 6 years, with a 45% RRR maintained over 23 years. The Diabetes Prevention Study (DPS) reported a 58% RRR over 3.2 years, which decreased to 43% during extended follow-up. The Diabetes Prevention Program (DPP) also showed a 58% RRR over 3 years, with a 34% RRR over 10 years. The Indian IDPP-1 study found a 29% RRR over 3 years, while a Japanese study reported a higher 67% RRR over 4 years. These findings highlight the long-term benefits of early intervention in high-risk populations, particularly those with IGT and additional risk factors such as elevated BMI or fasting glucose levels.
In diabetes, the processing and secretion of insulin are critical, as insulin is derived from proinsulin through the removal of the C peptide by specific enzymes in the Golgi complex and secretory granules. Insulin and C peptide are stored together and released in equal amounts during regulated exocytosis, though under normal conditions, over 95% of the secreted product is insulin rather than proinsulin.
The ADA Workgroup recommended that individuals with drug-treated diabetes, particularly those using insulin or insulin secretagogues, consider a plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L) as a threshold for concern regarding hypoglycemia; this value is within the margin of error of blood glucose monitoring methods and corresponds to the lower end of the normal post-absorptive glucose range in non-diabetic individuals, as well as the glycemic level at which the body's glucose counter-regulatory mechanisms typically activate, making it a conservative threshold for detecting hypoglycemia and potentially reducing the body's defenses against further drops in blood sugar.
Autoimmune thyroiditis in individuals with type 1 diabetes can impact growth, weight gain, diabetes management, menstrual regularity, and overall well-being. Screening for elevated thyroid-stimulating hormone (TSH) levels should occur after diabetes stabilization at onset and every 1–2 years thereafter, or sooner if symptoms of thyroid dysfunction arise. Testing may also include TPO antibodies, anti-thyroglobulin antibodies, and free T4 during TSH screening. Those with positive TPO autoantibodies and normal thyroid function require more frequent monitoring every 6–12 months. Thyroid disease treatment in children with type 1 diabetes follows the same guidelines as for the general population.
Ectopic fat storage contributes to diabetes pathogenesis by increasing plasma membrane sn-1,2-diacylglycerol levels, which activates protein kinase Cε in muscle, liver, and adipose tissue, resulting in threonine phosphorylation of the insulin receptor at position 160 and subsequent inhibition of insulin receptor kinase activity, thereby inducing insulin resistance.
Poorly managed diabetes leads to increased healthcare costs, with every 1 percentage point rise in HbA1c above 7% associated with a 10% increase in costs. The global prevalence of undiagnosed diabetes, especially in low-income countries, contributes to an underestimation of the true financial burden. In addition to medical expenses, diabetes management incurs lifestyle-related costs, such as those from regular physical activity and dietary modifications, which account for 20% of direct ambulatory care costs.
Short acting insulin is added to a 500 ml bag of 5% dextrose solution containing 1 gm of KCL according to the patient's blood glucose level, following a rough guide for insulin dosing.
Diabetic gastroparesis is associated with severe symptoms, nutritional compromise, impaired glucose management, and a poor quality of life, independent of age, tobacco use, alcohol use, or type of diabetes, and has been linked to cardiovascular disease, hypertension, retinopathy, and increased hospitalization. Studies show that among people with diabetes and delayed gastric emptying, approximately 25% died after at least nine years of follow-up, though gastroparesis itself was not significantly linked to mortality when adjusting for other disorders. However, in a cohort comparison, those with diabetic gastroparesis had more hospital days and higher mortality, although the latter was not statistically significant compared to those with gastrointestinal symptoms alone. Data from the National Institute of Diabetes, Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium showed a higher death rate in individuals with type 1 or type 2 diabetes and gastroparesis compared to idiopathic cases, with a higher death rate in those with delayed gastric emptying compared to normal emptying.
Intravenous insulin and dextrose infusions are used before transplantation to maintain euglycemia. Initially, insulin was stopped after transplantation unless hyperglycemia occurred, defined as serum glucose ≥11.1 mmol/L. Later, the threshold for administering insulin was lowered to intervene when pre-meal glucose exceeded 6.0 mmol/L or 2-hour post-meal glucose exceeded 8.0 mmol/L.
The renin-angiotensin-aldosterone system (RAAS), particularly angiotensin-converting enzyme 2, contributes to macrovascular disease in diabetes, and RAAS inhibitors have shown benefits in reducing endothelial dysfunction and atherosclerosis through suppression of inflammation, fibrosis, and oxidative stress. Other vasoactive components like endothelin and urotensin II also play a role in diabetes-related macrovascular complications and interact with RAAS. Novel factors such as TNF-related apoptosis-inducing ligand, osteoprotegerin, and the complement system are being studied for their involvement in atherosclerosis. Treatments targeting oxidative stress, including NADPH oxidase inhibitors and anti-inflammatory agents, show anti-atherosclerotic effects in experimental and clinical studies, though results vary. Inflammasome activation is implicated in diabetes-associated atherosclerosis, and a multifactorial treatment approach addressing both general cardiovascular and diabetes-specific risk factors is considered optimal for reducing cardiovascular disease burden in diabetes.
In cases of emergency surgery, the metabolic status of a diabetic patient should be rapidly assessed due to the potential coexistence of ketoacidosis and poor glycemic control. Standard therapy for diabetic ketoacidosis (DKA) should be initiated, and surgery should be delayed for 2–3 hours to allow for metabolic improvement. Preoperatively, glucose-insulin-potassium (GIK) should be used in all cases, considering the increased insulin requirements in conditions such as sepsis.
The World Health Organization (WHO) introduced a modern classification of diabetes in its 1980 report, defining four major groups: insulin-dependent diabetes mellitus (IDDM, type 1), noninsulin-dependent diabetes mellitus (NIDDM, type 2), other types, and gestational diabetes mellitus. Additionally, two risk classes were proposed: previous abnormality of glucose intolerance and potential abnormality of glucose tolerance, serving as alternatives to the terms pre-diabetes or potential diabetes.
More than 50% of people with type 2 diabetes mellitus (T2DM) will eventually require insulin injections during their lifetime, often due to disease progression. Transitioning from oral hypoglycemic agents to insulin can be a stressful and anxiety-inducing experience for various reasons. Patients may feel a sense of personal failure in managing their blood glucose levels through lifestyle, diet, and oral medications. Some perceive the need for insulin as an indication that their diabetes has become more severe. Concerns also arise from the necessity of self-injection, including apprehensions, fears, or even phobias related to needles. Additional anxieties include the risk of hypoglycemia leading to coma or death, potential weight gain associated with insulin use, and the impact of insulin therapy on occupation and lifestyle activities. Healthcare professionals use various strategies to ease this transition and address these concerns.
Insulin degludec is an ultra-long-acting insulin analogue with a fatty acid side chain that forms long multihexamer chains after subcutaneous injection, leading to a slow disassembly and a half-life exceeding 25 hours. This prolonged action provides a flat insulin profile and consistent duration of effect, making it less sensitive to variations in daily administration times. Studies have shown that insulin degludec is non-inferior to insulin glargine in achieving glycemic control while reducing the risk of overall and nocturnal hypoglycemia.
Advanced diabetes technologies require consistent user input and vigilance for proper functioning, and the effort involved may hinder their adoption or lead to discontinuation among teens and emerging adults. Factors associated with underuse include lower socioeconomic status and adolescence. Adolescents and young adults show the highest rate of insulin pump discontinuation, often due to issues with wearability and personal preference. To improve uptake and sustained use, healthcare teams should provide realistic expectations, ongoing education, and support to families and patients, including discussions on the optimal timing for initiating these devices. Similar strategies will likely be necessary for future automated insulin delivery systems, as human oversight remains essential for their effective operation.
The recent EASD/ADA consensus statement for type 2 diabetes treatment recommends selecting second-line therapies after metformin based on the presence of cardiovascular- and/or kidney-related comorbidities, risk of weight gain and hypoglycaemia, and cost. Most guidelines recommend treating individuals with established atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure with an SGLT-2 inhibitor or GLP-1 RA. Insulin use in type 2 diabetes has shifted to later stages of the disease as add-on therapy to other anti-diabetes agents, except in cases of obvious signs of catabolism.
Maturity-onset diabetes of the young (MODY) includes several subtypes caused by mutations in specific transcription factors, such as MODY 1 (HNF-4α), MODY 3 (HNF-1α), MODY 4 (IDF-1), MODY 5 (HNF-1β), MODY 6 (NeuroD1), and MODY 7 (CEL), while other genes like glucokinase (MODY 2), GLUT2, GATA, PAX genes, Nkx 2.2, Nkx 6.1, and Neurog3 also play roles in pancreatic development and regulation of glucose sensing and insulin secretion.
When individuals with diabetes experience difficulty eating or maintaining food intake and their blood glucose drops below 200 mg/dL (11.1 mmol/L), sports drinks may be administered to help raise blood glucose levels due to their high glucose content, such as Gatorade which contains 255 g/L of glucose along with lower amounts of electrolytes including 20 mEq/L sodium, 3 mEq/L bicarbonate, and 3 mEq/L potassium.
Glycaemic targets for managing diabetes, as advised by international bodies, include fasting plasma glucose (FPG) levels of less than 5.3 mmol/l, one-hour post-prandial glucose levels less than 7.8 mmol/l, and two-hour post-prandial glucose levels less than 6.7 mmol/l. FPG levels of 5.8 mmol/l are linked to a higher risk of preventable perinatal complications, indicating the potential need for pharmacological treatment. According to NICE guidelines, women diagnosed with gestational diabetes mellitus (GDM) who have a fasting blood glucose level of 7.0 mmol/l or higher should be treated with insulin rather than oral diabetes medications.
During hospital admission, effective communication of the individualized care plan among all staff involved in the care of a person with diabetes is essential, with efforts focused on minimizing the metabolic consequences of starvation and surgical stress.
Gene-gene interactions (epistasis) may influence the genetic architecture of diabetes, where rare variants with high penetrance can act together with common alleles to increase disease risk. The extent of allelic heterogeneity appears to be less significant for common forms of type 1 and type 2 diabetes compared to monogenic forms such as MODY, and phenotypic heterogeneity within type 2 diabetes cases may lead to differences in genetic predisposition. For example, lean individuals with type 2 diabetes are likely to carry a higher load of type 2 diabetes risk alleles.
Diabetes is associated with an increased risk of infections due to multiple disturbances in innate immunity, including impaired phagocytosis by neutrophils, macrophages, and monocytes, as well as impaired neutrophil chemotaxis and bactericidal activity, and compromised innate cell-mediated immunity. Humoral immunity remains relatively unaffected, so antibody levels and vaccine responses are generally preserved. Better glycemic control can improve cellular immunity and function. Additionally, diabetes increases the risk of infections such as Staphylococcus aureus and Candida species due to increased skin and mucosal colonization. Some microorganisms, like certain Klebsiella serotypes and Burkholderia pseudomallei, become more virulent in a high glucose environment. Viral infections like hepatitis C are more commonly associated with diabetes, and highly active antiretroviral therapy for HIV/AIDS may also precipitate diabetes.
Improved glycaemic levels can help prevent long-term complications of diabetes such as myocardial infarction or proliferative retinopathy, even though these conditions may not be immediately experienced by the individual. Effective diabetes education should focus not only on increasing knowledge but also on enabling the individual to apply that knowledge to enhance diabetes self-management, as simply providing information is often insufficient to drive behavioural change. Managing diabetes places high demands on the individual regardless of diabetes type, particularly since the benefits of improved management may only become apparent over time and may not be readily recognized.
The Italian Diabetes and Exercise Study compared structured exercise training to physical activity advice in 606 individuals with type 2 diabetes, showing that those who received supervised facility-based combined aerobic and resistance exercise training twice weekly plus physical activity advice experienced a greater reduction in HbA1c levels compared to those receiving physical activity advice alone.
Macrovascular complications occur in individuals with both type 1 and type 2 diabetes, with diabetes contributing to an increased risk of cardiovascular disease independent of other factors like hypertension and hyperlipidaemia. Diabetes accounts for 75–90% of the excess risk for coronary artery disease and amplifies the impact of other cardiovascular risk factors. Stroke and myocardial infarction are major causes of death in people with type 1 and type 2 diabetes, and the rising prevalence of diabetes among younger individuals is accelerating the onset of these long-term complications.
The number of adults in the USA with diagnosed diabetes is projected to rise from 11 million in 2000 (4.0% prevalence) to 29 million in 2050 (7.2% prevalence), with the fastest growth expected among Black Americans. In 2021, 32.2 million people in the USA had diabetes, including 4.0 million undiagnosed cases. In 2018, the CDC reported a total diabetes prevalence of 13.0%, with 10.2% diagnosed and 2.8% undiagnosed. The direct and indirect medical costs attributed to diabetes in the USA reached $327 billion in 2017. While improvements have been made in glycaemic goals and risk factor control over the last two decades, only 14% of diagnosed individuals met all three targets for glycaemic, blood pressure, and lipid management along with smoking cessation. There has also been a significant decline in diabetes-related complications, particularly myocardial infarction and acute hyperglycaemic emergencies.
The Diabetes Control and Complications Trial and the UK Prospective Diabetes Study (UKPDS) have shown that lower levels of glycemia are linked to a reduced risk of long-term microvascular complications in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), respectively. Based on these findings, organizations such as the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and government bodies like the National Institute for Health and Clinical Excellence have established strict glycemic targets to reduce complication risks for people with diabetes. Despite these targets, many individuals with diabetes struggle to achieve optimal glycemic control, and healthcare professionals should work with them to identify reasons for suboptimal control and provide guidance on treatment adjustments or additional education as needed.
Diabetes education must be continuous, age-appropriate, and adapted to the developmental stage of the child. Infants and toddlers present challenges due to unpredictable eating and activity patterns, difficulty distinguishing mood swings from hypoglycaemia or hyperglycaemia, and needle phobia that can affect diabetes management. Hypoglycaemia is common in this age group, and its prevention, recognition, and management are critical. Fear of hypoglycaemia can hinder achieving optimal glycaemic control and exercise goals, potentially increasing long-term diabetes-related complications such as cardiovascular morbidity. Continuous glucose monitoring (CGM) improves time spent in range without increasing hypoglycaemia risk. School-aged children can participate more actively in their diabetes care, including blood glucose monitoring and insulin injections at school, particularly during meals, exercise, and activities. Providers should engage both children and parents in education, focusing on age-appropriate transition of diabetes responsibilities, which becomes especially important during adolescence to balance independent management with parental support.
Neuropathic plantar ulcers are commonly associated with diabetes, particularly in individuals with peripheral neuropathy, which leads to a loss of protective sensation in the feet. These ulcers often develop under areas of increased pressure, such as the metatarsal heads, and can be exacerbated by structural deformities like dorsal dislocation of the digits, resulting in abnormal weight distribution and a "plunger effect" that further damages underlying tissues. Due to impaired sensation and compromised circulation, these ulcers are at high risk for infection and can progress to serious complications if not promptly managed.
Treatment decisions in glucokinase gestational diabetes are guided by fetal growth assessed through ultrasound scans rather than maternal glycaemia alone. Insulin may be used if the fetal abdominal circumference exceeds the 75th centile, though early delivery is considered the most effective approach. Non-invasive fetal genotyping using cell-free fetal DNA (cffDNA) in maternal serum has been developed to assist in managing maternal hyperglycaemia and identifying pregnancies at risk of macrosomia, with high sensitivity and specificity (86.8% and 100%, respectively) and no reported false positives or negatives. Invasive testing such as amniocentesis or chorionic villus sampling is not recommended solely for fetal genotype testing unless performed for other reasons. Guidelines for managing pregnancy in individuals with GCK variants are available online.
Constipation in diabetes is not well understood, though clinical observations suggest it may involve colonic dysmotility and anorectal dysfunction, such as impaired anal sphincter relaxation during defecation. Colonic dysmotility can lead to delayed colonic transit and a reduced contractile response to meals. Additionally, reduced rectal sensation may prevent individuals from feeling the urge to defecate. Studies indicate that acute hyperglycemia inhibits the colonic contractile response to gastric distention and proximal colonic contractions triggered by colonic distention in healthy individuals, though it does not significantly affect fasting or postprandial colonic tone, motility, compliance, or sensation, or rectal compliance and sensation in these individuals.
In patients with type 2 diabetes mellitus (T2DM), the ratio of proinsulin and its conversion intermediates to insulin in the circulation is at least twice as high as population norms, indicating less successful conversion of proinsulin to insulin within beta-cell secretory granules during both basal and stimulated insulin secretion states.
Structured diabetes education programmes have evolved from traditional didactic methods to evidence-based, group-based training that supports self-management. These programmes, initiated in Germany in the 1980s, focus on flexible intensive insulin therapy for type 1 diabetes, showing improved glycaemic control without increasing severe hypoglycaemia. The DAFNE programme in the UK demonstrated combined benefits for both biomedical and psychological outcomes, with long-term sustainability and real-world effectiveness. Qualitative research highlights areas for improvement, leading to ongoing studies like DAFNEplus. For type 2 diabetes, the DESMOND programme provides structured education, showing improvements in health beliefs, weight loss, and smoking cessation, though no significant glycaemic benefit was seen up to 12 months post-diagnosis. At three years, HbA1c levels improved in both intervention and control groups, with sustained improvements in health beliefs, which were linked to reduced psychological distress, underscoring the importance of early educational support at diagnosis.
DPP-4 inhibitors have a glucose-dependent mechanism of action, reducing HbA1c levels by approximately 0.7–1.0% (8–11 mmol/mol), decreasing post-prandial glucose excursions by around 3 mmol/l, and lowering basal glycaemia by about 1–1.5 mmol/l. These agents enhance insulin secretion only when glucose concentrations are elevated, thereby minimizing the risk of hypoglycaemia and eliminating the need for dose titration. Fasting and post-prandial glycaemia should be assessed after approximately two weeks of therapy, particularly when used as a second-line treatment. DPP-4 inhibitors do not significantly affect gastric emptying or induce satiety, and they are weight-neutral or may promote slight weight loss.
A multidisciplinary specialist diabetes pregnancy service should provide diet and lifestyle advice, appropriate contraception, alcohol and drug counselling, higher-dose folic acid supplementation, smoking-cessation support, and assessment and management of diabetes complications. The service should also involve setting glycaemic targets and regular discussion of self-monitoring results to help the woman achieve near-normal glucose levels before conception. Additionally, there should be discussions regarding diabetes pregnancy risks and management strategies, along with clear documentation of care and counselling. Once pregnant, a woman with diabetes should have access to a specialist multidisciplinary team including obstetricians, diabetologists, dieticians, diabetes specialist nurses, and midwives. This team should develop an individualized care plan covering the pregnancy and postnatal period up to six weeks, detailing glycaemic targets, retinal and renal screening schedules, fetal surveillance, delivery plans, and immediate post-delivery diabetes care.
Insulin has been tested via parenteral, oral, or intranasal routes in genetically predisposed individuals, first-degree relatives (FDR) and patients with type 1 diabetes mellitus (T1DM), though trials generally showed no effect on disease progression or beta-cell loss. However, a subanalysis from the oral arm of the Diabetes Prevention Trial-1 (DPT-1) found a statistically significant delay in the onset of T1DM in subjects with high titer insulin autoantibodies (IAA), prompting a repeat study of the oral insulin trial.
Pioglitazone, a selective ligand of the PPAR-γ receptor, modulates insulin action, glucose and lipid metabolism, inflammation, and adipose tissue biology, with one of its isoform targets, PPAR-γ2, playing a key role in redistributing intra-abdominal and subcutaneous adipose tissue by promoting triglyceride accumulation in peripheral adipose depots, and it has shown long-term benefits in individuals with biopsy-confirmed NASH, including those with type 2 diabetes, by improving serum liver enzyme levels, liver fat content, and resolution of NASH.
Metformin and thiazolidinediones are oral antidiabetic medications used in the management of type 2 diabetes mellitus. Metformin works primarily by decreasing hepatic glucose production and improving insulin sensitivity in peripheral tissues. Thiazolidinediones, also known as glitazones, act by activating peroxisome proliferator-activated receptor gamma (PPAR-γ), which enhances insulin sensitivity in adipose tissue, muscle, and liver. Both drug classes help lower blood glucose levels and are often used as second-line agents in diabetes treatment.
The adjusted prevalence of type 2 diabetes mellitus (T2DM) is higher in men compared to women, with rates of 7% in men and 3% in women aged 35–65 years, and increases significantly in both sexes with age, reaching 19% in males and 9% in females over 60 years. Additionally, the adjusted prevalence of impaired fasting glucose (IFG) is 12% in men and 5% in women within the 35–65 age group.
Erythrasma, caused by Corynebacterium minutissimum, occurs more frequently in obese patients with diabetes and presents as red, shiny, or scaly patches in intertriginous areas, exhibiting coral-red fluorescence under ultraviolet light, and is treated with topical or systemic erythromycin. Patients with diabetes are also at increased risk for unusual infections with coliforms, anaerobes, and Pseudomonas, including infections of the toe web spaces, nailfold paronychia, and secondary infection of venous ulcers. Anaerobic cellulitis with Clostridium species can occur in those with diabetic ketoacidosis and requires metabolic control, aggressive debridement, and intravenous antimicrobial therapy. Necrotizing fasciitis, a potentially lethal infection more common in patients with diabetes, can be caused by Streptococcus pyogenes, anaerobic streptococci, Bacteroides, and Staphylococcus aureus, often extending from minor wounds or ulcers, leading to rapid progression, extensive tissue destruction, and severe systemic toxicity that may result in death. This condition should be suspected in diabetic patients with cellulitis and systemic features such as tachycardia.
Parents of children newly diagnosed with diabetes may experience psychological responses similar to adjustment disorders, with mothers often showing mild depressive symptoms, anxiety, and generalized distress that typically subside within six months. Fathers generally exhibit fewer symptoms of emotional dysfunction, both shortly after diagnosis and up to a year later, though high emotional distress in fathers during the first two years is linked to poorer metabolic control and greater blood glucose variability in their children over the first five years. Elevated rates of post-traumatic stress disorder (PTSD) have been observed in parents, with 16–22% of mothers and 8–14% of fathers meeting DSM-IV criteria for PTSD at various points within the first year following diagnosis. These PTSD rates are higher than in the general population and comparable to those seen in mothers of children with cancer, with the severity of PTSD at 12 months being best predicted by its severity earlier in the adjustment period.
Diagnosis of glucokinase MODY is crucial in young patients who might otherwise be misdiagnosed with type 1 diabetes mellitus (T1DM) and unnecessarily treated with insulin. Glucokinase MODY is characterized by mild hyperglycemia, negative β-cell antibodies, and a likelihood that one parent also has mild hyperglycemia. In contrast to T1DM, fasting C-peptide levels remain detectable in glucokinase MODY, and the post-meal rise in glucose is significantly lower. Distinguishing glucokinase MODY from type 2 diabetes mellitus (T2DM) can be challenging since both have mild hyperglycemia and strong family histories, but features such as absence of obesity, lack of insulin resistance, a small glucose increment during oral glucose tolerance testing, and non-progression of the condition favor a diagnosis of glucokinase MODY.
During recovery from hypoglycaemia, interstitial glucose levels may lag behind blood glucose levels, meaning that even when blood glucose has normalized, sensor readings of interstitial glucose may still appear low. This delay highlights the importance of using capillary blood glucose measurements to accurately assess the response to hypoglycaemia treatment, especially for individuals who rely on real-time continuous glucose monitoring (rtCGM) to determine whether glucose levels are improving after carbohydrate intake.
An overall lack in numbers and of appropriately trained human resources is one barrier to diabetes management in low- and middle-income countries (LMICs), and the data generated by the health system are rarely used to inform planning and responses due to not being collected for these purposes, in addition to there being a lack of research into various areas of diabetes in LMIC contexts.
Familial mild fasting hyperglycaemia, also known as glucokinase maturity-onset diabetes of the young (MODY), is a form of diabetes characterized by mild fasting hyperglycemia that typically presents in early adulthood.
The ADVANCE Trial assessed the effects of intensive glucose control on major macrovascular and microvascular events in patients with diabetes. The primary outcome was a composite of major macrovascular events, including endovascular death, non-fatal myocardial infarction, or non-fatal stroke, as well as major microvascular events such as new or worsening nephropathy or retinopathy. The trial used Kaplan-Meier curves to evaluate the incidence of these outcomes and all-cause mortality over time in the study groups.
The text provides information on various combination medications used in the management of diabetes, primarily involving metformin combined with other antidiabetic agents such as sulfonylureas (e.g., glibenclamide, glipizide), thiazolidinediones (e.g., rosiglitazone, pioglitazone), DPP-4 inhibitors (e.g., vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin), SGLT2 inhibitors (e.g., dapagliflozin, canagliflozin, empagliflozin, ertugliflozin), and meglitinides (e.g., repaglinide). These combination therapies are available in varying strength ratios to allow for individualized treatment approaches, with the aim of improving glycemic control through complementary mechanisms of action. Some combinations also include non-metformin based pairings such as rosiglitazone with glimepiride, pioglitazone with glimepiride, and empagliflozin with linagliptin, offering alternative treatment strategies for patients with type 2 diabetes.
Liraglutide was evaluated in the SCALE programme, which included a 56-week trial involving individuals with obesity but without type 2 diabetes, resulting in significant weight loss and improvements in metabolic parameters including fasting glucose, fasting insulin, and HbA1c compared to placebo. Additional trials assessed liraglutide’s efficacy in individuals with obesity and sleep apnoea, type 2 diabetes, and for weight maintenance following diet-induced weight loss. A post hoc analysis confirmed cardiovascular safety and suggested potential benefits, consistent with evidence from lower-dose liraglutide and semaglutide formulations used in the treatment of type 2 diabetes.
Planning carbohydrate intake and premeal insulin dosage are key aspects in managing type 1 diabetes mellitus (T1DM) in children, requiring education for both the child and parents. As growth and energy needs change with age, meal plans should be reassessed at least annually, and if a child becomes overweight, caloric intake should be adjusted. Children with diabetes must also recognize early signs of hypoglycemia and respond by consuming fast-acting carbohydrates like glucose. Additionally, unusual physical activity necessitates blood glucose monitoring before and after exercise to determine if adjustments in carbohydrate intake or insulin dosage are needed.
The GRADE study compares the efficacy and safety of four anti-diabetes agents—glimepiride, sitagliptin, liraglutide, and insulin—among individuals with type 2 diabetes who have less than 10 years of diabetes duration and are on metformin therapy, with preliminary results suggesting that liraglutide and insulin may offer better glycaemic control than glimepiride and sitagliptin. The MASTERMIND study investigates individual variation in glycaemic response to gliclazide or sitagliptin in people with type 2 diabetes over a four-week period followed by a washout phase. The ROTATE trials use a crossover design to assess how individuals with type 1 or type 2 diabetes respond to four kidney-protective drugs: SGLT-2 inhibitors, DPP-4 inhibitors, ARBs, and JAK-STAT inhibitors. These studies aim to address gaps in understanding treatment response variability and the influence of the metabolic environment on the effectiveness of glucose-lowering therapies, potentially guiding more personalized treatment selection.
Nutrient excess contributes to insulin resistance by inhibiting proximal insulin receptor signals through chronic insulin secretion, feedback mechanisms, or inflammatory pathways, and elevated insulin levels can lead to hepatic lipogenesis, dyslipidaemia, white adipose tissue expansion, and hepatic steatosis, while increased circulating and hepatic lipids such as non-esterified fatty acids, diacylglycerol, and ceramides can further impair insulin signaling through kinase activation and inflammatory cascades, and nutrient excess also activates mTORC1-mediated feedback that disrupts insulin receptor coupling with IRS1/IRS2, all of which highlight mechanisms contributing to insulin resistance and diabetes pathology.
Orlistat has been shown to prevent progression to diabetes in the XENical in the prevention of diabetes in obese subjects (XENDOS) study, and both sibutramine and rimonabant demonstrated benefits on lipids in patients with the metabolic syndrome and diabetes.
Supplementation with cod liver oil, which provides vitamin D and omega-3 fatty acids, during the first year of life is associated with a reduced risk of type 1 diabetes mellitus (T1DM) in Norwegian children.
Choudhary et al. investigated brain responses to hypoglycaemia in individuals with type 1 diabetes, particularly those with impaired awareness of hypoglycaemia, using 3D pseudo-continuous arterial spin labelling MRI. They observed altered cerebral blood flow in brain regions related to arousal, decision making, and reward in those with impaired awareness, suggesting that disruptions in these neural pathways may hinder the ability to recognize and manage hypoglycaemia. Their work further showed that awareness of hypoglycaemia in people with type 1 diabetes can be restored through a structured education programme known as Dose Adjustment for Normal Eating, along with specialist support and sensor-augmented pump therapy.
Promoting self-care and healthy choices in adolescents with type 1 diabetes mellitus (T1DM) is crucial for better management before transitioning to adult services, with early and gradual encouragement of independence being particularly important during adolescence. Factors such as self-care practices, eating behaviors, depression, and peer relationships have been found to influence blood glucose control, with poor self-care, disturbed eating, depression, and negative peer interactions linked to poorer control. Supportive family relationships, especially parental support, contribute to better glycemic control in girls compared to boys. Monitoring diabetes knowledge and fostering self-efficacy from late childhood may help transfer self-care responsibilities from parents to adolescents, optimizing diabetes management.
Diabetes is associated with defects in nitric oxide-mediated smooth-muscle relaxation, contributing to erectile dysfunction. This occurs due to neuropathy affecting non-adrenergic, non-cholinergic (NANC) fibers and endothelial dysfunction. These impairments disrupt the normal pathways leading to corpus cavernosal smooth-muscle relaxation, which is essential for achieving and maintaining an erection. Key mediators in this process include acetylcholine, nitric oxide, and cyclic guanosine monophosphate, with phosphodiesterase type 5 playing a role in the degradation of cGMP, thereby reducing smooth-muscle relaxation.
SIRT1 is expressed in pancreatic β-cells where it may facilitate insulin secretion, and in other tissues such as liver, muscle, and fat, where it promotes mitochondrial biogenesis, increases thermogenesis, and reduces susceptibility to diabetes. Activators of SIRT1 have been shown to enhance insulin sensitivity and reduce plasma glucose in animal models.
Counter-regulatory failure in diabetes can result from antecedent hypoglycaemia, exercise, or sleep, each leading to reduced sympathoadrenal and symptomatic responses during hypoglycaemia. Late post-exercise hypoglycaemia typically occurs 6–15 hours after strenuous activity, often at night. Sleep-related counter-regulatory failure further dampens the body's response to low blood sugar during sleep, making individuals with diabetes less likely to wake up during hypoglycaemic episodes. These functional impairments may be reversible, and there could also be an underlying structural component contributing to hypoglycaemia-associated counter-regulatory failure.
Insulin receptor-deficient mice exhibit severe hyperglycaemia, pancreatic β cell failure, and ketoacidosis, leading to death shortly after birth, highlighting the essential role of insulin receptor signaling in postnatal nutrient homeostasis. These mice can be genetically rescued through transgenic expression of the insulin receptor in the brain, liver, and pancreatic β cells. In contrast, humans with rare mutations causing non-functional insulin receptors experience intrauterine growth retardation, failure to thrive, and initial hypoglycaemia before developing hyperglycaemia, possibly due to limited gluconeogenic substrates or compensatory activation of IGF-I receptors by hyperinsulinaemia.
Diabetes encompasses various types with distinct features, including Type 1 diabetes, young-onset Type 2 diabetes, and several forms of monogenic diabetes such as GCK MODY, HNF1A MODY, MIDD, and KATP PNDM. Type 1 diabetes typically presents from infancy to young adulthood, is insulin-dependent, and often involves β-cell autoantibodies, with low C peptide levels outside the honeymoon period. Young-onset Type 2 diabetes usually occurs in adolescents and young adults, is not insulin-dependent, and is associated with obesity and acanthosis nigricans, along with higher C peptide levels. GCK MODY may be diagnosed at any age, is non-insulin-dependent, and shows mild glycemia with normal to low C peptide levels. HNF1A MODY typically begins in the teens to young adulthood, does not involve autoantibodies, and has moderate glycemia with C peptide levels ranging from low to moderate. MIDD usually presents in young adults, is maternally inherited, and may require insulin, with variable glycemia and C peptide levels. KATP PNDM manifests under six months of age, is often insulin-dependent, and shows high glycemia with low C peptide levels. A family history is common in monogenic forms and young-onset Type 2 diabetes, whereas it is less frequent in Type 1 diabetes. Obesity is generally not associated with most monogenic types or Type 1 diabetes but is typical in young-onset Type 2 diabetes.
Patients with diabetes may experience a balance of risks and benefits from anticoagulation therapy, suggesting that the potential risks may outweigh the benefits gained from such treatment.
Diabetes can be diagnosed based on several criteria: fasting plasma glucose (FPG) of 126 mg/dl (7.0 mmol/l) or higher after at least 8 hours of fasting, a 2-hour plasma glucose of 200 mg/dl (11.1 mmol/l) or higher during an oral glucose tolerance test (OGTT) using 75 g of anhydrous glucose, HbA1C of 6.5% (48 mmol/mol) or higher measured using a method certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the Diabetes Control and Complications Trial (DCCT) assay, or a random plasma glucose of 200 mg/dl (11.1 mmol/l) in a person with classic symptoms of hyperglycaemia or hyperglycaemic crisis. In cases without clear hyperglycaemia, the diagnosis requires two abnormal results either from the same sample or from two separate tests.
In diabetes, the regulation of glucose production and release by the liver becomes dysregulated, contributing to hyperglycemia. Hepatic glucose output occurs through glycogenolysis and gluconeogenesis, with the latter being responsible for over 90% of glucose synthesized de novo from precursors such as pyruvate, lactate, amino acids, and glycerol. During prolonged fasting, increased gluconeogenesis compensates for diminished glycogen stores, a process that can be exacerbated in diabetes due to impaired insulin signaling, leading to excessive glucose production and worsening glycemic control.
Anxiety symptoms and anxiety disorders are associated with an approximately 50% increased risk of developing diabetes, and post-traumatic stress disorder (PTSD) is also linked to a higher diabetes risk with an odds ratio of 1.5. Some evidence suggests that diabetes may be a risk factor for anxiety, as indicated by a study using data from a Taiwanese insurance database, which found a higher annual incidence of anxiety disorder over five years in people with diabetes. However, the available studies on the incidence of anxiety in individuals with diabetes have significant methodological limitations, preventing definitive conclusions about the directionality of the relationship between diabetes and anxiety.
Insulin signaling plays a critical role in diabetes through the activation of two main pathways: the PI3K and Grb2/SOS cascades. Upon insulin stimulation, IRS proteins activate PI3K, which generates phospholipids that recruit PDK1 and AKT to the plasma membrane. AKT is phosphorylated at T308 by PDK1 and subsequently at S473 by mTORC2, enabling it to regulate downstream targets such as GSK3, BAD, AS160, and FOXO1. These proteins influence glucose metabolism, apoptosis, and gene expression, with FOXO1 being sequestered and degraded in the cytoplasm upon AKT phosphorylation, thereby reducing its transcriptional activity. Additionally, mTORC1, activated by RhebGTP, mediates the phosphorylation of S6K and SREBP1, promoting protein and lipid synthesis. Impairments in these signaling pathways, particularly in AKT activation and downstream effects, are associated with insulin resistance and the pathophysiology of diabetes.
Thiazolidinediones (TZDs) are associated with an increased risk of long bone fractures in women, as observed in the PROactive and ADOPT trials, with fracture rates approximately doubling compared to comparator groups. This complication occurs early in treatment and is not related to diabetic control. A possible explanation involves the role of PPAR in osteoblast cell differentiation, though the exact mechanism remains unclear. Screening for fracture risk, including assessment of cortical bone at the wrist, should be considered at the start of TZD therapy and periodically during treatment.
Islet transplantation has evolved significantly over the past decade, with more than 650 procedures performed worldwide using the Edmonton protocol or its variants, often incorporating newer advances.
Patients with diabetes have a higher incidence of large-vessel disease, which can present as dependent rubor with delayed return of skin color after pressure. They are also prone to macrovascular changes leading to cutaneous signs of ischemia in the lower limbs such as cold or cyanosed feet, erythema, hair loss, and atrophy. Additionally, they are more likely to develop non-healing ulcers due to a combination of venous insufficiency, arterial disease, and neuropathy. Venous stasis ulcers are common, especially in obese patients, due to increased lower extremity venous pressure resulting in venous hypertension and skin breakdown. Neuropathy further contributes to foot ulceration by impairing pain sensation, allowing repeated trauma and shear forces to cause skin breakdown without protective responses.
Hyperosmolar hyperglycaemic state (HHS) is associated with complications such as venous thrombosis linked to central venous catheter use, rhabdomyolysis, and malignant hyperthermia, with cerebral oedema being a rare occurrence. In children presenting with a mixed picture of diabetic ketoacidosis (DKA) and HHS, management typically involves administering more fluids than usual for DKA and initiating insulin earlier than in HHS, though treatment decisions should be guided by the individual clinical presentation.
Amylin, a 37 amino acid polypeptide co-secreted with insulin by pancreatic β-cells, is the principal constituent of amyloid deposits in the islets of Langerhans in type 2 diabetes mellitus (T2DM). Pancreatic amyloidosis has been associated with β-cell loss in both Caucasian and Chinese individuals. The formation of intracellular islet amyloid polypeptide (IAPP) oligomers contributes to β-cell loss and progressive hyperglycemia. Genetic variants affecting amylin metabolism or changes in the metabolic environment may lead to structural alterations in amylin, increasing oligomerization and resulting in β-cell death.
The association between schizophrenia and diabetes has been recognized since the early 20th century, with increased attention in the 21st century due to marketing claims about antipsychotic drugs. Early studies showed a link between schizophrenia and diabetes before antipsychotics were available, suggesting the disease itself may be a risk factor. More recent studies involving drug-naïve patients are limited due to ethical concerns. The introduction of phenothiazines in the 1950s and 1960s led to reports of "phenothiazine diabetes," but interpretation of historical research is complicated by differing diagnostic criteria for both psychiatric and diabetic conditions.
Metformin, available as an immediate-release tablet or liquid, should be taken with or immediately before meals to reduce gastrointestinal side effects. Treatment typically starts at 500 or 850 mg once daily, or 500 mg twice daily, with the dose gradually increased by one tablet every 1 to 2 weeks until blood glucose targets are met. If further dose increases do not improve control, the previous effective dose should be resumed. When monotherapy is insufficient, combination therapy with another agent such as an insulin secretagogue or thiazolidinedione may be considered. The maximal effective dose of metformin is around 2000 mg per day given in divided doses, though some countries allow up to 2550 or 3000 mg daily.
Genetic susceptibility plays a role in diabetic nephropathy among patients with type 1 diabetes mellitus (T1DM), with evidence showing that only about 40% of patients are at risk. The risk increases significantly if a sibling with diabetes has nephropathy, with the likelihood of a second sibling developing it rising four- to eightfold. Parents of patients with diabetes and nephropathy also show clustering of conventional cardiovascular risk factors and cardiovascular disease (CVD), indicating that genetic factors contributing to nephropathy may also influence CVD development. Multiple genes are likely involved in nephropathy, with different genetic loci potentially affecting urinary albumin excretion (UAE) and glomerular filtration rate (GFR) separately. However, many candidate genes identified in smaller studies have not been validated in larger, well-powered cohorts.
In the UK, individuals with diabetes must inform the DVLA when applying for or renewing a driving license, particularly if diabetes develops after obtaining the license, as failure to disclose can result in fines and invalidation of insurance claims. Drivers using diet or antidiabetic medications without insulin typically do not need to notify the DVLA unless they have diabetes-related complications affecting driving ability, such as visual impairment. Licenses are usually issued for up to 3 years and require a medical questionnaire for renewal, with additional medical reports requested in certain cases, especially when there is a report of a condition like recurrent hypoglycemia that may affect driving. GLP-1 agonists administered by injection generally do not impose restrictions unless combined with sulfonylureas for group 2 (vocational) licenses, which requires notification and assessment of medical fitness to drive. Healthcare providers are responsible for informing patients of these legal requirements and offering practical advice.
Sulfonylureas stimulate insulin secretion by acting on the β cells of the islets of Langerhans. They bind to the sulfonylurea receptor 1 (SUR1), which is part of a complex with ATP-sensitive potassium (KATP) channels, leading to channel closure, reduced potassium efflux, and subsequent membrane depolarization. This depolarization opens voltage-dependent calcium channels, increasing intracellular calcium levels and triggering insulin release through calcium-dependent signaling pathways. The release occurs in two phases: an immediate first phase involving preformed insulin granules and a second phase starting around 10 minutes later, involving both preformed and newly synthesized insulin granules. Sulfonylureas can cause hypoglycemia by stimulating insulin release even at glucose concentrations below the normal threshold of approximately 5 mmol/L, mainly due to insulin-induced suppression of hepatic glucose production, and their effectiveness depends on functionally competent β cells.
For individuals with diabetes and normal renal function, there is insufficient evidence to modify usual protein intake, and concerns about protein deficiency appear to be minimal based on nutrition intake data across countries and patient groups. However, the long-term effects of high protein intake above 20% of total energy on renal function remain unclear, and while high protein diets may lead to short-term weight loss and improved glycemia, the sustained benefits have not been established, leading to a current recommendation against their use for weight loss in diabetes management.
Excess ketones were identified in the 19th century, and a distinction was made between two main types of diabetes: one occurring in young individuals with a rapid progression to ketoacidosis, and another found in older, obese individuals. These types became known as juvenile-onset and maturity-onset diabetes, though the latter was considered a milder form. Diagnosis relied on glucose measurement, sometimes through glucose tolerance tests, although standardized criteria were initially lacking. Diagnosis typically occurred after clinical symptoms appeared, with elevated blood glucose or glycosuria being diagnostic, along with ketonuria in juvenile-onset diabetes.
Hyperglycemia does not downregulate glucose transport in cells affected by diabetic complications, as demonstrated by studies showing that vascular smooth muscle and aortic endothelial cells pre-exposed to high glucose levels (22 mmol/L) do not reduce their glucose uptake compared to those exposed to normal glucose levels (5.5 mmol/L).
Low-intensity laser therapy may have an anti-inflammatory effect and has been studied in individuals with painful diabetic neuropathy, showing a decrease in weekly mean pain scores in both the treatment and sham groups, though no significant differences were observed in neurological assessments such as the Toronto Clinical Neuropathy Score, nerve conduction studies, sympathetic skin response, or quantitative sensory testing. Additionally, recent evidence suggests that this therapy may improve the healing of diabetic foot ulcers.
Limited joint mobility is prevalent in both type 1 and type 2 diabetes, with estimates ranging from 9% to 66% in type 1 diabetes and from 25% to 75% in type 2 diabetes. Prevalence rates for limited joint mobility in type 1 diabetes have decreased over the past two decades, likely due to improved glycaemic management.
Older people with diabetes have an increased risk of geriatric syndromes such as cognitive and physical dysfunction, depression, falls, and urinary incontinence. Diabetes is linked to a twofold higher risk of difficulty performing daily physical tasks and a 1.6-fold greater risk of challenges with basic personal care. Complications like neuropathy, arthritis, and vascular disease contribute to physical disability in this population. Diabetes also raises the risk of falls, with contributing factors including arthritis, musculoskeletal pain, depression, poor vision, and peripheral neuropathy. Additionally, older adults with diabetes face a twofold higher risk of developing Alzheimer’s disease or vascular dementia. Studies show a higher incidence of depression in older individuals with diabetes compared to those without, as seen in the Health, Aging, and Body Composition Study where the rate was 23.5% versus 19.0%.
Insulin resistance and $\beta$-cell failure are key factors in the development of type 2 diabetes mellitus (T2DM), with evidence suggesting that a linear decrease in both first-phase insulin release and insulin sensitivity occurs as individuals progress from normal glucose tolerance to impaired glucose tolerance. When the plasma glucose concentration 2 hours after a 75g oral glucose challenge reaches 11.1 mmol/L (200 mg/dL), post-glucose insulin concentrations begin to fall, allowing glucose levels to rise into the diabetic range. Prospective studies show a similar pattern, indicating that low insulin sensitivity and impaired first-phase insulin release are predictive of T2DM onset. The progression to overt hyperglycemia appears to require a relative decrease in insulin secretion.
Tight glucose control is associated with reduced risks of diabetes-related deaths, stroke, and microvascular disease, as indicated by relative risk values of 0.76, 0.56, and 0.63 respectively, with statistically significant reductions observed in microvascular disease (p=0.009) and stroke (p=0.013). While tight control also shows lower relative risks for myocardial infarction, peripheral vascular disease, and all-cause mortality, these differences are not statistically significant.
Diabetic sensorimotor polyneuropathy is a symmetrical, length-dependent sensorimotor polyneuropathy caused by metabolic and microvascular changes from chronic hyperglycemia in diabetes or prediabetes, as well as cardiovascular risk factors. It typically begins subtly and progresses without early intervention, leading to a poor prognosis. The condition follows a glove and stocking distribution, initially affecting the toes and feet before involving the fingers and hands, with possible extension to the anterior abdominal wall and lateral trunk in advanced stages. It is associated with height and involves small nerve fibres (Aδ and C fibres) first, which are responsible for pain and hyperalgesia, followed by large-fibre (Aa, Aβ fibres) dysfunction. Early small fibre involvement is evidenced by reduced corneal and intraepidermal nerve fibres and occurs before nerve conduction abnormalities appear, as observed in individuals with type 1 diabetes, type 2 diabetes, impaired glucose tolerance, and children with type 1 diabetes.
Whole pancreas and islet cell transplantation offer optimal glycaemic management post-transplant and nearly eliminate severe hypoglycaemia. In islet cell transplantation, graft function is maintained for several years even after insulin independence is lost, leading to improved glycaemic control over time. However, despite advancements in β-cell replacement therapies, challenges persist such as limited availability of organs or tissue, difficulties in peri-procedural care, and the requirement for lifelong immunosuppression.
Certain drugs require caution when used in patients with specific diabetic complications, likely due to the risk of exacerbating conditions such as neuropathy, nephropathy, or cardiovascular issues, though the exact drugs and their associated complications are not listed in the provided sentence.
Microscopic haematuria can occur in individuals with type 1 diabetes, especially children, even without significant renal dysfunction, though concurrent renal disease must be ruled out. Renal complications, such as those arising from renal arterial atherosclerosis, may affect up to 20% of older individuals with type 2 diabetes, and if bilateral, can result in severe and potentially permanent kidney damage, particularly if angiotensin-converting enzyme (ACE) inhibitors are administered.
Some glucose-lowering agents are contraindicated or require dose adjustment in patients with chronic kidney disease. Metformin is contraindicated in severe chronic kidney disease due to the risk of lactic acidosis, while sulfonylureas such as glimepiride and glipizide are generally considered safe but may carry a risk of hypoglycemia. Insulin is a suitable option for glycemic control in chronic kidney disease and does not require dose adjustment in early stages, though careful monitoring is necessary as kidney function declines.
When using continuous glucose monitoring systems, fingerstick capillary blood glucose measurements are necessary in specific situations: if the sensor indicates elevated glucose, a fingerstick reading must confirm the level before administering a corrective insulin bolus; if subjective symptoms do not align with the sensor reading, a fingerstick test should be performed; before or during driving, if the sensor shows normal glucose but the rate of change suggests a decline, blood glucose should be checked via fingerstick; and after treating low glucose, if the sensor still indicates a low level, a fingerstick measurement should guide further carbohydrate intake to avoid overtreatment.
Selective insulin resistance in skeletal muscle contributes to the diversion of ingested carbohydrates from muscle glycogen synthesis to the liver, leading to increased hepatic de novo lipogenesis, triglyceride synthesis, and very low-density lipoprotein (VLDL) secretion, which results in hypertriglyceridaemia and reduced high-density lipoprotein (HDL) levels. This process, linked to compensatory hyperinsulinaemia, is associated with the development of atherogenic dyslipidaemia and non-alcoholic fatty liver disease. Physical activity can restore this abnormal energy storage pattern by enhancing glucose uptake and glycogen synthesis in muscle through insulin-independent activation of AMPK and GLUT4, thereby improving hepatic carbohydrate and lipid metabolism.
Diagnostic testing for monogenic diabetes is widely available, and molecular testing should be reserved for individuals with a moderate to high likelihood of a positive result due to its cost and complexity. Testing should be guided by clinical phenotype and mutation prevalence in the population, and family history should be considered since many forms are familial. Caution is advised because monogenic diabetes can coexist with T1DM or T2DM in the same family, and molecular test results must be interpreted in the context of clinical findings, as individuals with monogenic diabetes may also develop other forms of diabetes such as T1DM or T2DM.
In some cases, individuals initially presenting with acute ketosis may not require insulin treatment and may follow a clinical course similar to type 2 diabetes, particularly in certain ethnic groups such as African-American youths and Asians. This presentation often lacks the typical HLA genotypes or autoantibodies associated with autoimmune type 1 diabetes, and may instead be linked to obesity, insulin resistance, and glucotoxicity contributing to the initial ketotic state.
The case describes a 67-year-old man with type 2 diabetes, presenting with elevated liver enzymes (ALT 66 IU/l, AST 72 IU/l) and an AST/ALT ratio of 1.1, alongside hypertriglyceridemia (2.1 mmol/l or 186 mg/dl). His HbA1c is elevated at 8% (64 mmol/mol), indicating suboptimal glycemic control. He is being treated with metformin at a dose of 1000 mg twice daily. Clinical findings include obesity (BMI 30 kg/m², waist circumference 107 cm), moderate hepatomegaly, and hypertension (blood pressure 144/90 mmHg). He has no history of viral hepatitis, cardiovascular disease, or chronic kidney disease, and his kidney function and other lipid parameters, including LDL cholesterol, are normal.
Excessive flux of fatty acids to the liver contributes to non-alcoholic fatty liver disease (NAFLD) through increased hepatic esterification, a process that occurs largely independently of insulin, and thus is not solely dependent on selective hepatic insulin resistance. Hepatic mitochondria may initially adapt to the increased substrate availability by enhancing their oxidative capacity, though this comes at the cost of reduced coupling efficiency. As substrate overloading continues, the liver's antioxidant defenses are overwhelmed, leading to increased oxidative stress, mitochondrial dysfunction, and decreased mitochondrial biogenesis, which can progress to non-alcoholic steatohepatitis (NASH) and worsen insulin resistance.
HbA1c is a blood test that measures average blood glucose levels over the past 2 to 3 months and is used to diagnose and monitor diabetes. Microalbuminuria, detected through a spot urine sample, indicates early kidney damage and is a common complication of diabetes. Urine protein and urine creatinine tests assess kidney function, which is often affected in diabetic patients. Haemoglobin levels may also be evaluated in diabetes management, as chronic hyperglycemia can impact red blood cell function and oxygen transport.
Self-monitoring of blood glucose is important for dose titration in diabetes management, typically performed by the patient at home. However, the ultimate measure of the effectiveness of basal insulin therapy is the HbA₁c value. If HbA₁c remains difficult to control despite satisfactory fasting plasma glucose levels, the next step may involve adding a prandial or rapid-acting insulin component to the treatment regimen.
Ophthalmoplegia secondary to diabetes has a prevalence of approximately 0.32%, with third nerve palsy being the most common type, occurring in about 53% of cases and being painful in roughly half. This condition presents with sudden-onset retro-orbital and supra-orbital pain, which may precede ptosis and diplopia, and involves pupillary dysfunction in 14–18% of cases. Ophthalmoplegia typically persists for several weeks, with full recovery usually within 12 weeks, and can also affect the 4th, 6th, and 7th cranial nerves. Key risk factors include age over 45 years, diabetes duration greater than 10 years, male sex, and presence of retinopathy and nephropathy.
Maturity-onset diabetes of the young (MODY) is a form of diabetes caused by single gene mutations, often involving genes such as GCK (glucokinase) or HNF1A (hepatocyte nuclear factor 1A), and may also include mutations in HNF4A. Another genetic form of diabetes is maternally inherited diabetes and deafness (MIDD), which is passed down through the mother. Permanent neonatal diabetes (PNDM) is a rare type of diabetes diagnosed in newborns and is often caused by genetic mutations. Treatment options for diabetes include oral anti-diabetes drugs (OADs) such as sulfonylureas (SU), which help manage blood glucose levels.
Insulin detemir is a long-acting insulin formulation with a dose-dependent duration of effect, achieving an average of about 20 hours at a common dosage of 0.4 units/kg and up to 24 hours with higher doses. In a 24-week study comparing twice daily insulin detemir to NPH in subjects with type 2 diabetes mellitus (T2DM) inadequately controlled on oral agents, both insulins reduced HbA1c significantly, with detemir decreasing it by 1.8% to an average of 6.8% and NPH by 1.9% to 6.6%. Most subjects achieved HbA1c below 7%, but more subjects on detemir reached this target without experiencing hypoglycemia. Insulin detemir demonstrated significantly less hypoglycemia and comparable glycemic efficacy to NPH, although the required insulin doses were higher than typically expected.
Urine glucose measurement has limited clinical utility in diabetes management because it does not accurately reflect fluctuating blood glucose levels, and the renal threshold for glucose excretion varies among individuals, during pregnancy, and with age. However, it may still be useful in resource-poor settings where identifying and treating individuals with poorly controlled diabetes is a priority.
When plasma glucose concentration exceeds the renal threshold for tubular reabsorption, which averages 11 mmol/l but varies individually between 6–14 mmol/l, glucose begins to appear in the urine. The maximum absorptive capacity of the renal tubules also influences this process, and it changes with age, with older individuals typically exhibiting glycosuria at higher plasma glucose levels.
Insulin treatment for diabetes must be carefully managed as it carries the risk of hypoglycaemia and requires varying daily doses. While insulin significantly improved survival rates for people with diabetes, it also changed the course of the disease from an acute, rapidly fatal condition into a chronic one with long-term complications. For example, kidney disease became a much more common cause of death among diabetic patients after the introduction of insulin, with over 50% of Joslin's patients dying from it during 1944–1955, compared to only 2% before 1937.
People with diabetes have a two- to fourfold increased risk of cardiovascular disease (CVD) compared to non-diabetic individuals, and while guidelines do not recommend formal CVD risk estimation for these patients due to already elevated risk and limitations of tools like the Framingham algorithm in underestimating it, clinicians may still use risk calculators such as the UK Prospective Diabetes Study (UKPDS) model, which varies in predictive accuracy. Given the limitations of all CVD risk estimation methods, clinical judgment is essential for accurate risk assessment and appropriate treatment selection and adjustment.
Dulaglutide is a GLP-1 receptor agonist used for the treatment of type 2 diabetes, administered as a once-weekly injection. It has been shown in clinical trials to cause dose-dependent reductions in HbA₁c and fasting plasma glucose levels, as well as weight loss. It demonstrates a low incidence of hypoglycemia, with the most common adverse events being gastrointestinal, such as nausea and diarrhea, which are typically mild to moderate and transient. Dulaglutide 1.5 mg once weekly has shown non-inferiority to liraglutide 1.8 mg once daily in reducing HbA₁c after 26 weeks, although liraglutide resulted in greater weight loss. Dose escalation of dulaglutide to 3.0 mg or 4.5 mg has demonstrated clinically relevant, dose-related improvements in glycemic control and body weight reduction while maintaining a similar safety profile, and all three doses are now available for treating type 2 diabetes.
Prepregnancy care for women with diabetes aims to optimize glycemic control, reduce the risk of congenital anomalies, manage diabetes-related complications, and ensure maternal and fetal health during pregnancy.
Diabetic dyspepsia refers to upper gastrointestinal symptoms such as bloating, post-prandial fullness, and upper abdominal pain, often occurring after meals, and is associated with delayed gastric emptying that is not severe. Delayed gastric emptying, along with impaired gastric accommodation and abnormal gastric sensation, contributes to gastrointestinal symptoms in diabetes. When gastric emptying is significantly delayed, with less than 65% emptied at four hours, it is considered a substantial delay, often leading to nutritional consequences that may require interventions such as nutritional supplementation, jejunal feeding, or gastric decompression. Distinguishing between diabetic dyspepsia and gastroparesis remains challenging due to the lack of a clear threshold between moderate and severe delays in gastric emptying.
The incidence of type 1 diabetes varies across age groups, with studies indicating that in Olmsted County, Minnesota, between 1994 and 2010, approximately half of the 233 individuals with incident type 1 diabetes developed the condition before 15 years of age, 25% between 15 and 30 years, and 25% after 30 years of age. In contrast, a nationally representative study from China (2010–2013) showed different proportions among over 5000 individuals with incident type 1 diabetes, with 25% diagnosed before 15 years, 33% between 15 and 29 years, and nearly 40% after 30 years of age.
Poor long-term glycemic control, indicated by higher mean HbA1c levels, is strongly associated with an increased risk of developing moderately elevated albuminuria and reduced estimated glomerular filtration rate (eGFR) in individuals with type 1 diabetes. Maintaining a long-term weighted mean HbA1c below 60 mmol/mol (7.6%) appears protective against albuminuria, while levels above 80 mmol/mol (9.5%) are linked to a 23% incidence of elevated albuminuria. Additionally, greater variability in HbA1c levels independently contributes to the development of albuminuria and diabetic nephropathy, highlighting the importance of stable glycemic control in preventing kidney complications.
Insulin was initially available only in a short-acting soluble form, requiring multiple daily injections. Delayed-action insulin preparations were later developed, starting with protamine insulinate in 1936, followed by protamine zinc insulin, globin insulin in 1939, NPH in 1946, and the lente series in 1952. While long-acting insulins were welcomed, their use as a single daily injection likely resulted in poorer glycaemic control compared to multiple injections of soluble insulin. Some diabetes specialists initially opposed delayed-action formulations due to the risk of hypoglycaemia without warning.
Insulin suppresses glucagon release after meals and during hyperglycaemia, and other compounds such as zinc, γ-aminobutyric acid, and glutamate from β cells may also inhibit glucagon although their physiological relevance is unclear. Somatostatin, both exogenous and secreted from islet δ cells, inhibits glucagon secretion, particularly during exposure to circulating nutrients. Additionally, α cells secrete glutamate and express ionotropic glutamate receptors, which play a role in stimulating glucagon release and are important for the response to low plasma glucose, as blocking these receptors impairs hypoglycaemic counter-regulation in mice.
Patients with an absolute insulin deficiency are prone to unopposed lipolysis and ketone body formation, which can ultimately lead to diabetic ketoacidosis.
Motivational interviewing, initially utilized in the addiction field, is now being applied to chronic diseases including diabetes, showing promise in improving patient adherence. This approach involves a directive, patient-centered counseling style that helps patients explore and resolve ambivalence, emphasizing that motivation must come from the patient. Brief motivational interviewing has adapted traditional techniques for use in time-pressured healthcare settings, and early studies in diabetes have shown promising results, with larger scale trials currently underway.
In individuals with type 2 diabetes mellitus (T2DM), exercise typically does not lead to hypoglycemia and can serve as a beneficial strategy to enhance glycemic control and support weight management, making carbohydrate supplementation generally unnecessary during physical activity. However, if blood glucose levels drop rapidly during exercise, particularly in those using oral hypoglycemic agents or insulin, it may be necessary to adjust or withhold the medication on days when exercise occurs.
Low- and middle-income countries are expected to experience the greatest increase in diabetes prevalence by 2030, rising by 69% compared to 20% in higher-income countries, influenced by population growth, aging, lifestyle changes, and urbanization. In rural Taiwan, the prevalence of diabetes among older Chinese individuals increased from 16.9% in 2000 to 23.7% in 2005. Minority ethnic groups in high-income countries, such as Mexican Americans aged 75 years and older, show higher diabetes prevalence than white European populations, with rates nearly doubling between 1993–1994 and 2004–2005, from 20.3% to 37.2%, compared to an increase from 10.4% to 16.4% in the general population of the same age.
Mothers with untreated gestational diabetes mellitus (GDM) have a significantly increased risk of developing a disorder of glucose metabolism compared to those without GDM, as shown in the Hyperglycaemia and Adverse Pregnancy Outcomes Follow-Up Study (HAPOFUS), where 52.2% of mothers with untreated GDM developed such a disorder versus 20.1% of mothers without GDM after a median of 11.4 years. The risk is further influenced by the diagnostic criteria used, with more mothers meeting the IADPSG definition compared to the Carpenter–Coustan criteria progressing to glucose metabolism disorders.
Treatment of obese individuals with type 2 diabetes mellitus (T2DM) is generally more challenging compared to obese individuals without diabetes. This difficulty arises because people with T2DM are typically older, which may result in smaller weight loss due to decreased energy expenditure with age. Additionally, individuals with diabetes often prioritize blood glucose control, potentially neglecting other health issues. Furthermore, the impact of certain antidiabetic medications, which may either increase weight or hinder weight loss, must be taken into account.
Gastrointestinal symptoms are reported as common in diabetes mellitus according to studies conducted in tertiary referral centers; however, such studies may be influenced by selection and other biases. Community-based studies show that the prevalence of gastrointestinal symptoms among people with diabetes is either similar or only slightly higher compared to those without diabetes. In the Rochester Diabetic Neuropathy Study, 1% of patients experienced symptoms of gastroparesis, and 0.6% had nocturnal diarrhea.
Glycaemic levels should be monitored regularly for all people with diabetes, with $\mathrm{HbA_{1c}}$ measurement being the optimal method for determining the risk of long-term complications; if $\mathrm{HbA_{1c}}$ is unavailable, a series of blood glucose measurements including fasting tests may be used. $\mathrm{HbA_{1c}}$ methods should be standardized to the IFCC reference method, reported in SI units mmol/mol along with derived percentage units. Continuous glucose monitoring (CGM) is playing an increasingly important role in diabetes care and is expected to become more prominent. New aspects of diabetes monitoring, such as assessing remission following surgical intervention, are emerging, highlighting the need for investment and research into affordable, reliable, and accurate testing for low-resource settings.
Ageing contributes to increased insulin resistance through various mechanisms, including increased visceral fat leading to elevated free fatty acid levels, which reduce peripheral insulin sensitivity. Sarcopenia from physical inactivity decreases glucose consumption, further increasing insulin resistance, while lipid accumulation in muscles also impairs insulin sensitivity. Reduced mitochondrial function associated with ageing decreases oxidative metabolism and physical fitness, contributing to glucose intolerance. Additionally, low levels of adiponectin, leptin, and insulin-like growth factor I (IGF-I), along with high levels of tumour necrosis factor α (TNF-α), are linked to ageing and associated with greater insulin resistance and an increased risk of developing diabetes.
Hypoglycemia is a significant concern in diabetes management, particularly with certain sulfonylureas such as glibenclamide and chlorpropamide. Glibenclamide can accumulate within pancreatic beta cells, and its metabolites have hypoglycemic effects, increasing the risk of pronounced hypoglycemia. Chlorpropamide has a long elimination half-life of around 35 hours, leading to accumulation with continued use and delayed steady-state achievement. Renal impairment can further prolong hypoglycemia caused by sulfonylureas that are cleared by the kidneys. Short-acting alternatives like gliclazide and tolbutamide may offer a safer profile in this context.
Blood glucose should be monitored hourly, and urine acetone every two hours, along with hourly assessments of arterial blood gases (ABG) and potassium levels. Typically, blood sugar decreases by approximately 90 mg% per hour during treatment. When blood glucose reaches 250 mg%, the insulin infusion rate is reduced to 2–3 units per hour, and for children under 10 years of age, a rate of 3 units per hour of insulin is considered sufficient.
Offspring of women with diabetes have an increased risk of diabetes and cardiometabolic abnormalities, partly due to maternal overnutrition and intrauterine hyperglycaemia affecting fetal growth, and potentially involving epigenetic changes. The rising prevalence of young-onset diabetes and obesity in women may further worsen the diabetes epidemic through a cycle of diabetes begetting diabetes. Additionally, there is ongoing investigation into a possible link between assisted reproduction technology and an increased risk of diabetes and obesity in offspring, although current evidence is limited and conflicting.
Patients with diabetes experience significant psychological distress due to the chronic nature of the disease, which shortens lifespan and leads to complications such as blindness and neuropathy. The condition requires constant daily management involving medications, insulin injections, and careful monitoring of diet, exercise, and blood glucose levels. Diabetes also affects social identity, particularly in children, and places a heavy burden on families who may struggle with the demands of care, contributing to elevated rates of emotional disturbances and behavioral problems among patients and their families.
Glycaemic management in individuals with type 1 diabetes has been shown to reduce the development of cardiac autonomic neuropathy by 45%. Currently, there are no FDA-approved disease-modifying treatments to reverse cardiac autonomic neuropathy. While a small study indicated potential benefits of alpha-lipoic acid on cardiac autonomic neuropathy, a larger intervention using triple antioxidant therapy, including allopurinol, alpha-lipoic acid, and nicotinamide, in individuals with mild to moderate cardiac autonomic neuropathy did not demonstrate any benefit.
Increased gastric emptying can occur in individuals with diabetes, particularly those with diabetic gastroparesis, where the stomach takes longer to empty its contents, leading to delayed digestion and potential fluctuations in blood glucose levels.
Inhaled insulin, such as Exubera (Pfizer, New York, USA), was introduced in Europe in 2006 as an alternative route for insulin delivery, particularly beneficial for individuals with needle phobia, though it was withdrawn within a year due to poor uptake.
Progressive decline in cognitive function leading to dementia is common in older people with diabetes, with persistent hyperglycaemia increasing the risk of cerebrovascular disease through mechanisms such as inflammation, endothelial dysfunction, oxidative stress, and insulin resistance, contributing to vascular dementia. Accelerated brain ageing due to altered amyloid metabolism, increased protein glycation, and direct cerebral glucotoxicity may also lead to a higher incidence of Alzheimer’s dementia. Structural brain changes, including cerebral and hippocampal atrophy, occur more frequently in older individuals with diabetes and contribute to cognitive dysfunction, particularly in immediate memory. Brain insulin resistance increases in Alzheimer’s disease, suggesting a possible cerebral manifestation of diabetes in the development of Alzheimer’s.
Rapid-acting insulin analogues are effective in managing both type 1 and type 2 diabetes, particularly when used in basal-bolus regimens or continuous subcutaneous insulin infusion. These analogues closely mimic the body's natural insulin response during meals, making them more effective than soluble insulin in controlling postprandial hyperglycaemia. This leads to improved glycaemic control and fewer hypoglycaemic episodes. The advantages of rapid-acting analogues are more pronounced in individuals with type 1 diabetes and those using insulin pumps rather than multiple-dose injections.
Women with diabetes are at increased risk of late stillbirth and shoulder dystocia, leading to historical variations in recommended delivery timing, from 36 weeks in 1949 to later delivery by 1980 to avoid complications of prematurity. By 1990, some units allowed spontaneous labor for women with T1DM and uncomplicated pregnancies, though policies allowing delivery past 38 weeks in low-risk women were associated with increased perinatal deaths. Current UK guidelines recommend offering induction of labor after 38 weeks or elective cesarean section if indicated for women with pre-gestational diabetes or GDM, with the ADA emphasizing estimated fetal weight in determining the timing and mode of delivery.
Glycated hemoglobin (A1c) is a measure used in diabetes management to reflect average blood glucose levels over time, and low-density lipoprotein cholesterol (LDL) is a type of cholesterol that can contribute to cardiovascular risk, which is often monitored in individuals with diabetes.
Diabetic diarrhea can be differentiated through assessment of stool fat, which indicates malabsorption as the underlying pathophysiology. Additionally, small intestinal bacterial overgrowth, which may be associated with diabetes, can be evaluated using lactose or glucose hydrogen breath tests, though these tests have limitations in sensitivity and specificity. The lactulose hydrogen breath test has a sensitivity of 68% and specificity of 44%, while the glucose breath test has a sensitivity of 62% and specificity of 83% in detecting small bowel bacterial overgrowth.
The text describes different types of insulin preparations and their pharmacokinetic profiles, which are relevant to diabetes management. Regular (plain) insulin has an onset of action within 0.5 to 1 hour, peaks at 2 to 4 hours, and lasts up to 6 to 8 hours. Lente insulin starts acting at 2 to 5 hours, peaks at 6 to 14 hours, and has a duration of up to 18 to 24 hours. Semi Lente insulin has an onset of 1 to 3 hours, peaks at 6 to 12 hours, and lasts 12 to 18 hours. Ultra Lente insulin begins action at 4 to 6 hours, peaks at 18 to 24 hours, and remains effective for 36 to 40 hours. Mixtard insulin, a combination of short- and intermediate-acting insulins, starts acting within 0.5 to 1 hour, peaks at 6 to 12 hours, and lasts up to 18 to 24 hours.
In diabetes, hepatic glucose production is inappropriately elevated, and this can be influenced by counter-regulatory hormones such as glucagon, epinephrine, glucocorticoids, and growth hormone, which increase blood glucose concentrations by promoting hepatic glycogenolysis and gluconeogenesis.
The incidence of diabetes varies significantly across different regions, with moderate to high rates observed among children in New Zealand and parts of Australia, ranging from 15 to 25 per 100,000 per year. In contrast, the mean incidence rate in China during the early 1990s was much lower at 0.8 per 100,000 per year, though more recent data from China shows an increase, with rates varying between 1.2 and 3.6 per 100,000 per year. Kuwait experienced a dramatic rise in diabetes incidence, increasing from 17.7 per 100,000 per year in 1992–1994 to 40.9 per 100,000 per year in 2011–2013.
In type 1 diabetes, the incidence and severity of periodontitis are linked to elevated HbA₁c levels, with additional contributing factors including age over 32 years, diabetes duration of 10 to 24 years, tobacco smoking, presence of late diabetes-related complications, and dental care habits influencing the development and progression of periodontitis.
The text discusses the application of genome-wide approaches in studying type 1 diabetes and type 2 diabetes mellitus (T2DM), highlighting that over 20 genome scans for T2DM have involved thousands of pedigrees across diverse populations. It notes that the genome-scan method has limited power to detect weak linkage signals due to the relatively low sibling risk for diabetes (three- to fivefold increase compared to the general population). Improvements in detecting linkage have been achieved through the use of large family collections (over 500 sib-pairs), more homogeneous ethnic groups, or large pedigrees analyzing quantitative intermediary traits instead of binary diabetes status, as intermediary phenotypes show higher heritability. To reduce bias from chronic hyperglycemia's influence on traits, alternative strategies suggest studying the general population or non-diabetic offspring of diabetic individuals who are at high risk. The text warns of potential false-positive results, recommending stringent linkage criteria (P < 10^−5) to reduce errors from multiple testing, with genome-wide significance requiring multipoint lod scores above 3.6. Validation of linked loci is crucial and often relies on replication by independent studies, although challenges like genetic heterogeneity, ascertainment biases, phenotypic variation, and genotyping errors can hinder confirmation.
Non-surgical periodontal treatment has been shown to have a positive effect on metabolic management in individuals with diabetes, particularly those with type 2 diabetes, leading to significant reductions in HbA₁c levels by approximately 0.3–0.6% (3–6 mmol/mol) and fasting plasma glucose by 9.0–13.6 mg/dl (0.5–0.8 mmol/l) over 3–6 months. Additionally, markers of systemic inflammation such as TNF-α and hs-CRP were reduced following treatment, although adjunctive antimicrobials did not show added benefit. A UK study found that intensive periodontal treatment reduced HbA₁c by 0.6 percentage points (7 mmol/mol) after one year compared to a control group, and a reduction of 0.9 percentage points (10 mmol/mol) in HbA₁c has been associated with a 10% reduction in mortality.
Soluble and insoluble plant polysaccharides can delay carbohydrate digestion and absorption, potentially altering the intestinal microbiome through a prebiotic effect, and may help reduce postprandial hyperglycaemia and basal glycaemia modestly when used with glucose-lowering medications. Fibre supplements can also extend digestion time, reducing inter-prandial hypoglycaemia in those on insulin therapy. Changes in the intestinal microbiome have been observed in type 2 diabetes, and some probiotic cultures have shown inconsistent, modest glucose-lowering effects.
Tight blood glucose control has limited evidence in influencing the progression of abnormal UAE, as studies conducted were small, short in duration, or failed to achieve sufficiently tight control. However, in a highly selected group of patients undergoing serial renal biopsies after pancreas transplantation, renal structural changes were observed to regress, but only after 10 years of extremely good glucose control, suggesting that very prolonged periods of optimal control may be necessary to reverse structural kidney damage indicated by microalbuminuria or proteinuria.
Coxsackie B virus has amino acid sequences similar to islet autoantigens, and molecular mimicry may explain the link between prolonged viral infection and the development of islet autoantibodies such as IAA.
Foxo1 is the most highly expressed isoform in insulin-responsive tissues such as liver, adipose tissue, and pancreatic β-cells, and under basal conditions resides in the nucleus where it actively regulates gene transcription. Upon insulin stimulation, Akt/PKB phosphorylates Foxo1 at conserved residues, leading to dissociation from DNA binding sites, nuclear exclusion, and suppression of transcriptional activity. This nuclear exclusion involves binding of 14-3-3 proteins to phosphorylated sites on Foxo1, masking its nuclear localization signal. The phosphorylation of Foxo1 by Akt/PKB is crucial for insulin-mediated suppression of gene transcription, as mutations at Thr24 or Ser253 prevent phosphorylation, nuclear export, and insulin’s suppressive effects.
Type 2 diabetes progresses over time, as demonstrated by the UK Prospective Diabetes Study (UKPDS), which followed 5102 individuals with newly diagnosed type 2 diabetes for a median of 10 years. In this study, participants received either conventional therapy (diet alone) or intensive therapy using oral glucose-lowering agents or insulin, with insulin introduced earlier than typical clinical practice and used when oral agents were insufficient. Despite deterioration in glycated haemoglobin (HbA1c) levels over time regardless of treatment, intensive therapy reduced median HbA1c by 0.9% (10 mmol/mol), leading to a 12% reduction in overall diabetes-related endpoints and a 25% reduction in microvascular complications. Epidemiological analysis indicated that the benefits of intensive glucose control continued to accumulate as glucose levels were lowered.
Repaglinide produces a prompt insulin response that lasts about three hours, coinciding with the duration of meal digestion, and nateglinide has a slightly faster onset and shorter duration of action.
Exercise training may improve insulin action and blood glucose control in type 2 diabetes through several mechanisms, including enhancing glucose uptake (Rd), modulating hepatic glucose output (HGO), altering glucose transporter (GLUT) activity, reducing levels of free fatty acids (FFA), and influencing inflammatory factors such as tumor necrosis factor-alpha (TNF-α).
LADA can be distinguished from classic type 1 diabetes through HLA studies, with LADA in white European populations being associated with specific HLA DQA1-DQB1 alleles that are uncommon in typical type 1 diabetes. Measurement of C-peptide levels is recommended to assess endogenous pancreatic β-cell function, guiding diagnosis and management. Individuals with C-peptide levels below 0.3 nmol/l should be managed as type 1 diabetes, while those above 0.7 nmol/l should be managed as type 2 diabetes; for those in the intermediate range (≥0.3 and ≤0.7 nmol/l), insulin should be considered alongside other therapies to slow the progression of β-cell failure.
Prevention of diabetic nephropathy was studied in the PRIORITY trial using spironolactone in individuals with type 2 diabetes and normoalbuminuria, where a urinary proteomic-based risk score (CKD-273) identified those at high risk for progression to chronic kidney disease or moderately elevated albuminuria; however, spironolactone did not reduce kidney disease progression compared to placebo over three years despite the biomarker's predictive ability.
Increased physical activity reduces the risk of developing diabetes by 58% in individuals with impaired glucose tolerance, and this protective effect is maintained over time. A study in three regions of Finland found a lower prevalence of impaired glucose tolerance compared to earlier reports from northern Finland, with 10.5% in men and 9.2% in women, though it is uncertain whether this difference is due to regional variation or changes in the ratio of diabetes to impaired glucose tolerance.
Hypoglycemia management in diabetes includes the use of HypoboxesTM, which are prominently placed and contain treatment supplies such as fruit juice and intravenous 20% glucose. General guidelines for treating in-hospital hypoglycemia should be accessible in all wards and outpatient settings, but individualized care is essential, with local guidance from diabetes teams for self-management. Treatment may need to be adapted for patients with conditions like renal impairment or heart failure to avoid fluid overload. Patients who are able and suitable should be encouraged to self-manage hypoglycemic events, with their capacity for self-management documented during admission assessment.
Gene therapy strategies for diabetes have explored the use of surrogate cells to produce insulin, as most other cells lack the proprotein convertases PC1/3 and PC2 that are required to process proinsulin into mature insulin. To overcome this limitation, new proteolytic sites recognized by furin, a widely present protease, have been engineered into the proinsulin molecule. Various cell types have been tested in ex vivo gene transfer approaches to enable ectopic insulin production; however, the therapeutic effects in most studies were short-lived due to the loss of transplanted cells.
Intrauterine growth restriction influences $\beta$-cell function and insulin sensitivity in children and young adults, with maternal diet and placental function during critical periods of fetal development affecting pancreatic gene expression through DNA methylation. Exposure to hyperglycemia in utero also impacts $\beta$-cell number and function in rodents, although these effects may differ in humans due to differences in pancreatic development, as human $\beta$-cells are less mature in utero and continue to proliferate after birth.
In diabetes, blood vessels exhibit reduced nitric oxide (NO) production or altered NO metabolism, impairing its role as a vasodilator and protector against platelet aggregation. This decrease in NO activity leads to increased vasoconstriction and a diminished capacity of blood vessels to respond effectively to ischemic conditions.
Type 2 diabetes mellitus (T2DM) has become increasingly prevalent in Japan since the 1960s, with a reported prevalence of 9.1% in men and 10.8% in women in rural areas, and corresponding impaired glucose tolerance (IGT) prevalence of 12% and 16.5% respectively. A national diabetes survey in 2002 estimated a 9% prevalence of diabetes. T2DM has emerged as a critical issue among Japanese children, outnumbering type 1 diabetes mellitus (T1DM) in children and adolescents at a ratio of 4:1, with an incidence rate of 4.1 per 100,000 person-years between 1981 and 1990, approximately twice that of T1DM. Nutritional factors are considered significant contributors, as evidenced by the approximately doubled prevalence of diabetes among Japanese-Americans compared to Japanese individuals in Japan.
Sulfonylureas are commonly used in the treatment of diabetes, either as monotherapy or in combination with other glucose-lowering agents such as metformin, thiazolidinediones, α-glucosidase inhibitors, or SGLT-2 inhibitors. They may also be combined with incretin agents or insulin in certain cases. Combining sulfonylureas with other antidiabetic medications typically results in additive glucose-lowering effects, although this combination therapy increases the risk of hypoglycemia. The effectiveness of combining sulfonylureas with other insulin secretagogues depends on their differing mechanisms of action on the β cells.
Hyperglycemia, defined as serum glucose greater than 144 mg/dL, is associated with a higher risk of poor functional outcomes in patients treated with intravenous thrombolysis, with an odds ratio of 2.89 for lack of improvement at 24 hours, which in turn predicts worse outcomes at 3 months.
Diabetes self-care often loses priority to competing demands related to social, emotional, educational, and occupational needs during the transition to adulthood, putting emerging adults with diabetes at high risk for chronic hyperglycaemia. Mental health issues such as depression, anxiety, and disordered eating behaviours are common in this age group, and risk-taking behaviours involving alcohol, smoking, and drug use typically increase, further elevating the likelihood of acute complications like diabetic ketoacidosis and severe hypoglycaemia. Additionally, there is a risk of missing important screenings for eye and kidney complications as well as cardiovascular risk factors during this transitional period. Chronic diabetes complications may begin to emerge in late adolescence and young adulthood and may go undetected or untreated. The transition from paediatric to adult healthcare also presents challenges, as adult clinics may lack the multidisciplinary, family-centred care model familiar to young adults, and differences in healthcare delivery can make appointment scheduling and continuity of care more difficult, contributing to loss to follow-up.
Around 40 subtypes of monogenic diabetes have been identified, with variants in 14 genes being best described, including six genes associated with MODY subtypes 1-6: HNF4a, GCK, HNF1a, PDX1, HNF1β, and NEUROD1. Eight additional genes are linked to MODY subtypes 7-14, such as KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1. There is a shift towards using gene-specific names like HNF4a-MODY or GCK-MODY for clarity. Most monogenic diabetes genes are transcription factors involved in pancreatic β-cell development, structure, and function, such as Pax6, Nkx2-2, Nkx6-1, and Pax-4, while others are transmembrane channels involved in insulin secretion, like Kir6.2 (KCNJ11) and SUR1 (ABCC8). These rare variants in transcription factors typically lead to significant insulin insufficiency and hyperglycaemia, with strong familial inheritance and full penetrance.
Rapid improvement or intensification of glycemic control during pregnancy, particularly in women who entered pregnancy with poor blood sugar management, is associated with a transient worsening of retinopathy. This phenomenon was observed in studies such as the DCCT and the Diabetes in Early Pregnancy Study, which suggest that abrupt changes in glucose levels may contribute to the progression of retinopathy. These findings emphasize the importance of achieving optimal glycemic control before conception to minimize risks during pregnancy.
Most people with diabetes and no complications can be effectively managed within the community, though more complex cases require specialist referral. A key challenge in diabetes care is designing a system that allows patients to remain in the community while ensuring timely access to specialists. Community-based primary care is central to diabetes management globally, and improving its effectiveness is a strategic priority. Enhancing community care to a specialist level may reduce cost advantages, so a balance is needed. Specialist diabetes care, often hospital-based, must focus on complementing rather than duplicating primary care. Diabetes educators and non-medical staff trained in managing glycemic control, hypertension, dyslipidemia, and patient education play a supportive role, allowing doctors to focus on complex cases. Diabetes centers offer integrated specialist care, handling tasks such as insulin initiation, complication screening, diabetic foot management, pregnancy-related diabetes care, neuropathic pain, and insulin pump therapy. These centers also educate community healthcare providers and demonstrate best practices, with effective communication being essential to coordinate care between community and specialist levels.
In people with diabetes, alcohol consumption may impede recovery from insulin-induced hypoglycaemia, with the effect often delayed up to 24 hours and potentially occurring during the night or the following day. Individuals with a deficient glucagon response to hypoglycaemia are at greater risk due to their inability to increase hepatic gluconeogenesis. The signs of hypoglycaemia may be overlooked or confused with alcohol intoxication by both the individual and observers, and even moderate alcohol consumption exacerbates cognitive impairment during hypoglycaemia. Therefore, people with insulin-treated diabetes should avoid drinking alcohol before driving.
Insulin's amino acid sequence was identified in 1955 and its three-dimensional structure in 1969, both discoveries being critical for understanding diabetes. The complete synthesis of insulin was achieved in 1965, contributing to diabetes treatment advancements. Proinsulin, the precursor to insulin, was discovered in 1967, furthering knowledge of insulin production. In 1950, a bioassay for insulin was developed using alloxan-diabetic rats, which was later replaced in 1956 by a more precise radio-immunoassay method based on insulin's antigenic properties; this method significantly impacted diabetes research and endocrinology overall.
Insulin inhibits gluconeogenesis through receptor-mediated tyrosine phosphorylation of IRS2 in the liver, followed by activation of PI3 kinase and Akt/PKB, with Akt2 playing a critical role as its knockout leads to hepatic insulin resistance, increased hepatic glucose output, and hyperglycemia. Activated Akt2 phosphorylates and inhibits GSK-3, promoting hepatic glycogen synthesis, while also suppressing PEPCK and G-6-Pase gene expression through transcription factors such as Foxo, SREBP-1c, LXR, and Sp1. The regulation of hepatic metabolism by insulin involves a complex interplay of cis- and trans-acting factors that is not yet fully understood.
GLP-1 is an incretin hormone secreted from intestinal L cells during meal digestion that potentiates nutrient-induced insulin secretion, suppresses excess glucagon secretion, exerts a satiety effect, and delays gastric emptying. Several subcutaneously injected analogues of GLP-1 that mimic the effects of the native hormone are established therapies for type 2 diabetes, and an oral formulation of the GLP-1 receptor agonist semaglutide was introduced in 2019.
Teplizumab treatment in individuals who are HLA-DR4 positive or Znt8A negative results in fewer diabetes diagnoses compared to placebo. Screening for islet autoantibodies, potentially combined with enhanced genetic risk scores, aids in identifying candidates for secondary prevention trials for type 1 diabetes, supported by the EMA's recognition of islet autoantibodies as effective enrichment biomarkers in such trials.
Various skin conditions are associated with diabetes, including necrobiosis lipoidica diabeticorum, which is unrelated to glycemic control and may be treated with topical steroids in early stages. Diabetic dermopathy, the most common skin disorder in diabetes, appears as shin spots in longstanding cases and typically resolves within 1–2 years. Thickened skin in diabetes can lead to yellowish discoloration due to irreversible glycation of collagen, especially in palmar creases. Acanthosis nigricans, linked to insulin resistance, presents as hyperpigmented plaques in flexural areas like the axillae or neck. Erythema may occur on the face, nail margins, and lower limbs, while calciphylaxis indicates severe vascular damage with a poor prognosis. Large vessel injury can result in difficult-to-treat leg ulcers.
Diabetes, particularly type 2 diabetes, is not necessarily incurable and can be reversed in some cases through substantial and sustained weight loss, especially when the duration of diabetes is short. Accumulation of excess fat, beyond what an individual can tolerate, plays a key role in the development of type 2 diabetes, and reducing this fat, particularly intra-pancreatic fat, can lead to the recovery of pancreas function and insulin production. Bariatric surgery can result in long-term remission of type 2 diabetes in its early stages due to enforced calorie restriction. Additionally, community-based weight management programs, as demonstrated in the Diabetes Remission Clinical Trial (DiRECT), can achieve remission in over a third of participants with type 2 diabetes through primary care support. Remission rates decrease with longer diabetes duration, with only about 50% of those with diabetes for more than eight years achieving reversal, compared to around 90% for those with less than four years of disease duration.
Prolonged exposure to antiretroviral therapy increases the risk of diabetes, particularly when protease inhibitors (PI) are used, as these medications directly inhibit cellular glucose transport. However, increased diabetes prevalence is also observed in individuals on PI-sparing regimens, and insulin resistance can occur even in PI-naive individuals with HIV infection, often linked to fat redistribution. Mitochondrial toxicity caused by nucleoside analogs is considered a contributing factor. Discontinuation of PIs may improve diabetes metabolic control but has limited benefit in reversing lipodystrophy, while switching thymidine analog reverse transcriptase inhibitors may positively affect lipodystrophy.
Low glycemic index foods may be beneficial for individuals with diabetes as they can help manage blood glucose levels, provided other nutritional attributes of these foods are appropriate.
Effective treatment of hypertension can slow the progression of diabetic nephropathy by lowering urinary albumin excretion and decreasing the rate of decline in glomerular filtration rate. Improved blood pressure management has been shown to enhance cardiovascular outcomes in type 2 diabetes, as confirmed by the UKPDS study, where tighter blood pressure control (averaging 144/82 mmHg over eight years) led to significant benefits compared to less strict control (averaging 154/87 mmHg). This included reduced risks of microvascular complications such as retinopathy and nephropathy, as well as significant reductions in the risk of stroke (44%) and heart failure (56%), although myocardial infarction and peripheral vascular disease showed non-significant reductions.
Patients may transition to a subcutaneous insulin regimen once diabetic ketoacidosis (DKA) has resolved and they are able to eat. To avoid rebound hyperglycemia, the insulin infusion should continue until 15–30 minutes after the first subcutaneous dose of rapid-acting insulin. Long-acting insulin analogs take 4–6 hours to reach therapeutic levels capable of replacing the insulin infusion. Monitoring blood ketones at the bedside helps adjust insulin dosing and prevent relapse.
In the context of diabetes, particularly during episodes of hyperglycaemia and ketoacidosis, intravenous bicarbonate therapy is not routinely recommended as it does not improve cardiac or neurological function or accelerate recovery. Excessive use of bicarbonate can lead to complications such as hypokalaemia, reduced tissue oxygen uptake, increased lactate levels, and cerebrospinal fluid acidosis due to elevated $\mathrm{CO}_{2}$ partial pressure. Despite this, some guidelines suggest that in cases of severe metabolic acidosis (pH $< 6.9$), sodium bicarbonate may be administered until the pH reaches 6.9–7.0, as severe acidosis can impair myocardial contractility and cause cerebral vasodilatation and coma. However, there is a lack of data from randomized controlled trials to strongly support this recommendation.
Gestational diabetes mellitus (GDM) is distinguished from overt diabetes in pregnancy by organizations such as IADPSG, WHO, and FIGO, with overt diabetes defined using nonpregnant glucose thresholds including fasting glucose ≥7.0 mmol/l (126 mg/dl) or two-hour glucose ≥11.1 mmol/l (200 mg/dl). Women with more severe hyperglycaemia, including pre-pregnancy cases, are presumed to have higher diabetic and obstetric risks, such as malformations, and thus require more intensive management. These women were excluded from studies like HAPO, ACHOIS, and MFMU for ethical reasons, which may have influenced the observed outcomes.
Adjunctive pramlintide administration in individuals with type 1 diabetes mellitus (T1DM), who are receiving intensive treatment with multiple daily injections or pump therapy, leads to greater treatment satisfaction compared with placebo, despite similar reductions in HbA1c levels; however, insulin and pramlintide cannot be mixed in the same pen due to biochemical compatibility issues, necessitating separate injections which some patients find burdensome.
A consultation or education program for diabetes should aim to ensure that individuals with diabetes develop a clear understanding of their condition, which can be achieved through effective collaboration between healthcare professionals and patients. The approach should emphasize equal involvement in decision-making and care, rather than a one-sided delivery of care by healthcare providers.
Chronic hyperglycaemia in diabetes alters renal sensitivity to vasopressin, reducing the sensation of thirst despite increasing plasma osmolarity, which can lead to delayed recognition of dehydration, particularly in older individuals. In advanced age, polydipsia may be absent during osmotic diuresis, making nocturia, especially an noticeable increase from baseline, the most reliable indicator of an osmotic presentation.
For treatment of hyperglycaemia, metformin remains the initial choice in most people, including those with newly diagnosed type 2 diabetes, due to the extensive experience with its use, overall efficacy and safety profile, and affordability. In those with non-alcoholic steatohepatitis (NASH), pioglitazone and some GLP-1RAs are recommended. Additional important considerations affect real-life therapeutic decisions and the likelihood that people will take their medication as prescribed, including the values and preferences of the informed individual, tolerability issues, practical matters, and drug availability and affordability. Clinicians should continually update their knowledge of the pharmacological management of type 2 diabetes and avoid clinical inertia by regularly reassessing the overall clinical profile of those they treat.
The commonest treatment for steroid-induced hyperglycaemia is a sulfonylurea, such as gliclazide, or isophane (neutral protamine Hagedorn, NPH) insulin. People taking very short courses of steroids may only require close monitoring. Target ranges should aim to achieve a blood glucose concentration between 6 and 15 mmol/l (108–270 mg/dl) with no osmotic symptoms, and any diabetes treatments should be reduced or stopped alongside steroid reduction to avoid hypoglycaemia.
GLP-1 receptor agonists (GLP-1 RAs) are a class of glucose-lowering drugs that induce significant weight loss and improve insulin resistance. Liraglutide, a GLP-1 RA, has been evaluated in individuals with NAFLD or NASH, showing improvements in serum liver enzyme levels and histological resolution of NASH, including hepatic steatosis and hepatocyte ballooning, with generally good tolerability and a similar adverse event profile to placebo except for increased gastrointestinal symptoms.
In the treatment of type 2 diabetes, targeting multiple regulatory pathways is often beneficial due to additive effects, leading to the development of dual or triple receptor agonists that combine activation of the GLP-1 receptor with other hormone receptors such as GIP, glucagon, or amylin. Several unimolecular multiagonist compounds that activate two or more of these receptors are in late-stage clinical development for type 2 diabetes, obesity, and non-alcoholic steatohepatitis. However, challenges remain regarding their clinical efficacy and safety in humans, including the risk of immunological reactions and off-target effects, which must be favorable compared to established GLP-1 receptor agonists.
For individuals with diabetes receiving insulin treatment, participation in sports where hypoglycemia could be dangerous, such as diving, climbing, single-handed sailing, and motor racing, requires frequent capillary blood glucose testing and strict measures to prevent hypoglycemia, with another person nearby for assistance if needed; the Amateur International Boxing Association bans participation in boxing for those with insulin-requiring diabetes. Patients with untreated proliferative retinopathy should avoid very strenuous exercise due to the risk of hemorrhage, although those whose retinopathy has been treated with laser therapy and are under regular retinal specialist care may engage in such activities without significant risk.
Individuals with type 1 diabetes experience higher mortality than the general population across all age groups, leading to a reduction in life expectancy, particularly for those with young age at onset. Life expectancy is a complex summary measure of mortality and applies only to hypothetical individuals. Despite improvements in care, a significant mortality gap persists in high-income countries, and mortality rates are especially high in low- and middle-income countries. A major challenge is the occurrence of deaths among individuals with undiagnosed type 1 diabetes and those lacking access to insulin and healthcare in resource-limited settings.
Nutritional recommendations with evidence grade B for persons with type 1 and type 2 diabetes are based on well-designed and controlled studies without randomization, well-designed quasi-experimental studies, or non-experimental descriptive studies.
Type 1 diabetes results from autoimmune destruction of pancreatic β cells, a theory first proposed in 1979. Insulitis, characterized by lymphocytic infiltration of the islets, was observed as early as 1901, but its role in β-cell destruction was not recognized until much later. Islet cell antibodies, which are transient, can appear up to 10 years before the onset of diabetes in siblings of affected individuals, suggesting a long preclinical phase. This observation has led to the possibility of early interventions to prevent β-cell destruction. Cyclosporine can prolong the honeymoon period in newly diagnosed individuals but does not provide permanent benefit. While interventions like nicotinamide and low-dose insulin prevent diabetes in non-obese diabetic (NOD) mice, they have shown no effect in humans at risk based on high titers of islet cell antibodies.
Many women with type 2 diabetes mellitus (T2DM) attending pre-pregnancy care need to start insulin for the first time or have their insulin regimen intensified to achieve the recommended HbA1c level, and they require advice on the frequency and timing of self-monitoring of blood glucose as well as the need for extra snacks between meals and before bed.
Immunohistochemical studies have identified the presence of the C9 component of the membrane attack complex (MAC) in the glomerular basement membrane, tubuli, and Bowman capsule of individuals with type 1 diabetes. Research has shown a correlation between MAC deposition and the extent of mesangial expansion in those with type 1 diabetes, indicating involvement of the complement system. More recent studies have confirmed the deposition of MAC in diabetic glomeruli, suggesting widespread activation of the complement system in diabetes, from components like MBL and MASP to C3 and ultimately MAC.
People with advanced type 2 diabetes and type 1 diabetes face greater challenges due to compromised defences against falling plasma glucose levels, leading to a higher risk of iatrogenic hypoglycaemia. Repeated episodes of hypoglycaemia can damage counter-regulatory mechanisms and lead to impaired awareness of hypoglycaemia. Despite extensive research, effective therapeutic approaches focus on reducing the time individuals spend in hypoglycaemia. However, concerns about hypoglycaemia should not justify suboptimal glycaemic control, as evidence from the DCCT shows that improved glycaemic management significantly lowers the risk of microvascular complications compared to little or no management.
Necrobiosis lipoidica is a chronic granulomatous skin condition most frequently affecting the shins of individuals with type 1 diabetes, although it can also occur in those without diabetes. It has a prevalence of about 1% in people with diabetes and typically develops in young adults or early middle life, though it has been reported in children with type 1 diabetes. Women are three times more likely to be affected than men. While the exact cause is unknown, microangiopathy, metabolic changes, and trauma are thought to contribute. The condition may precede, coincide with, or develop after the onset of diabetes, and its presence warrants investigation for diabetes and ongoing monitoring. Although not directly linked to glycemic levels, necrobiosis lipoidica in diabetic individuals is associated with a higher incidence of chronic complications such as retinopathy, neuropathy, and microalbuminuria.
GLP-1, released by enteroendocrine L cells in response to nutrients such as glucose and fatty acids as well as bile acids, acts on widely distributed GLP-1 receptors in organs including the hypothalamus, liver, skeletal and cardiac muscle, and vagus nerve, contributing to reduced appetite and energy intake, which are relevant to diabetes management.
Monogenic diabetes may be diagnosed before pregnancy, though some women initially thought to have type 1 or type 2 diabetes during pregnancy are later found to have genetic forms such as GCK or HNF1A mutations or mitochondrial diabetes. This diagnosis is suggested by fasting hyperglycaemia with normal one- and two-hour glucose values on OGTT screening in women with a normal BMI. Identifying this condition is important due to the risk of accelerated fetal growth, depending on whether the mutation is inherited.
Treatment of depression in individuals with type 1 or type 2 diabetes is effective, particularly through psychotherapeutic interventions such as cognitive behavioral therapy (CBT), which helps reduce depressive symptoms and diabetes-specific distress by training individuals in problem-solving strategies and cognitive techniques. A web-based, diabetes-specific CBT intervention has shown benefits in reducing both depression and distress related to diabetes management. Additionally, eHealth interventions have demonstrated positive effects on depressive symptoms and short-term improvements in glycemic control as measured by HbA1c, though the latter effect is not consistently maintained.
Alpha-lipoic acid, an antioxidant, has been studied as a potential disease-modifying therapy for diabetic neuropathy, with some trials showing that 600 mg intravenous administration over three weeks can significantly improve neuropathic symptoms. However, long-term benefits on symptoms, quantitative sensory testing, or nerve conduction velocity were not observed, and the therapy has not been approved by the FDA or endorsed by the ADA due to lack of efficacy in pivotal phase III studies on diabetic sensorimotor polyneuropathy.
LADA is a slowly progressive form of T1DM characterized by confusion in nomenclature, with various terms used to describe it, including T2DM with islet autoantibodies, slowly progressive insulin-dependent diabetes mellitus, type one-and-a-half diabetes, latent autoimmune diabetes in children (LADC), latent autoimmune diabetes in the young (LADY), autoimmune diabetes, and autoimmune diabetes in adults with slowly progressive β-cell failure (ADASP), although LADA remains the most commonly used term.
Astrocytes, the most common glial cell type in the brain, play a role in glucose homeostasis through gap junctions involving connexins 30 and 43, which are critical for brain glucose sensing and insulin secretion during a glucose challenge. These cells contribute to the blood-brain barrier and are involved in glucose transport into the brain via GLUT1 and possibly GLUT2. Glucose taken up by astrocytes can be metabolized into lactate, which serves as a fuel source for neurons through the astrocyte-neuron lactate shuttle. Additionally, astrocytes express insulin receptors, and their deletion reduces the responsiveness of POMC neurons to elevated glucose levels.
Segmental pancreatic transplantation techniques, such as open drainage and duct polymer injection, were developed in the 1970s–1980s to achieve insulin independence in diabetes patients, with some recipients maintaining insulin independence for up to 18 years. Bladder drainage, introduced in the 1980s, became a common method due to fewer complications and the ability to monitor rejection noninvasively, though it was later associated with urinary tract infections, reflux pancreatitis, and metabolic acidosis, leading many patients to require surgical conversion to enteric drainage.
Individuals with type 1 diabetes have a significantly higher risk of in-hospital mortality due to Covid-19, with the risk being threefold higher compared to those without diabetes. The relative risk is particularly elevated in younger age groups, with mortality being around sixfold higher in 50-59-year-olds with type 1 diabetes compared to their non-diabetic counterparts. Higher glycated haemoglobin (HbA1c) levels are associated with increased Covid-19-related mortality in people with type 1 diabetes, even after adjusting for other risk factors.
Hypersecretion of glucagon or somatostatin from pancreatic islet cell adenomas is a rare endocrine cause of diabetes, and hypersecretion of androgenic steroids leads to insulin resistance and glucose intolerance in up to 50% of women with polycystic ovarian syndrome. Additionally, hypersecretion of thyroid hormones in thyrotoxicosis results in mild, often transient glucose intolerance, while excess aldosterone, parathyroid hormone, or vasoactive intestinal peptide due to hyperplasia or adenoma is linked to mild glucose intolerance.
In the TrialNet Pathway to Prevention study, participants younger than 12 years had a higher risk of progressing to clinical onset of diabetes regardless of whether they had two autoantibodies or more than two. These findings suggest that islet autoantibody screening may have potential for use in clinical practice and highlight the importance of considering age and the number of autoantibodies in understanding the heterogeneity of progression to clinical diabetes, which has implications for secondary prevention clinical trials.
Type 2 diabetes mellitus (T2DM) pharmacogenetic studies have investigated the influence of genetic variants on drug response. The PPARG P12A variant does not appear to explain differences in insulin sensitivity response to thiazolidinediones, as shown in the TRIPOD and DPP studies. Additionally, the KCNJ11 E23K variant's impact on sulfonylurea therapy remains unclear, with conflicting results from different studies; however, carriers of the 23K allele may have a higher risk of therapy failure, earlier diabetes onset, and worse metabolic control. In the DPP study, metformin was less effective in improving insulin sensitivity and reducing diabetes risk in carriers of the K-allele compared to E23E homozygotes.
Oral glucose tolerance testing involves administering 75g of anhydrous glucose in 250ml of water to adults, with blood sugar levels measured after fasting and 2 hours post-consumption for diagnostic purposes, while children receive a dose of 1.75g per kg of body weight up to a maximum of 75g.
Anti-CD3 monoclonal antibodies, such as teplizumab, have demonstrated some success in delaying the autoimmune destruction of beta cells, preserving their function, and enhancing endogenous insulin production. These antibodies, including variants with mutated or glycosylated Fc regions, have been tested in clinical trials where they improved C-peptide levels and clinical variables for up to two years, although they did not lead to long-term tolerance of beta cell autoantigens. The beneficial effects appear transient, as the treatment only slowed the decline in C-peptide without preventing it entirely, and was associated with significant adverse events such as cytokine release syndrome, bone marrow suppression, serious infections, and Epstein-Barr virus reactivation. Despite these limitations, the findings supported the initiation of a phase II trial and planning for a third phase.
Cotton wool spots are mentioned as an example of a clinical finding in diabetic retinopathy, which is a complication of diabetes affecting the eyes.
Children with diabetes should be screened for IgA transglutaminase autoantibodies at the onset of diabetes, with repeat screening within two years if initially negative and asymptomatic, and again after five years. Those exhibiting symptoms or having a family history of coeliac disease may require more frequent monitoring. In cases where autoantibodies are negative but symptoms suggestive of coeliac disease persist, alternative causes such as hyperglycaemia or food intolerances should be investigated. Strongly and persistently positive autoantibody levels, defined as a radioimmunoassay index greater than 0.5 or an ELISA result over 60, warrant a biopsy even in asymptomatic children, whereas lower positive levels may lead to false-negative biopsy results and necessitate continued follow-up.
Diabetes is a polyuric disease with a history spanning over 3500 years, named from the Greek word for a syphon, and the sweet taste of diabetic urine was recognized in ancient times, with the term "mellitus" added in the late 18th century. The sugar in diabetic urine was identified as glucose in 1815, and it was later understood that glucose is stored in the liver as glycogen and secreted during fasting. The role of the pancreas in diabetes was established in 1889 when pancreatectomy was shown to cause diabetes in dogs, and the importance of pancreatic islets in glucose regulation was proposed in 1893. Insulin was discovered in 1921 and first used for treatment in 1922. Historical classifications of diabetes included lean and obese types, leading to the modern distinction between type 1 and type 2 diabetes. Research into type 2 diabetes has focused on insulin resistance and β-cell failure, with methods like the insulin clamp developed to measure insulin action, and variants such as maturity-onset diabetes of the young identified. Autoimmune involvement in diabetes was noted through observations of insulitis and the discovery of islet cell antibodies.
Excess secretion of certain hormones is associated with impaired glucose homeostasis and hyperglycaemia, contributing to diabetes-related conditions. Specifically, hypersecretion of glucocorticoids in Cushing syndrome leads to insulin resistance and impaired glucose regulation in about 70% of cases. Similarly, hypersecretion of growth hormone from pituitary adenomas, seen in acromegaly, is linked to impaired glucose homeostasis in up to 38% of individuals. Additionally, hypersecretion of catecholamines from adrenal or paraganglioma tumors results in hyperglycaemia in approximately 50% of cases.
Hyperglycaemia in diabetic ketoacidosis (DKA) causes osmotic diuresis, leading to depletion of sodium, potassium, phosphates, and water, resulting in profound dehydration and significantly low total body potassium. Despite overall potassium depletion, serum potassium levels may appear normal or elevated due to extracellular shifts caused by severe acidosis. Insulin treatment can cause a rapid drop in serum potassium, requiring careful and repeated monitoring.
GLP-1 and GIP enhance nutrient-induced insulin secretion, increase insulin biosynthesis, and expand β-cell mass, with GLP-1 also suppressing glucagon secretion and increasing somatostatin secretion, while extrapancreatically, GLP-1 slows gastric emptying, promotes satiety, and aids in weight reduction, in contrast to GIP which decreases gastric acid secretion and promotes lipogenesis.
Pancreas allograft biopsies from transplant patients receiving ciclosporin show histologic changes indicative of islet cell damage, such as cytoplasmic swelling, vacuolization, and apoptosis. The risk of post-transplant diabetes mellitus (PTDM) increases progressively with time after transplantation. Newer formulations of ciclosporin, which are better absorbed from the gastrointestinal tract, lead to higher blood concentrations and greater cumulative exposure, thereby increasing the incidence of diabetes.
Hyperglycaemia in type 1 and type 2 diabetes adversely affects periodontitis, increasing its extension and severity, and the global rise in diabetes prevalence suggests that its influence on periodontitis may be a growing concern; furthermore, periodontitis may negatively impact diabetes progression, with systemic low-grade inflammation and inflammatory cells likely playing a key role in their interaction, and the formation of AGEs potentially contributing by altering cellular functions.
The Heart Outcomes Prevention Evaluation (HOPE) trial included individuals with diabetes and at least one additional cardiovascular risk factor, such as hypertension, tobacco use, or elevated LDL cholesterol levels. In this population, the ACE inhibitor ramipril reduced the risk of death from cardiovascular causes with a relative risk of 0.74 and lowered the risk of stroke with a relative risk of 0.68, independent of its mild blood pressure-lowering effect of approximately 3/2 mmHg. The cardiovascular benefits of ramipril were observed regardless of whether participants had previously experienced a stroke.
Diabetic shin spots are well-circumscribed, atrophic, brownish scars that often appear on the shins, though they may also affect the forearms, thighs, and bony prominences. These lesions are typically bilateral and may occur in crops, starting as oval, red papules up to 1 cm in diameter that gradually develop scaling and a brown color due to haemosiderin-laden histiocytes and extravasated erythrocytes in the superficial dermis. They are usually asymptomatic and tend to resolve over 1–2 years without treatment. Improvement may vary with better glycaemic control, and it is important to screen for other microangiopathic complications of diabetes.
Activation of the complement system, particularly the MBL pathway, is associated with the development of diabetic macrovascular and microvascular complications. Elevated levels of MBL in patients with type 1 diabetes mellitus (T1DM) are linked to an increased risk of nephropathy and cardiovascular disease, with higher circulating MBL observed in those with complications compared to normoalbuminuric patients. High MBL levels early in T1DM correlate with the later onset of persistent microalbuminuria and macroalbuminuria. Similarly, in type 2 diabetes mellitus (T2DM), MBL measurement offers prognostic value regarding mortality and microalbuminuria development. The exact mechanism behind complement system activation in diabetes remains unclear, though hyperglycemia may trigger it through mitochondrial reactive oxygen species production or increased RAGE activation.
People with diabetes have an increased risk of developing Alzheimer’s disease, vascular dementia, and all types of dementia compared to those without diabetes, with relative risks of 1.56, 2.27, and 1.73 respectively. A prospective study identified factors such as age, microvascular disease, diabetic foot, cerebrovascular disease, cardiovascular disease, acute metabolic events, depression, and education level as contributors to a risk score for dementia in older individuals with diabetes, with 10-year dementia risk ranging from 5.3% for the lowest score to 73.3% for the highest score. Additionally, diabetes accelerates mortality in people with dementia, as shown by a retrospective Australian study indicating a nearly two-fold higher mortality rate in those with both diabetes and dementia compared to those with dementia alone.
Sulfonylureas are commonly used in the treatment of diabetes, but their cardiovascular safety has not been evaluated in placebo-controlled trials. Glimepiride, a sulfonylurea, was studied in the CAROLINA trial, a randomized, active-controlled study comparing glimepiride to linagliptin in people with type 2 diabetes. The trial involved 6991 participants and found no significant difference in the rate of heart failure hospitalizations between those receiving linagliptin (3.7%) and those receiving glimepiride (3.1%).
Type 1 diabetes shares several genetic associations with rheumatoid arthritis, including PTPN22, HLA-DR9, the chromosome 4q27 region, the IDDM5 region, and the IDDM8 region. There is evidence of familial clustering between these disorders, with 2.8% of first-degree relatives of individuals with rheumatoid arthritis having type 1 diabetes, compared to 0.35% in the general population. Additionally, the presence of type 1 diabetes is a risk factor for anti-cyclic citrullinated peptide (CCP)-positive rheumatoid arthritis, and this association is partly due to the influence of PTPN22 variants on the risk of both conditions.
Infections contribute to significant health complications and death in individuals with diabetes and can also trigger metabolic disturbances, creating a bidirectional relationship between high blood sugar levels and infection. Additionally, certain infections may play a more direct role in the development of diabetes.
Severe type 1 diabetes mellitus (T1DM) requires careful management through a stepwise titration process to avoid treatment side effects, with a recommended slow reduction in HbA1c of no more than 20 mmol/mol (2%) over two months. Rapid improvement in glycaemia can lead to treatment-induced worsening of pre-existing retinopathy, particularly in individuals who already have diabetic retinopathy at the start of treatment. Large reductions in HbA1c are associated with this risk, emphasizing the need for retinal screening and assessment during diabetes management.
Islet graft function declines over time, leading most patients to resume insulin use. The GLP-1 agonist exenatide can reduce insulin requirements in islet transplant recipients with failing grafts, but its effect is not sustained after discontinuation, indicating no lasting trophic effect on β-cell mass. Non-immunologic factors, such as increased metabolic demand and immunosuppressant toxicity, are thought to contribute to gradual graft loss, as there is typically no significant immune response detected.
Insulin resistance in individuals with type 1 diabetes is associated with lower insulin-stimulated ATP synthase flux, which negatively affects glucometabolic regulation. In healthy humans, short-term lipid infusion reduces muscle ATP synthase flux, particularly at the onset of insulin resistance. Reduced insulin-stimulated ATP synthase flux correlates with impaired increases in muscle glucose-6-phosphate concentrations due to diminished insulin-stimulated glucose uptake. In type 2 diabetes, lipid lowering through inhibition of lipoprotein lipase by acipimox improves insulin resistance without altering oxidative capacity, indicating that glucose- and lipid-induced mitochondrial dysfunction in muscle is not a primary cause of insulin resistance in common type 2 diabetes.
Globally, nearly half of all people with type 2 diabetes are unaware of their condition, and dentists may play a role in early detection by identifying signs such as altered periodontal attachment loss and oral candidiasis. A study in Denmark found that 3.1% of individuals without a prior diabetes diagnosis had HbA1c levels indicating type 2 diabetes, while 27.1% had HbA1c values above the threshold for prediabetes. Periodontitis is associated with elevated HbA1c levels, suggesting it may serve as an indicator for prediabetes or type 2 diabetes. Early diagnosis of diabetes is important not only for managing the disease but also for preventing complications such as cardiovascular disease, neuropathy, nephropathy, and oral health issues like attachment loss.
Glycemic control in type 2 diabetes mellitus (T2DM) raises debate over whether primary care or specialist care is most appropriate, with differing views on how treatment guidelines should be structured. Some advocate for an HbA1c target of less than 7.0% (less than 53 mmol/mol) as a realistic goal within primary care, while others argue that this standardized approach may not be sufficiently individualized and could discourage more stringent glycemic control when appropriate.
Somatostatin analogues, used in the treatment of neuroendocrine tumours, can impact glycaemic levels by reducing insulin secretion, potentially leading to hyperglycaemia; however, in some individuals, these analogues may increase insulin sensitivity and decrease gastrointestinal macronutrient absorption, resulting in low glucose levels.
The cardinal symptoms at the diagnosis of diabetes include polyuria, often with nocturia or bed-wetting, polydipsia, weight loss, and fatigue. Diabetic ketoacidosis (DKA) typically presents with Kussmaul breathing, abdominal pain, vomiting, dehydration, and impaired neurological status, though this classic presentation affects fewer than 30% of cases in developed countries. Increased community awareness has led to more children presenting with milder hyperglycemia of shorter duration, yet 75% of children, especially those under five years old, have symptoms lasting more than two weeks, indicating potential for earlier diagnosis. Young children may present less specifically, such as with vomiting or rapid breathing during infections. Diabetes should be considered in any ill child, and urine or blood testing for glucose and ketones can lead to early diagnosis, potentially preventing DKA and hospitalization, as nearly all patients admitted with severe DKA had prior contact with healthcare providers who missed the diagnosis.
New-onset diabetes mellitus has been observed in patients with HIV wasting syndrome who are treated with human growth hormone in supraphysiological doses.
The movement of insulin secretory granules in β cells involves a complex interplay of cellular structures and proteins, with microtubules providing a structural framework and other contractile proteins such as actin and myosin contributing to the actual propulsion of granules. Actin exists in both globular (G-actin) and filamentous (F-actin) forms, and its remodeling in β cells is linked to insulin secretion, as pharmacological disruption of microfilament formation can inhibit insulin release. Additionally, myosin light and heavy chains are highly expressed in β cells, suggesting a role for myosin in granule movement along the microtubular network. A protein called MyRIP (myosin- and Rab-interacting protein) is involved in cAMP-dependent insulin secretion through its interaction with the motor protein MyoVa. Other molecular motors, including myosin 5a, kinesins, and dynein, are also likely involved in the transport of secretory granules and possibly other organelles within β cells.
The prognosis of diabetes is worsened by the presence of congestive heart failure (CHF), which is a major cause of morbidity and mortality in diabetic patients with acute myocardial infarction, accounting for 66% of total mortality in the first year. Diabetes also serves as a serious prognostic factor for cardiovascular mortality in individuals with left ventricular dysfunction due to ischemic heart disease (IHD), and its coexistence with CHF significantly decreases survival in the general population, independent of other cardiovascular risk factors and IHD.
Rosiglitazone and pioglitazone have similar blood sugar-lowering effects, with pioglitazone showing a modest improvement in lipid profile; the full benefits of these medications may take 6 to 8 weeks to become apparent, and they can be taken once daily, which is particularly beneficial for older patients.
Low-dose glucagon can be used to treat persistent hypoglycemia when oral intake is not possible, administered at a dose of one unit per year of age up to 15 years using an insulin syringe. Glucagon remains stable for at least 48 hours at 4°C after mixing with water and can be repeated every 2–4 hours, though its effectiveness may decrease with prolonged fasting. This low dose is not intended for emergency treatment of severe hypoglycemia.
Children with diabetes should optimize glucose management and follow dietary and lifestyle interventions if they have LDL levels greater than or equal to 100 mg/dl; statin therapy is recommended if LDL is 130 mg/dl or higher and there is one or more cardiovascular risk factors, particularly in those over 10 years of age.
Stem cell therapy aims to treat type 1 diabetes mellitus (T1DM) by generating cells that closely resemble $\beta$-cells, which are capable of producing insulin. These stem cells are self-renewing and, in some cases, can be propagated clonally from a single cell, offering reproducibility in their use as a therapeutic tool. Advances have been made in engineering stem cells to avoid immune detection and in deriving patient-specific induced pluripotent cells (iPS) that match individual patients immunologically. Progress has also been achieved in producing insulin-secreting cells from embryonic stem cells or exocrine cells, with future efforts focusing on enhancing the efficiency and accuracy of $\beta$-cell derivation to obtain sufficient numbers of functional mature $\beta$-cells capable of addressing hyperglycemia.
In patients with diabetes, the use of ACE inhibitors results in a greater reduction in protein excretion compared to other antihypertensive agents, which may help slow the progression of diabetic nephropathy since proteinuria can contribute to worsening kidney damage.
Individuals with fully developed type 1 diabetes and advanced insulin-treated type 2 diabetes are unable to self-regulate endogenous insulin secretion in response to falling plasma glucose concentrations, compromising the first counter-regulatory defense against hypoglycaemia. Therapeutic delivery of insulin or sulfonylureas leads to unregulated hyperinsulinaemia, which promotes glucose lowering through peripheral glucose uptake in the liver, skeletal muscle, and adipose tissue, while also suppressing gluconeogenesis and inhibiting lipolysis. Additionally, insulin inhibits pancreatic α-cell glucagon release, both through direct local action in the pancreas and through central modulation in the ventromedial hypothalamic nucleus.
Transition programmes for individuals with diabetes moving from paediatric to adult care can significantly impact outcomes. A structured transition approach, involving planning during the final year of paediatric care, joint appointments with both paediatric and adult teams, and provision of a medical summary, has been shown to result in shorter gaps between the last paediatric and first adult appointments, better clinic attendance in the first year post-transfer, and improved HbA1c levels compared to a less structured method involving only a letter with medical history and a scheduled appointment. Participants in the structured programme also reported greater satisfaction with the transition process.
The text includes several medical knowledge points related to diabetes such as diabetic ketoacidosis, a serious complication of diabetes characterized by high blood sugar, ketone production, and acidosis; diabetic maculopathy and diabetic retinopathy, which are complications affecting the eyes and involving damage to the retina or macula; distal symmetrical sensory or sensorimotor polyneuropathy, a type of nerve damage commonly seen in diabetes affecting the peripheral nerves; diabetes self-management education, which refers to educational programs aimed at helping individuals manage their diabetes effectively; and continuous subcutaneous insulin infusion, a method of insulin delivery used in diabetes management. Other related concepts include estimated average glucose measurement, which reflects average blood glucose levels over time, and various studies and programs like the Diabetes Control and Complications Trial, the Diabetes Prevention Program, and the Diabetes Antibody Standardization Program that focus on understanding, preventing, and treating diabetes and its complications.
Hybrid closed-loop insulin pumps integrate continuous glucose monitoring (CGM) data to adjust basal insulin delivery based on glucose values and trends, offering improvements in time in range and HbA1c levels. These systems function similarly to conventional insulin pumps in other aspects, requiring users to manage mealtime boluses, troubleshoot hyperglycemia, and identify pump site issues. Currently, two hybrid closed-loop systems are FDA-approved, with more anticipated, and their use is linked to enhanced quality of life and psychosocial outcomes. However, disparities in access to these technologies are emerging based on race, ethnicity, and socioeconomic status.
Soluble fiber, including gums, pectins, hemicelluloses, mucilages, and fructans, reduces post-prandial hyperglycaemia and causes modest reductions in fasting plasma glucose and glycated haemoglobin (HbA1c), by slowing digestion and absorption of carbohydrates. Insoluble fiber, such as celluloses and wheat bran, and probiotics may also influence glycaemic control, although their mechanisms are less clear and may involve decreasing gut permeability and immunomodulation, with some studies showing small reductions in plasma glucose and HbA1c.
Neonatal diabetes and maturity-onset diabetes of the young (MODY) are forms of monogenic diabetes with distinct molecular diagnoses, pathophysiological mechanisms, and treatment approaches. Neonatal diabetes typically presents within the first six months of life and may be transient or permanent, often caused by mutations affecting pancreatic beta-cell function or development. MODY usually manifests in adolescence or early adulthood, is characterized by autosomal dominant inheritance, and results from mutations in genes involved in insulin secretion regulation. Genetic testing is essential for accurate diagnosis, enabling tailored management strategies that may include sulfonylureas, insulin, or lifestyle modifications depending on the specific genetic subtype.
The text includes several medical knowledge points related to diabetes, such as the use of fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) in diagnosis, the significance of glycated haemoglobin ($\mathsf{HbA}_{1\mathsf{c}}$) in monitoring long-term glucose control, and the association of diabetes with conditions like gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS), and cardiovascular disease (CVD). It also highlights organizations like the American Diabetes Association (ADA) and the National Institute for Health and Care Excellence (NICE) that provide clinical guidelines, along with the Australasian Diabetes in Pregnancy Society (ADIPS) which focuses on diabetes during pregnancy. Additionally, it notes the importance of body mass index (BMI) and lipid markers such as high-density lipoprotein (HDL) in diabetes management.
Prandial insulin releasers can be used as monotherapy in people whose diabetes is inadequately managed by non-pharmacological measures, particularly in those with post-prandial glycaemic excursions while maintaining near-normal fasting glycaemia. These rapid-acting insulin releasers are beneficial for individuals with irregular lifestyles and unpredictable or missed meals, and their lower risk of hypoglycaemia makes them a useful option for some older individuals, especially when other agents are contraindicated, though multiple daily doses may be a drawback.
The study compared one-step and two-step diagnostic processes for gestational diabetes mellitus (GDM) using the 75 g oral glucose tolerance test (OGTT) interpreted by IADPSG criteria, identifying 16.5% of women with GDM using the one-step method and 8.5% with the two-step method. No significant differences were found in maternal or perinatal outcomes between the two strategies, with a small reduction in large-for-gestational-age (LGA) infants in the one-step group. The one-step approach nearly doubled the frequency of GDM diagnosis and identified women at similar risk of requiring pharmacotherapy for hyperglycaemia. The study could not determine whether the additional 8% of women diagnosed with GDM using the one-step method would benefit from treatment, and concerns were raised about potential residual bias due to provider discretion in diagnostic strategy.
Programs for managing diabetes often include booster sessions held 6 or 12 months after the initial program to reinforce previously learned material, and may involve spouses or family members either in joint or separate sessions. Some programs focus on basic diabetes management and problem-solving skills, while others address stress management or psychological issues specific to diabetes, such as fears about hypoglycemia or concerns about hyperglycemic complications. Many programs incorporate homework assignments and extensive self-monitoring. Approaches like cognitive behavioral therapy (CBT) and motivational interviewing or motivational enhancement therapy, originally developed for individuals with psychological distress without diabetes, are increasingly used for people with diabetes and have shown modest improvements in HbA1c levels and self-reported quality of life.
In diabetes, particularly diabetic nephropathy, the albumin excretion rate is an important marker of kidney damage, with values ranging from 20 to 200 µg/min or 30 to 300 mg/24h in 24-hour urine collections indicating abnormal protein loss.
Preventing or delaying the onset of diabetes and its complications is crucial due to its significant cost. Understanding the natural history of type 2 diabetes and the influence of modifiable risk factors has led to clinical trials examining lifestyle interventions. Evidence shows that lifestyle measures, such as structured education, exercise programs, reduced fat intake, increased fibre intake, moderate daily exercise, and weight reduction of at least 5%, are effective in preventing diabetes. These interventions are not only cost-effective but also demonstrate long-term benefits in reducing diabetes risk. For example, in the China Da Qing Diabetes Prevention Study, participants receiving lifestyle intervention had a 51% lower incidence of diabetes during a six-year active intervention period and a 43% lower incidence over 20 years. Extended follow-up revealed a 41% reduction in cardiovascular mortality and a 29% reduction in all-cause mortality among those receiving lifestyle interventions over 23 years.
Necrobiosis lipoidica is associated with diabetes and can lead to significant morbidity and cosmetic distress. The condition often presents with shiny, waxy yellowish lesions due to lipid deposition, typically located on the shin, though the thighs, ankles, and feet may also be affected. Lesions may become ulcerated in up to 35% of cases, healing very slowly, and can be partially or completely anaesthetic. Alopecia is frequently present, and while the number of lesions is usually few, they tend to expand slowly over years, sometimes merging with adjacent lesions. Diagnosis is typically clinical, avoiding skin biopsy when possible due to the risk of ulceration in atrophic lesions. The differential diagnosis for early lesions includes granuloma annulare, cutaneous sarcoid, necrobiotic xanthogranuloma, and diabetic dermopathy.
The Hypo-compass trial compared continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) with or without continuous glucose monitoring (CGM) in individuals with type 1 diabetes and impaired awareness of hypoglycaemia, showing that both treatment approaches led to significant reductions in severe hypoglycaemia and improvements in hypoglycaemia awareness over six months, with higher treatment satisfaction in the CSII group. These improvements were maintained even after returning to routine care, as observed in a 24-month follow-up. All participants received standardized hypoglycaemia psycho-education and clinical support during the trial period.
Several studies have reported associations between various molecules and substances and type 1 diabetes mellitus (T1DM), including minor or candidate autoantigens such as ICA12/SOX13, glima-38, vesicle-associated membrane protein 2 (VAMP2), neuropeptide Y, carboxypeptidase H, GLUT-2, heat shock protein 60, Imogen 38, and ICA69, which are thought to be linked to T1DM and autoimmunity.
The development of lente insulins in 1951 allowed for prolonged insulin action without protamine by adding excess zinc in acetate buffer, forming relatively insoluble zinc-insulin complexes. By adjusting the pH, crystal size could be controlled, producing larger, slower-absorbing crystals known as ultralente and smaller, faster-acting crystals called semilente. A 70:30 mixture of ultralente and semilente insulins became the most popular zinc insulin preparation, widely used in diabetes management.
Regional osteopenia secondary to neuropathy is a condition that can occur in individuals with diabetes, particularly those with long-standing disease and peripheral neuropathy. This condition involves localized bone density loss in areas innervated by affected nerves, often leading to structural weakness and increased fracture risk. It is commonly associated with diabetic neuropathic arthropathy, also known as Charcot joint, which results from nerve damage and impaired sensation, leading to joint degeneration and bone changes.
The World Health Organization global diabetes report highlights the increasing prevalence of diabetes worldwide, emphasizing its significant impact on public health. The report outlines that diabetes is a chronic metabolic disorder characterized by elevated blood glucose levels, which can lead to severe complications such as cardiovascular disease, kidney failure, neuropathy, and retinopathy. It identifies type 1 diabetes as an autoimmune condition typically diagnosed in childhood, requiring lifelong insulin therapy, while type 2 diabetes, often linked to obesity and sedentary lifestyles, can sometimes be managed through diet, physical activity, and oral medications. The report stresses the importance of early diagnosis, regular monitoring of blood sugar levels, and maintaining glycemic control to prevent complications. Risk factors such as family history, poor diet, lack of physical activity, and obesity are noted as key contributors to the rising incidence of diabetes globally.
Blood glucose monitoring is essential for managing diabetes, and factors such as extreme temperatures and high altitudes can interfere with the accuracy of blood glucose meters and test strips. However, typical cabin pressure in passenger aircraft, equivalent to an altitude of up to 8000 feet, should not cause issues. To ensure continued monitoring while traveling, especially during holidays, it is advisable to carry a spare meter and/or visually readable glucose strips in case the primary meter fails.
Studies on diabetes have often relied on convenience samples from specialist clinics, introducing potential biases due to referral patterns and unknown demographic factors like ethnicity. Additionally, many studies have low or unclear response rates, with depressive symptoms possibly reducing participation, thereby further skewing prevalence estimates. More recent research employing improved methodologies and meta-analyses has generally reported lower prevalence rates of diabetes.
The World Health Organization (WHO) DIAMOND Study and the EURODIAB ACE Study have gathered standardized incidence data for type 1 diabetes in children under 15 years of age, relying on notifications from diagnosing physicians and defining the diagnosis date as the date of the first insulin injection; both studies have also assessed the extent of undercounting cases through secondary information sources, and further population-based incidence studies have since been published from different countries.
A significant dose-dependent increase in insulin sensitivity and a reduced insulin response were observed in women with previous gestational diabetes mellitus (GDM) who were treated with troglitazone, with those receiving 400 mg/day in the TRIPOD trial showing a 55% reduction in the risk of diabetes progression. The US Diabetes Prevention Program (DPP) found that metformin reduced the cumulative incidence of diabetes by 50.4% in women with impaired glucose tolerance and prior GDM compared to placebo, indicating that interventions like metformin are effective in preventing diabetes progression even years after delivery.
In diabetes, higher fasting plasma glucose levels are associated with more severe retinopathy, as observed in the UKPDS. Increased alcohol consumption in men is linked to greater severity of retinopathy, while leaner women tend to experience more severe eye lesions. Despite this, most individuals maintain normal visual acuity, although men with more advanced retinal damage show a trend toward reduced visual acuity.
Oxidative stress, caused by increased reactive oxygen species (ROS) generation and/or compromised antioxidant systems, plays a key role in the development of insulin resistance and related conditions such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). Nutrient excess, physical inactivity, and hyperglycemia contribute to oxidative stress and low-grade inflammation, with dysfunctional mitochondria in skeletal muscle being a significant source of ROS production. Although the exact relationship is unclear, mitochondrial dysfunction is closely linked to increased ROS generation. Excess ROS production can be triggered by inflammation and proinflammatory cytokines like TNF-α, and oxidative stress can become self-reinforcing as ROS activates NF-κB, leading to increased expression of proinflammatory genes such as TNF-α, IL-6, and C-reactive protein (CRP). Oxidants impair insulin signaling by inducing serine phosphorylation of IRS, which interferes with tyrosine phosphorylation and increases IRS protein degradation.
People with diabetes have an increased risk of impaired physical health leading to inpatient admission, requiring regular physical monitoring due to high risks of complications and mortality. Managing acute metabolic decompensation in individuals with type 1 diabetes and eating disorders (T1DE) involves challenges such as electrolyte and fluid shifts during re-insulinization and refeeding, sensations of pseudo-hypoglycaemia, rapid weight gain from fluid retention, and halting catabolism by reintroducing insulin. Dehydration from hyperglycaemia necessitates proper fluid access, which conflicts with standard eating disorder care that limits fluid intake to avoid fluid overload mimicking weight gain. Nutrient and vitamin deficiencies combined with chronic hyperglycaemia and rapid glycaemic improvement can worsen autonomic or painful peripheral neuropathy.
Glycogen phosphorylase inhibitors are being explored as potential treatments for diabetes by reducing hyperglycemia through the prevention of glycogen breakdown. These inhibitors target different sites on the enzyme, including the active site and the AMP site, with some examples like the dihydropyridine derivative BAY R3401 acting as a prodrug that binds at the AMP site, leading to allosteric inhibition and conversion of active glycogen phosphorylase a to the inactive b form. Although these agents have shown improved glycemic control in animal models of type 2 diabetes mellitus (T2DM), clinical studies are limited and suggest only modest or unsustained efficacy.
Diagnosis of diabetes involves specific thresholds for plasma glucose levels, including a fasting plasma glucose of 7.0 mmol/L (126 mg/dL) or higher, or a 2-hour plasma glucose level of 11.1 mmol/L (200 mg/dL) or higher during an oral glucose tolerance test. Impaired glucose tolerance is characterized by a fasting plasma glucose below 7.0 mmol/L (126 mg/dL) and a 2-hour plasma glucose level between 7.8 and 11.1 mmol/L.
The Diabetes Control and Complications Trial (DCCT) demonstrated that participants with type 1 diabetes initially had normoalbuminuria, and those receiving intensive treatment experienced a 39% relative risk reduction for developing moderately elevated albuminuria and a 54% reduction for progression to grade A3 albuminuria compared to those managed conventionally over 6.5 years. The mean achieved HbA1c levels were 52 mmol/mol (7.0%) in the intensively treated group and 76 mmol/mol (9.1%) in the conventionally managed group, indicating that lower HbA1c levels are associated with reduced risk of kidney complications, with no clear HbA1c threshold below which additional risk reduction ceases.
The growth factor FGF-1 elicits a durable anti-diabetes action, initially observed following systemic administration but found to be highly effective when administered intracerebroventricularly at doses too low to have systemic effects. Unlike other treatments for type 2 diabetes, a single intracerebroventricular injection of FGF-1 can normalize glycaemia for weeks to months in rodent models without affecting food intake, body weight, or adiposity. The mechanism involves glia-neuron interactions in the hypothalamus that enhance melanocortin signaling and reverse maladaptive changes in the extracellular matrix. Additionally, FGF-1, like leptin, not only lowers elevated plasma glucose but also restores the BDLG to normal in diabetic animals, though the applicability of these findings to humans remains to be studied.
Pramlintide, an amylin analog developed by Amylin Pharmaceuticals Inc., was approved by the FDA in 2005 for use in insulin-treated individuals with either type 1 or type 2 diabetes. When used over a period of 6 to 12 months, pramlintide treatment resulted in a decrease in HbA1c levels by 0.4–0.6% (4–7 mmol/mol) compared with placebo, and led to a small but clinically significant weight loss of 0.8–1.4 kg compared with placebo. The main side effects include nausea, which is often transient, and hypoglycemia, though both can be significantly reduced when the drug is titrated properly, especially with a reduction in insulin dose.
Insulin resistance can occur independently of inadequate insulin secretion and is considered a prerequisite for the development of type 2 diabetes. Evidence from the Whitehall II study shows that individuals who develop diabetes have 29% lower insulin sensitivity (HOMA-S) but 13% higher insulin secretion (HOMA-B) 13 years before diagnosis. Insulin sensitivity declines linearly until about five years before diagnosis, with a steeper decline in the final five years, indicating that insulin resistance is an early abnormality that is initially compensated by increased beta-cell function before the insulin-glucose feedback loop fails. Furthermore, insulin resistance not only predicts type 2 diabetes but also correlates with cardiovascular disease and related outcomes.
The intestinal microbiome has the potential to impact type 2 diabetes through crosstalk with immunological and metabolic pathways, including activation of innate immune pathways, modulation of enteroendocrine cell function, and regulation of metabolic signaling, all of which can disrupt insulin signaling and contribute to impaired glucose metabolism. In type 1 diabetes, inappropriate immune education by the microbiome may increase the risk of autoimmune destruction of pancreatic β cells in susceptible individuals. Understanding these microbiome-related mechanisms may aid in developing better risk-stratification tools and improving diabetes management strategies.
Studies indicate that the absorption rate of subcutaneously administered insulin varies between individuals and within the same individual, with slower absorption observed in obese patients compared to non-obese patients. In non-obese individuals, the abdomen shows faster absorption of soluble insulin than the arm or leg, and the upper abdomen absorbs insulin faster than the lower abdomen. These variations across injection sites are less pronounced with insulin analogs than with soluble insulin.
Osteomyelitis, particularly of the foot, is more common in people with diabetes, often secondary to vascular insufficiency such as in diabetic foot infections. Individuals with diabetes are at increased risk for various types of osteomyelitis, including hematogenous vertebral osteomyelitis, which occurs two to six times more frequently and may involve unusual organisms. Effective management of osteomyelitis in diabetic patients requires a multidisciplinary approach that includes expertise in orthopedic surgery, infectious diseases, and vascular surgery, along with early diagnosis, bone sampling for targeted antimicrobial therapy, and consideration of surgical intervention if medical treatment fails or complications arise.
Insulin resistance, a key feature in diabetes, may be influenced by the SOCS family of proteins, particularly SOCS-1, SOCS-3, and SOCS-6, which can bind to the COOH-terminus of the insulin receptor β-subunit and block the interaction between the insulin receptor and IRS. This inhibition interferes with insulin signaling, contributing to reduced insulin sensitivity. Factors such as TNF-α, growth hormone, and leptin, which are known to induce cellular insulin resistance, also promote SOCS-3 expression, suggesting a potential mechanism linking inflammation and hormonal imbalances to the development of diabetes.
Bone fragility in patients with diabetes may be influenced by abnormalities in bone strength and quality not detected by DEXA assessment, potentially linked to elevated levels of advanced glycation end-products (AGEs) in diabetic individuals. AGEs, which result from non-enzymatic glycation, are found in higher amounts in the skeletons of diabetic animals and may impair bone biomechanics by glycation of matrix proteins, leading to reduced bone strength. In vitro studies indicate that AGEs hinder osteoblast differentiation while promoting osteoclast differentiation, negatively affecting bone remodeling and strength. Although some AGEs like pentosidine may decrease osteoclast development, overall increased AGE signaling appears harmful to bone health, as suggested by studies on mice lacking the receptor for AGEs, which show increased bone mass and reduced osteoclast activity.
Weight loss and fitness improvements from an intensive lifestyle intervention in adults with diabetes and overweight or obesity were not sustained over time, which may explain the lack of reduction in cardiovascular disease risk, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for angina, as well as no difference in heart failure rates between intervention and control groups. However, post hoc analyses showed that reductions in BMI, waist circumference, and fat mass were each associated with a significantly lower risk of heart failure, and the intervention did improve several cardiovascular risk factors.
Insulin therapy in diabetes management is adjusted based on hourly measurements of blood glucose and, if possible, blood ketones, aiming for a gradual decline in both. The initial reduction in glucose levels is largely due to rehydration and expansion of the extracellular volume. Urine ketone measurements are generally unreliable during this phase, as they primarily detect acetoacetate, which is less significant compared to 3-OH-butyrate, and may paradoxically increase early in treatment despite improving blood concentrations. Standard urine dipstick methods also detect acetone, which can remain in urine for up to 48 hours after treatment begins because it is fat-soluble and clears slowly.
To avoid hypoglycemia during exercise, individuals should avoid heavy exercise during peak insulin action, use non-exercising sites for insulin injection, and adjust insulin dosages—reducing pre-exercise insulin by 20–50% if using multiple daily injections or adjusting basal rates and bolus amounts if using an insulin pump. These adjustments should be individualized based on blood glucose monitoring. Glycemia should be monitored before, during, and after exercise as needed. Extra carbohydrates should be taken before and hourly during exercise, with amounts individualized and based on monitoring. After prolonged exercise, glycemia should continue to be monitored and additional carbohydrates consumed to prevent delayed hypoglycemia, with the quantity estimated as 1 g CHO/kg body weight/hour of activity or referenced from energy requirement tables. Extra caution in glycemic monitoring is advised if exercising within 24 hours of a prior hypoglycemic episode.
The relative contribution of fasting plasma glucose (FPG) and post-prandial plasma glucose (PPG) to overall hyperglycemia varies depending on the level of glycemic control as measured by HbA1c. When HbA1c is close to the ADA goal of less than 7.0% (53 mmol/mol), post-prandial glucose has a greater impact on overall hyperglycemia, suggesting that managing blood sugar after meals becomes more critical as patients approach target glycemic goals. Conversely, when HbA1c is far above the target, fasting glucose contributes more significantly to hyperglycemia, indicating that improving fasting glucose levels should be a priority in patients with poor glycemic control. The corresponding IFCC units for HbA1c quintiles are provided as follows: <56 mmol/mol, 56–58 mmol/mol, 69–77 mmol/mol, 78–88 mmol/mol, and >88 mmol/mol.
The lipid-induced insulin resistance or lipotoxicity hypothesis suggests that when there is an imbalance between fatty acid delivery and muscle triglyceride (TAG) synthesis via DGAT-1 as well as oxidation in the mitochondria, lipotoxic species such as sn-1,2-DAGs accumulate in the plasma membrane and activate PKCε/PKCθ in skeletal muscle. This activation inhibits insulin receptor kinase (IRK) activity and IRS-1-associated PI3K, resulting in impaired insulin signaling and reduced insulin-stimulated glucose uptake. Mechanisms that decrease lipid delivery to the muscle, enhance lipid oxidation, or promote TAG synthesis may lower long-chain fatty acyl-CoA and plasma membrane sn-1,2-DAG levels, thereby preventing lipid-induced muscle insulin resistance.
Hypoglycaemia in children with diabetes is often predictable and preventable, requiring education for both children and caregivers on recognizing symptoms and administering immediate treatment. Children should carry rapid-acting glucose sources and wear diabetes identification. Recurrent hypoglycaemic episodes or hypoglycaemia unawareness warrant contacting the diabetes care provider to adjust insulin regimens, food intake, blood glucose targets, and monitoring strategies. Continuous glucose monitoring (CGM) aids in detecting and avoiding hypoglycaemia, while hybrid closed-loop insulin pumps with predicted low glucose suspend features can prevent hypoglycaemia by reducing insulin delivery in response to declining blood glucose levels.
Adipose tissue plays a significant role in diabetes-related processes, with certain genes showing differential expression in this tissue, either increasing or decreasing activity, though some effects remain unconfirmed. Several proteins and enzymes associated with inflammation, glucose metabolism, and insulin resistance are linked to diabetes, including C-reactive protein (CRP), interleukin 6 (IL-6), matrix metalloproteinase 9 (MMP-9), nuclear factor κB (NFκB), plasminogen activator inhibitor 1 (PAI-1), retinol-binding protein (RBP), tumor necrosis factor α (TNF-α), and uncoupling protein 1 (UCP-1). Glucose transporters (GLUT) are involved in glucose uptake, and phosphoenolpyruvate carboxykinase (PEPCK) is a key enzyme in gluconeogenesis, both of which are relevant to diabetes pathophysiology.
The target glucose concentration for certain patients should be between 6.0 and 10.0 mmol/l (108 and 180 mg/dl), with a broader range of 4.0–12.0 mmol/l (72–216 mg/dl) considered acceptable for medical patients and conscious surgical patients, though the lower limit of 4.0 mmol/l has been questioned. In the USA, fasting glucose targets are below 7.8 mmol/l (140 mg/dl) and random glucose targets below 10.0 mmol/l (180 mg/dl). For end-of-life care, more relaxed targets are recommended to avoid symptomatic hypoglycemia or hyperglycemia, with the UK suggesting a range of 6.0–15.0 mmol/l (108–270 mg/dl) and the USA suggesting similar but slightly lower levels.
Continuous low-dose intravenous infusion of insulin is the preferred method for managing diabetic ketoacidosis (DKA) in children, typically starting with an initial bolus of 0.1 unit/kg followed by a continuous infusion at 0.1 unit/kg/hr. The goal is to lower blood glucose levels at a rate of 50-100 mg/dL per hour. A common preparation involves adding 1 unit/kg of plain insulin to 100 ml of 0.9% saline, infused at 10 ml/hour, with the dose potentially reduced to 0.05 units/kg/hr once blood sugar levels decrease.
Emphysematous pyelonephritis is an infection that primarily affects individuals with diabetes, accounting for 90% of cases, and is more common in females. It is a severe necrotizing infection of the renal parenchyma and surrounding tissues, which can spread to the collecting system or perinephric areas. The presence of gas in these regions may result from the fermentation of glucose at high concentrations.
People with advanced type 2 diabetes are at risk for acquired counter-regulatory impairment, characterized by a loss of glucagon responses to hypoglycaemia, similar to those observed in type 1 diabetes; additionally, the glycaemic thresholds for sympathoadrenal and symptomatic responses to hypoglycaemia are shifted to lower plasma glucose concentrations due to recent antecedent hypoglycaemia, a feature also seen in type 1 diabetes.
The structure and blood flow within islets, which constitute only 2-3% of the pancreatic mass but receive up to 15% of the pancreatic blood supply, are important for insulin secretion. Each islet has an arteriolar blood supply that forms a capillary bed in the islet core, and imaging studies suggest that most β cells, which produce insulin, are in direct contact with capillaries and are structurally polarized to target insulin secretion toward the capillary bed. Earlier studies in rodent islets suggested a blood flow pattern from inner β cells to outer α and δ cells, but more recent in vivo imaging reveals more complex flow patterns, including both inner-to-outer and top-to-bottom directions.
Ethnic minorities in the USA, including non-Hispanic Black, Hispanic, and non-Hispanic Asian populations, have a higher prevalence of diabetes compared to white European adults, with rates of 20.4%, 22.1%, and 19.5% respectively, as reported in a 2019 study.
In the context of diabetes, particularly type 1 diabetes mellitus (T1DM), the addition of an ARB to therapy with an ACE inhibitor provides further short-term reductions in blood pressure and urinary albumin excretion, though there is no evidence of long-term benefit and some concern about hyperkalemia. Additionally, adding spironolactone to other antihypertensive therapy, including RAS blockade, reduces urinary albumin excretion in the short term. However, there are no good data on the use of direct renin inhibition in T1DM.
Increased expression of the receptor for AGEs (RAGE) and its activating ligands contributes to the development and progression of diabetes-related complications by promoting inflammation and oxidative stress, which are key mechanisms in the pathophysiology of diabetic tissue damage.
Commercially available insulin was initially extracted from porcine and bovine pancreata, with the tissue undergoing acid-ethanol treatment to solubilize insulin, followed by salting out with sodium chloride, precipitation, and crystallization, resulting in insulin with 80–90% purity, though contaminants such as pancreatic polypeptides and glucagon remained. Despite its effectiveness, this form of insulin was associated with immune-mediated side effects including lipoatrophy and antibody-mediated insulin resistance, both of which can significantly affect insulin action kinetics, and also contributed to allergic reactions.
Sulfonylurea-induced hypoglycemia requires prompt hospital admission and is treated with continuous intravenous glucose infusion, often for more than 24 hours due to the risk of recurrent hypoglycemia, especially with long-acting sulfonylureas. In cases of chlorpropamide accumulation, forced alkaline diuresis may enhance renal elimination. The vasodilator diazoxide and the somatostatin analog octreotide can be used cautiously to inhibit insulin secretion in severe cases. Glucagon should be avoided in patients with type 2 diabetes mellitus (T2DM) because it acts as an insulin secretagogue.
In diabetes management, short-term blood glucose targets of greater than 4 but less than 15 mmol/L are considered more important than long-term glycated haemoglobin (HbA1c) targets, especially for very frail older individuals with limited life expectancy. Considerations such as hypoglycaemia risk, dementia, polypharmacy, and care home residency play a role in determining appropriate management strategies and glycaemic goals.
GLP-1 receptor agonists have shown beneficial effects on cardiovascular outcomes in individuals with type 2 diabetes, with recent meta-analyses indicating that these benefits are consistent not only in those with established cardiovascular disease but also in those with multiple risk factors in the absence of clinically apparent cardiovascular disease.
Diabetes prevalence in sub-Saharan Africa has increased over time, with early studies showing low rates such as 0.2% in urban Ghana in 1963 and 1.65% in urban Nigeria in 1985. By 2000, diabetes prevalence in Nigeria had risen to 6.8% among adults aged ≥40 years, and in Ghana, it reached 6.3% among adults aged ≥25 years in 1998. In Cameroon, the overall diabetes prevalence among adults aged 24–74 years was 1.1%, with higher rates in urban areas (1.3% in Yaounde) compared to rural areas (0.8%). Impaired glucose tolerance was also present, with rates of 2.7% overall, 1.8% in Yaounde, and 3.9% in rural areas. A significant proportion of cases were undiagnosed, indicating a growing but underrecognized diabetes burden in the region.
Diabetes is associated with an increased risk of macrovascular disease, including coronary artery disease, which is influenced by a range of hemodynamic and metabolic factors, and the condition enhances the effects of other cardiovascular risk factors, with 90% of the excess coronary artery disease risk seen in people with diabetes attributed to these interactions; although the link between glucose control and cardiovascular disease is not as strong as with microvascular complications, there is clear evidence that glucose exerts both direct and indirect toxic effects on the vasculature, contributing to vascular damage; the concept of glycemic memory highlights the long-term negative effects of prior glycemic status, suggesting that early glycemic control is crucial for reducing vascular complications over time; additionally, specific insulin resistance pathways contribute to atherogenesis in diabetes, and the accumulation of advanced glycation end-products (AGEs) exerts pro-inflammatory and pro-fibrotic effects on blood vessels through both receptor-independent and receptor-dependent mechanisms, with the AGE receptor (RAGE) playing a key role in diabetes-accelerated atherosclerosis.
HCV infection is associated with an increased risk of developing type 2 diabetes mellitus (T2DM), particularly in older individuals (>40 years) and those with advanced cirrhosis. The presence of diabetes is linked to more severe hepatic fibrosis, and the higher prevalence of diabetes in HCV compared to other liver diseases suggests a specific mechanism related to hepatitis C. Tumor necrosis factor α has been proposed as a potential contributor to this association.
CSII (continuous subcutaneous insulin infusion) may offer advantages over MDI (multiple daily injections) in pre-pregnancy and pregnancy management for women with pre-gestational type 1 diabetes, as it is associated with lower HbA1c levels at booking and reduced glycemic variability during the pre-conception period and each trimester of pregnancy. However, the difference in HbA1c between CSII and MDI groups decreases as pregnancy progresses, suggesting that both methods can achieve good glycemic control when the woman is highly motivated. Despite better glycemic management with CSII in the first trimester, possibly due to greater participation in pre-conception care, studies have noted increased maternal gestational weight gain and a higher incidence of large for gestational age babies in the CSII group, highlighting the importance of education on appropriate gestational weight gain for women with type 1 diabetes planning pregnancy. Women with pre-gestational type 1 diabetes are at increased risk of adverse outcomes such as spontaneous abortions, congenital malformations, macrosomia, pre-eclampsia, need for operative delivery, and progression of diabetes complications.
Ertugliflozin, a medication used in the management of type 2 diabetes, was studied in the VERTIS CV trial for its cardiovascular effects in individuals with established atherosclerotic cardiovascular disease. The trial demonstrated that ertugliflozin was non-inferior to placebo in preventing major adverse cardiovascular events (MACE), which include heart attack, stroke, and cardiovascular death, over a median follow-up of 3.0 years. While it did not show superiority over placebo in reducing MACE or its individual components, it did significantly lower the risk of hospitalization for heart failure, with a hazard ratio of 0.70. Additionally, the drug showed neutral effects on kidney outcomes, including renal death, renal replacement therapy, and doubling of serum creatinine.
In diabetes, behavioral changes, including adhering to a meal plan and engaging in regular physical activity, are important for disease management. Patient education, reminders, and financial incentives have been shown to improve disease control, with effect sizes of 0.24, 0.27, and 0.40 respectively. Patient adherence to treatment is a critical factor in realizing the benefits of care processes, and patients should be encouraged to actively participate in defining and achieving their treatment goals rather than simply following medically prescribed regimens.
Poorly controlled diabetes can lead to hypertriglyceridemia, which may result in eruptive xanthomas due to triglyceride deposition in the skin, presenting as small red or yellow nodules typically found on the extensor surfaces of the limbs and buttocks. These lesions often appear rapidly and in groups, are more common in men, and may regress over months when hypertriglyceridemia is addressed through lipid-lowering drugs or improved glycemic control.
Increased hepatic glucose production contributes significantly to fasting hyperglycemia in diabetes, making regulatory pathways that control hepatic glucose output potential targets for drug therapy. Hormones that increase cAMP and induce PEPCK promote hepatic glucose production, while insulin suppresses both; insulin also reduces hepatic glucose output by decreasing the availability of gluconeogenic substrates such as free fatty acids through its antilipolytic action in adipocytes and by inhibiting glucagon secretion from pancreatic α cells.
Microbial metabolites, such as branched-chain amino acids (BCAAs) synthesized by species like Prevotella copia, have been linked to increased circulating BCAA concentrations and exacerbated insulin resistance in high-fat fed murine models. Additionally, imidazole propionate, a byproduct of microbial metabolism of dietary histidine, is found at higher levels in individuals with type 2 diabetes and is associated with the severity of insulin resistance. Administration of imidazole propionate in mice impaired glucose tolerance independently of insulin concentrations, and in vitro studies showed that it alters phosphorylation of the insulin receptor substrate (IRS) and activates the mechanistic target of rapamycin complex (mTORC1), suggesting a causal relationship between gut microbiota and disruptions in insulin signaling pathways.
For individuals managing diabetes, carbohydrate supplementation strategies are important during physical activity to match glucose utilization by working muscles. Methods include a basic approach of consuming 15–30 g of carbohydrate every 30–60 minutes of exercise, a semi-quantitative approach involving approximately 1 g of glucose per kilogram of body weight per hour, or a quantitative method using standardized energy requirement tables known as "excars." However, due to the limited absorption capacity of 40–60 g/hour during moderate to vigorous activity, some carbohydrates should be consumed before exercise or during recovery. Regular glucose monitoring remains essential, especially to prevent hypoglycemia and manage energy needs effectively.
Type 2 diabetes is associated with an increased risk of several adult cancers, likely mediated by hyperglycaemia and hyperinsulinaemia, and is linked to higher cancer-related mortality, with cancer becoming a leading cause of death in some diabetes populations. Certain glucose-lowering therapies, such as insulins, thiazolidinediones, and incretin-based drugs, may increase cancer risk, while metformin may decrease it, though recent large-scale studies suggest these associations may be weaker than previously thought. Individuals with diabetes who develop cancer may experience poorer treatment responses and reduced survival, although the extent to which diabetes directly affects cancer biology remains unclear. Clinically, this relationship has implications for cancer screening in diabetes patients, considerations of cancer risk when initiating glucose-lowering medications, and the management of cancer treatment effects in those with diabetes, giving rise to the field of onco-diabetology.
Orlistat treatment in obese subjects with type 2 diabetes mellitus (T2DM) results in greater weight loss compared to placebo, with an average difference of 2.0 kg over at least 12 weeks, and is associated with a small improvement in HbA1c levels; additionally, orlistat moderately reduces low-density lipoprotein (LDL) cholesterol concentrations.
Excessive weight gain during pregnancy, independent of initial BMI, may increase the risk of early development of obesity in the offspring, which in turn may increase the lifetime risk for T2DM. Hyperglycemia and chronic overnutrition during pregnancy can lead to fetal hyperinsulinemia, hypercortisolemia, and hyperepitemia, potentially causing a persisting malprogramming of hypothalamic centers that control energy homeostasis and metabolism. The mechanisms behind these effects are not fully understood, but epigenetic processes such as DNA methylation, histone modification, and changes in microRNA patterns are thought to be involved, potentially affecting central neuroendocrine pathways and modifying appetite regulation.
The early use of metformin and glibenclamide in the 1970s for women with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) in South Africa was linked to reduced neonatal mortality. Switching pregnant women from oral hypoglycemic agents to insulin early in pregnancy was found to result in better pregnancy outcomes compared to treatment with oral agents alone. Earlier observational studies suggested that poor glycemic control, rather than the use of oral agents, was responsible for high rates of malformations and perinatal mortality. Subsequent studies on the use of oral agents in pregnancy were largely observational, involved diverse populations, and often lacked appropriate control groups, making meta-analysis difficult.
Intensified multifactorial risk intervention including intensive diabetes treatment, ACE inhibitors, antioxidants, statins, aspirin, and smoking cessation did not affect the progression of diabetic peripheral neuropathy (DPN) after 3.8 years but showed benefits on other microvascular complications such as diabetic nephropathy and retinopathy. A positive effect on autonomic neuropathy was observed, as indicated by an increase in heart rate variability. After 7.8 years, the same intervention continued to show effects on these outcomes.
Hypoxia in adipose tissue due to fat cell hypertrophy contributes to chronic inflammation, macrophage infiltration, impaired adipokine secretion, ER stress, and mitochondrial dysfunction, which are associated with obesity. These changes also lead to inhibited adipogenesis, reduced triglyceride synthesis, elevated free fatty acid levels, and decreased mitochondrial respiration with increased lactate production. In humans, hypoxia response genes such as HIF-1α are elevated in obese individuals and decrease after weight loss, and hypoxia reduces adiponectin expression in adipocytes.
In people with diabetes and heart failure with reduced ejection fraction (HFrEF), implantable cardioverter-defibrillators (ICDs) may have a reduced beneficial effect on mortality compared to those without diabetes. While ICDs reduce the risk of death in the general HFrEF population, subgroup analyses suggest that this benefit may not extend to individuals with diabetes, potentially due to less effective ICD therapy or higher risk of death from non-sudden cardiac causes. Additionally, inappropriate ICD therapy is less common in people with diabetes, and those with a high burden of comorbidities may derive less benefit from ICD therapy. The risk-benefit profile of ICD therapy should be carefully considered in individuals with diabetes and HFrEF.
Insulin resistance is closely linked to elevated blood pressure in humans and animals, with experimental models such as fructose-fed rats showing increased blood pressure alongside induced insulin resistance. In humans, an inverse relationship exists between blood pressure and insulin sensitivity. Several mechanisms explain how insulin resistance or the resulting hyperinsulinaemia might raise blood pressure, including the role of insulin as an endothelium-dependent vasodilator that releases nitric oxide to relax vascular smooth muscle. Insensitivity to insulin's effects on the endothelium and other tissues may lead to increased peripheral resistance, a key feature of hypertension in obesity and type 2 diabetes. Additionally, impaired endothelium-mediated vasodilation, associated with insulin-resistant states, may contribute to the development and progression of atherosclerosis, a risk further exacerbated by smoking.
High-dose glucocorticoid therapy, such as prednisolone at 40 mg/day or more, can lead to significant hyperglycemia, requiring insulin therapy typically initiated at 0.5 U/kg body weight per day, divided into morning and evening doses of short- and intermediate-acting insulin. This initial insulin dose may need progressive increases based on blood glucose monitoring due to steroid-induced insulin resistance, and in cases of hyperglycemic emergency, intravenous insulin therapy at 6–8 U/hour is recommended.
Sulfonylurea derivatives are commonly prescribed for individuals with MODY, particularly those with HNF1A and HNF4A mutations, who respond well to low-dose treatment. DPP-4 inhibitors and GLP-1 receptor agonists may be added to further optimize glycemic control. However, individuals with HNF1B mutations require insulin therapy as they show minimal or no response to oral anti-diabetes medications. Those with GCK-MODY typically do not require treatment, as they do not respond to either oral agents or insulin therapy.
Type 1 diabetes risk is influenced by specific motifs within or near anchoring pockets of the peptide-binding region, including residues at positions α44, β9, β30, β57, and β70, as well as α41 at the N-terminal of the alpha chain, β135 in the CD4-binding region, α157 involved in TCR-induced αβ homodimerization, and α196 in the intra-membrane domain of the alpha chain. These motifs are significant for understanding how immunological tolerance is disrupted, leading to islet autoimmunity, and the structure and physicochemical properties of high-risk HLA class II molecules are key in determining which peptides form a trimolecular complex that interacts with CD4+ T cells to trigger autoimmunity.
Mild or moderate hypoglycaemia is common in both type 1 and type 2 diabetes when treated with insulin, and the most effective treatment is immediate administration of glucose. Guidelines recommend giving 15–20g of glucose initially, followed by an additional 15g if blood glucose does not increase to at least 4 mmol/l within 15 minutes. A follow-up carbohydrate snack of 15–20g may also be needed to prevent further hypoglycaemia, especially after alcohol consumption or physical activity.
The absence of long-acting basal insulin in pump users can lead to rapid development of diabetic ketoacidosis during infusion set failures, raising concerns about the safety of continuous subcutaneous insulin infusion therapy for type 1 diabetes. However, recent data indicate that DKA rates in pump users are not higher than in those using multiple daily injections, and in some cases, such as in large clinics with over 250 individuals on CSII, DKA rates were even lower, likely due to better diabetes self-management education. To prevent ketosis, patients are advised to change infusion sets if they experience two consecutive high glucose readings that do not respond to a correction bolus.
Insulin resistance is a key characteristic of most cases of type 2 diabetes, arising from multiple pathogenic factors that impair the kinase activity of insulin receptors and disrupt post-receptor signaling pathways. This variability in insulin resistance manifestations has made it challenging to develop agents that can effectively bypass or overcome these disruptions. While replicating the normal binding of insulin to the extracellular regions of the insulin receptor is difficult with small molecules, alternative approaches have shown promise. For instance, a monoclonal antibody that binds to different sites on the insulin receptor than insulin itself can induce conformational changes that initiate some of insulin's metabolic effects, improving glucose homeostasis in diabetic animals. Additionally, certain small molecules, like the fungal metabolite chaetochromin, can interact with the extracellular part of the insulin receptor to trigger insulin-like actions independently. Other compounds, such as demethylasterriquinone, may bypass the extracellular domains and activate receptor signaling by interacting with the cytosolic regions of the receptor's β subunits. Despite these findings, none of these small molecules have yet been validated for clinical use.
C3 deposition in glomeruli and glomerular capillaries has been observed in KK mice, a model of type 2 diabetes, and in Zucker rats, which exhibit hypertension, dyslipidemia, obesity, and hyperglycemia as features of type 2 diabetes. Following a single episode of renal ischemia, Zucker rats showed increased renal mRNA levels for complement components C3, C4, C5, C6, C8, and C9, as well as elevated mRNA for C3a and C5a in the kidney.
Improved insulin administration using the i-Port system is associated with reduced hypoglycaemia and hospitalizations, though it does not significantly affect glycaemic levels or treatment satisfaction. The i-Port has also been used to desensitize individuals with type 1 diabetes and insulin allergies to subcutaneous insulin. Despite potential benefits for those with severe needle phobia, i-Port use remains limited in clinical practice, likely due to the availability of newer, smaller needles that make insulin injections nearly painless.
Chronic overnutrition increases white adipose tissue size and promotes macrophage recruitment, leading to local inflammation and macrophage-induced lipolysis, which releases TAGs and fatty acids. These metabolic changes elevate the hepatic acetyl-CoA pool, driving hepatic gluconeogenesis and contributing to the progression from insulin resistance to impaired glucose tolerance and type 2 diabetes. Chronic hepatic gluconeogenesis impairs pancreatic β-cell insulin secretion and α-cell glucagon secretion due to glucose toxicity, worsening both fasting and post-prandial hyperglycemia in overt type 2 diabetes.
Obesity and a family history of diabetes are significant risk factors for developing diabetes. In Cushing syndrome, diabetes caused by glucocorticoid excess is clinically similar to type 2 diabetes. Excess glucocorticoids lead to both hepatic and peripheral insulin resistance, which is accompanied by hyperinsulinemia as a compensatory response. Increased hepatic glucose production primarily results from enhanced gluconeogenesis rather than glycogenolysis. Glucocorticoid excess also promotes proteolysis in muscle, releasing amino acids, and lipolysis in peripheral adipose tissue, releasing glycerol and free fatty acids. These metabolic changes support the activity of hepatic gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PEPCK). Additionally, glucocorticoids enhance hepatic glycogen storage.
Acute diabetes-related foot ulcers often coexist with macrovascular complications and other multimorbidities, necessitating healthcare professionals to consider these factors in patient care. Foot ulceration is a leading cause of hospital admission and amputation in individuals with diabetes, highlighting its severity. Effective management of these ulcers requires a multidisciplinary approach that includes debridement, offloading, appropriate dressing, infection control, modified footwear, and addressing extrinsic factors. The quality of treatment can vary based on the expertise of the clinicians involved, and while best practice emphasizes personalized, holistic care plans, access to comprehensive multidisciplinary teams is not always available. Ideal care involves a range of specialists such as podiatrists, vascular surgeons, diabetologists, and diabetes specialist nurses, among others, to address the complex needs of patients with diabetes-related foot ulcers.
A substantial proportion (30%) of islet transplant recipients have pre-existing coronary artery disease (CAD) prior to transplantation, with triglyceride levels increasing significantly post-transplant (0.82±0.04 vs 1.09±0.06 mmol/L, P<0.001), while low-density lipoprotein (LDL) cholesterol levels decreased (2.53±0.06 vs 2.14±0.06 mmol/L, P<0.001), likely due to increased statin use; blood pressure remained unchanged, and the rate of incident CAD following islet transplantation was similar to the general population with type 1 diabetes mellitus (T1DM) at 8.9 events/1000 patient years.
The text provides data on the incidence rates of diabetes among individuals aged 15–29 years in various European regions, reporting rates between 5 and 12 per 100,000 per year during 1996–1997. Earlier studies in specific areas such as Rzeszow, Poland (1980–1992), Turin, Italy (1984–1991), and two regions of Denmark (1970–1976) reported rates of 5.5, approximately 7, and approximately 13 per 100,000 per year, respectively. While Sweden and Sardinia showed higher incidence rates in children, the rates among young adults in these regions were not significantly higher compared to other centers. Older data from Norway (1978–1982) indicated a higher rate of 17 per 100,000 per year.
In diabetes, the LDL particle contains increased linoleic acid, likely due to reduced activity of the insulin-sensitive enzyme $5\alpha$-desaturase, which correlates with a higher likelihood of LDL oxidation. Uncontrolled diabetes increases free radical production, further promoting oxidation. Smaller, denser LDL particles carry less cholesterol per particle, making LDL cholesterol estimates potentially misleading since more particles exist for any given cholesterol concentration.
Many men with diabetes take medications that can cause erectile dysfunction, but altering the treatment to address sexual function is often ineffective and may lead to delays and frustration; therefore, such changes are not recommended unless there is a clear link between the start of treatment and the onset of erectile dysfunction.
In diabetic ketoacidosis (DKA), ketogenesis becomes uncontrolled, leading to a rapid and excessive rise in circulating ketone bodies, which occurs due to increased fatty acid supply to the liver and is promoted by low insulin and high glucagon levels in the liver; this process is normally prevented in non-diabetic individuals by compensatory increases in insulin secretion, but this regulatory mechanism is absent in those with type 1 diabetes mellitus (T1DM).
Mild elevations in plasma glucose can be harmful to the fetus and are often not high enough to cause osmotic symptoms. Screening for gestational diabetes mellitus (GDM) is important as symptomatic presentation of GDM is uncommon in settings with universal screening. When osmotic symptoms and superficial fungal infections are present, it is crucial to determine whether the condition is new-onset type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM), with T1DM typically associated with higher plasma glucose levels and ketonuria.
Future models of diabetes care focus on improving quality through frameworks like the Chronic Care Model (CCM), which emphasizes productive interactions between proactive practice teams and informed patients. Implementing this model across various settings has already led to improvements in diabetes care, with challenges remaining in broader dissemination and adaptation. Patient-centered care, collaboration between patients and teams, and system-based approaches are essential to optimize clinical outcomes, reduce costs, and enhance the lives of individuals with diabetes. Supporting patient self-management is a critical component of achieving these goals.
Insulin lispro, a rapid-acting insulin analog, has been studied for its efficacy and safety in pregnant women with diabetes, particularly type 1 diabetes mellitus (T1DM). Clinical studies involving small numbers of women have shown a trend toward fewer hypoglycemic episodes and a significantly greater reduction in HbA1c during the first trimester in those treated with insulin lispro compared to regular human insulin. Early concerns about an increased risk of retinopathy progression with insulin lispro have not been supported by subsequent research.
Urine glucose testing can serve as an alternative to blood testing or HbA₁c measurement for diabetes management in settings with limited healthcare resources or where patients bear the cost of testing equipment. However, there is limited data on its effectiveness for self-monitoring, and studies show little difference in HbA₁c reduction compared to self-monitoring of blood glucose. Urine glucose testing should not replace blood glucose monitoring but may be used when blood testing is not accessible or preferred. The accuracy of urine glucose testing is limited by the renal threshold for glucose, which is typically around 8 mmol/L, meaning it does not reflect lower blood glucose levels. Additionally, the renal threshold may decrease during pregnancy, making glycosuria more common in this population.
During Ramadan, individuals with diabetes may face challenges related to fasting, requiring careful management of blood glucose levels. Adjustments to medication regimens, particularly insulin and oral hypoglycemic agents, may be necessary to prevent hypoglycemia and hyperglycemia. Monitoring blood glucose frequently, maintaining proper hydration, and making appropriate dietary choices during breaking of the fast are important strategies. Those at higher risk, such as individuals with type 1 diabetes or a history of complications, should be closely evaluated before and during fasting.
The incidence of diabetes varies significantly across European countries, with the lowest rate reported in Macedonia at 3.6 per 100,000/year during 1989–1994, and the highest in Sweden at 30 per 100,000/year. Intermediate rates are observed in France and mainland Italy at around 10 per 100,000/year, while some other European countries exhibit intermediate to high incidence rates. Generally, eastern European countries have lower incidence rates, although recent data from EURODIAB indicate an increase in several regions, such as Lithuania, Bucharest in Romania, and Katowice in Poland, where rates rose to 10 per 100,000/year or higher during 1999–2003.
Regular self-measurement of capillary blood glucose has long been essential for effective metabolic management in people with diabetes, following the earlier use of urinary glucose determination. The introduction of capillary blood glucose monitoring in the 1960s significantly improved glycaemic control, and recent technological advancements have further enhanced the reliability and usability of monitoring devices. Continuous glucose monitoring (CGM) systems, introduced in recent decades, have rapidly become a valuable tool for managing diabetes, offering real-time data and contributing to better metabolic control. Modern glucose monitoring systems often integrate with computers and smartphone apps, providing advanced data analysis and insulin dose calculation features. Glucose monitoring remains a critical component of therapy for insulin-treated diabetes.
People with advanced type 2 diabetes mellitus (T2DM) are at risk for hypoglycemia-associated autonomic failure (HAAF), characterized by a loss of glucagon responses to hypoglycemia and a shift in glycemic thresholds for sympathoadrenal and symptomatic responses to lower plasma glucose concentrations, similar to what is observed in type 1 diabetes mellitus (T1DM).
Moderate intake of sucrose or other added sugars, up to 10% of total energy, can be included in the diet of individuals with diabetes without negatively affecting glycemic control. While fructose may reduce postprandial glycemia when substituted for sucrose, its use is limited by potential increases in serum triglycerides and uric acid levels. People with diabetes do not need to avoid naturally occurring fructose found in fruits and vegetables, but added fructose, sugar alcohols, and other nutritive sweeteners offer no significant advantage over sucrose and should not be encouraged. High consumption of sugar substitutes may cause gastrointestinal side effects, and although sugar alcohols are only partially absorbed in the small intestine, they are unlikely to lead to a meaningful reduction in overall energy intake.
Glucocorticoid-induced hyperglycaemia commonly presents with a rise in blood glucose starting in midmorning and continuing until bedtime, which may not be detected by monitoring only fasting blood glucose. Oral glucocorticoids are usually administered in the morning to mimic endogenous cortisol secretion, and their peak effect (e.g., prednisone at 4–6 hours) should be considered when timing blood glucose checks. Checking 1–2 hours post-lunch or pre-dinner blood glucose a few days after treatment initiation can help detect hyperglycaemia. Fasting hyperglycaemia may occur with higher doses of once-daily glucocorticoids (e.g., prednisone ≥40 mg) or with twice-daily administration. Individuals with pre-existing diabetes should monitor blood glucose more frequently during glucocorticoid treatment, and all patients should be aware of symptoms of hyperglycaemia. There are currently no published guidelines on treating glucocorticoid-induced hyperglycaemia with diabetes medications, although various management strategies have been suggested.
Intermediate hyperglycemia, while not definitively linked to stroke on its own, contributes to the metabolic syndrome, a cluster of conditions including hypertension, hyperlipidemia, insulin resistance, and abdominal obesity that collectively increase susceptibility to vascular damage and ischemic complications.
Pump therapy (CSII) has been associated with improved quality of life in youths with type 1 diabetes compared to multiple daily injections (MDI), with benefits including better physical, emotional, and school-related functioning and reduced diabetes-related worry. Studies have shown that CSII users report greater treatment satisfaction, perceived clinical efficacy, and less interference with daily activities, particularly benefiting those with initially lower quality-of-life scores.
People with diabetes have an increased risk of both macrovascular and microvascular disease, which suggests that the WHO/ISH blood pressure threshold is too high for this group. There are definite benefits from treating microalbuminuric individuals whose diastolic blood pressure is below 90 mmHg. Various expert bodies recommend generally lower target levels for blood pressure in diabetic patients, with a consensus aiming for less than 130–140 mmHg systolic and below 80–85 mmHg diastolic, and treatment is advised for those consistently above these thresholds.
Type 1 diabetes is treated with daily intensive insulin therapy, and up to 20% of individuals with type 2 diabetes also require insulin. Exogenous insulin therapy can be challenging due to frequent episodes of hyper- and hypoglycaemia. In some cases, pancreas or islet transplantation is necessary to achieve normal glucose metabolism, particularly for those experiencing recurrent severe hypoglycaemic episodes despite optimal management. Pancreas transplantation involves major surgery and lifelong immunosuppression, while islet transplantation is less invasive and repeatable, making it a preferable option for individuals ineligible for pancreas transplantation. However, both approaches are limited by the scarcity of donor organs and the need for immunosuppressive therapy.
Lipohypertrophy, which presents as soft subcutaneous nodules or thickening at sites of repeated insulin injections, occurs due to the lipogenic action of insulin stimulating adipocytes locally over time. This condition may delay insulin absorption, potentially disrupting glycemic control, but it resolves spontaneously when the injection site is changed. Hyperkeratotic verrucous variants of lipohypertrophy have also been reported.
Gestational diabetes mellitus (GDM) is defined as glucose intolerance occurring or first recognized during pregnancy. In the general non-diabetic antenatal population, there is no clear cutoff between adverse pregnancy outcomes and fasting or 1- or 2-hour oral glucose tolerance test (OGTT) blood glucose values. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study performed OGTTs at 24–32 weeks' gestation in women without diabetes and found a continuous relationship between maternal glucose concentrations and increased birth weight and elevated cord-blood serum C-peptide levels, both of which are surrogate markers for fetal exposure to maternal glucose. These associations were observed at glucose levels below those currently used to diagnose GDM.
The text highlights the disparity in healthcare resource allocation for diabetes, noting that only 20% of global expenditure occurs in regions where 80% of people with diabetes live, aligning with Julian Tudor Hart's "inverse care law," which states that availability of good medical care tends to vary inversely with the need for it in the population served. In low- and middle-income countries (LMICs), such as India, only 2% of the government's annual budget is devoted to healthcare, leading to significant proportions of household income being spent on health care costs. In Africa, 40% of people earn less than US$1 per day, and in Sudan, nearly two-thirds of family incomes are required to pay for the care of one child with diabetes. In Mozambique, less than one-fifth of all health facilities have the capacity to offer blood glucose and urinary ketone measurement.
Improvement in insulin action and glucose tolerance occurs rapidly after successful treatment of Cushing syndrome, necessitating careful monitoring and adjustment of anti-diabetes treatments during and after pituitary surgery. Reducing total glucocorticoid exposure post-surgery requires caution to avoid hypoglycaemia, particularly in individuals dependent on hydrocortisone replacement. Some individuals will require ongoing diabetes care and treatment due to persistent changes in body composition following the resolution of Cushing syndrome.
Diabetes is influenced by the regulation of insulin secretion, which involves multiple steps including the sensing of blood glucose levels by glucose transporter 2 (GLUT2), glycolysis by glucokinase (GK), and ATP production by mitochondria. The ATP produced closes potassium channels, leading to membrane depolarization and opening of calcium channels, resulting in intracellular calcium influx. This influx facilitates the translocation of insulin- and amylin-containing vesicles to the cell surface for extracytosis. Transcription factors are also activated during this process, promoting insulin gene transcription and production to replenish insulin-containing vesicles, ensuring a continuous insulin supply for rapid release. MIDD, or maternally inherited diabetes and deafness, is a genetic condition associated with diabetes.
The $\mathrm{K_{ATP}}$ channels in $\beta$-cells play a central role in glucose recognition and are considered candidates for $\beta$-cell dysfunction in type 2 diabetes. Studies have found polymorphisms in genes encoding Kir6.2 and SUR1 subunits of the $\mathrm{K_{ATP}}$ channel that are associated with an increased risk of type 2 diabetes. Activating mutations in the Kir6.2 gene have been identified as causal for permanent neonatal diabetes (PNDM), allowing affected individuals to achieve glycemic control with sulfonylurea treatment instead of insulin. Conversely, loss of functional $\mathrm{K_{ATP}}$ channels in $\beta$-cells contributes to persistent hyperinsulinemic hypoglycemia of infancy (PHHI), a condition marked by inappropriate insulin secretion despite hypoglycemia, with numerous mutations in Kir6.2 and SUR1 linked to severe glucose homeostasis impairment in these patients.
Erectile dysfunction in diabetes is associated with endothelial dysfunction, autonomic neuropathy, hypertension, and large-vessel disease. Men with diabetes and erectile dysfunction have a higher prevalence of complications such as cardiovascular disease, neuropathy, and nephropathy compared to those without erectile dysfunction. Additionally, medications commonly taken by men with diabetes, particularly antihypertensive agents like beta-blockers, aldosterone receptor blockers, and thiazide diuretics, may impair erectile function, though evidence is largely anecdotal. Alpha-blockers are considered to have the least risk in this regard. It is also important to consider that erectile dysfunction can stem from causes unrelated to diabetes.
Painful diabetic peripheral neuropathy has been linked to sleep impairment, and studies show differing associations between obstructive sleep apnea (OSA) and neuropathy depending on diabetes type: OSA was not found to be correlated with neuropathy in people with type 2 diabetes, although significant heterogeneity was present, while an association between OSA and neuropathy was observed in those with type 1 diabetes.
An effective diabetes education programme's mechanisms of action are complex due to multiple interacting components, making it difficult to determine which elements should be replicated or modified for implementation in different settings or populations. The success of such programmes depends on educators' competencies, participants' preconditions and motivation, and organizational factors, which are often challenging to account for in randomized controlled trials. To address these complexities, theory-driven evaluation approaches have become increasingly important, as they provide insights not only into programme effectiveness but also into the underlying mechanisms that produce those effects.
Neonatal diabetes mellitus (NDM) has about 22 identified genetic causes and can be classified into transient and permanent forms based on the affected gene. Transient NDM caused by methylation of chromosome 6q24 typically presents with hyperglycaemia that resolves within the first year of life, though relapses may occur during childhood or puberty. In contrast, NDM resulting from mutations in the potassium ATP (KATP) channel genes KCNJ11, ABCC8, or INS does not relapse and generally persists throughout life.
In a study (LEAD-5), patients with diabetes on metformin and a sulfonylurea were switched to either liraglutide or insulin glargine, with liraglutide showing a greater reduction in HbA₁c levels (1.1% vs. 0.9%) and more patients achieving ADA targets of HbA₁c < 7.0% and < 6.5%. Liraglutide also resulted in a 3.5 kg greater weight loss compared to insulin glargine, though it was associated with a higher risk of major hypoglycemic episodes (2.2%) due to the combined use of a sulfonylurea and a GLP-1 receptor agonist, which can uncouple glucose-dependent insulin secretion. Minor hypoglycemic events occurred at similar rates between the two treatment groups.
Latent autoimmune diabetes of adults (LADA) is a form of diabetes where patients are initially misclassified as having type 2 diabetes mellitus (T2DM) but test positive for islet cell antibodies (ICA), with around 10% of adult T2DM patients falling into this category. LADA shares genetic and autoimmune features with childhood type 1 diabetes mellitus (T1DM), particularly in relation to human leukocyte antigen (HLA) associations, though there are also distinct differences in their genetic and autoimmune processes.
Gestational diabetes mellitus (GDM) can progress to overt diabetes mellitus in 50 to 60% of cases, while others may revert to impaired glucose tolerance (IGT); a 75-gram oral glucose tolerance test (OGTT) is recommended at 6 weeks postpartum for classification, with yearly follow-up OGTTs advised for reclassification. Women with normal postpartum OGTT results are considered to have a previous abnormality of glucose tolerance with statistical risk, whereas those with abnormal results are classified as having either IGT or diabetes mellitus in the non-pregnant state.
Gestational diabetes mellitus (GDM) shares risk factors with type 2 diabetes, including insulin resistance and hyperinsulinaemia, and is considered a form of type 2 diabetes. Women with a history of GDM have a higher prevalence of cardiovascular risk factors such as obesity (BMI ≥ 30 kg/m²), hypertension, and dyslipidaemia, with 40% exhibiting metabolic syndrome, three times that of the control group.
Pathophysiological changes in diabetes, such as non-enzymatic glycation of proteins, impair endothelium-dependent relaxation of blood vessels, contributing to erectile dysfunction. Structural changes from large-vessel disease and widespread endothelial dysfunction are also associated with erectile dysfunction in diabetes, though distinguishing the relative impact of each factor is challenging.
There are differences in the cascades of care for type 2 diabetes between people who are aware of their diabetes status, those treated for their diabetes, and those who have well-managed diabetes. In many low- and middle-income countries (LMICs), under 60% of people with diabetes are aware they have the condition, and many of those receiving treatment do not reach glycaemic targets. In India, sex and geographical differences exist, with women being more likely to be aware, treated, and within target compared to men, and people in urban areas generally faring better than those in rural areas.
Neuropathic foot ulcers in diabetic patients can be managed without systemic antibiotics if there is no infection, as appropriate wound care can lead to similar outcomes with or without antibiotics. However, frequent review, debridement, callus removal, and offloading are crucial for effective management, and antibiotics may be necessary if signs of infection develop. In cases where ulcers have an ischemic component but lack gross signs of infection, antibiotics are likely beneficial due to the high risk of lower extremity amputation when infection and ischemia coexist in diabetic foot complications.
Pain or paresthesia in diabetic neuropathy may be related to the degree of compensatory regeneration rather than the degree of nerve fiber damage, suggesting that symptom or pain scores should not be used to evaluate the overall presence or progression of diabetic neuropathy but only to assess pain severity.
Type 2 diabetes mellitus (T2DM) affects 10–30% of individuals above pensionable age in Europe and accounts for about 40% of all diabetes cases in the USA. Older people with diabetes use primary care services two to three times more than those without diabetes, with insulin-treated patients contributing significantly to service utilization, primarily due to macrovascular disease. The burden on hospital care is also markedly increased, with two to three times higher hospitalization rates, more frequent clinic visits, and a fivefold higher admission rate compared to the general aged population, where acute admissions account for 60% of total expenditure. In the UK, 5–8% of general hospital beds are occupied by patients with diabetes aged 60 or more, representing 60% of all inpatients with diabetes. Hospital stays for older patients with diabetes last twice as long as those for age-matched controls without diabetes, averaging 7 and 8 days per year for men and women, respectively. Initiating insulin treatment increases costs fourfold both in the community and in hospital settings, with bed occupancy rising to 24 days per year.
DM refers to diabetes mellitus, a condition characterized by high blood sugar levels, and includes various types such as permanent neonatal diabetes (PNDM), which is diagnosed in newborns, and maternally inherited diabetes and deafness (MIDD), a genetic form of diabetes. Certain genes like GCK (glucokinase) and HNF1A (hepatocyte nuclear factor 1A) are associated with specific subtypes of diabetes, with HNF4A being similar to HNF1A in its involvement. The population frequency (Pop freq) of obesity, a known risk factor for diabetes, is also relevant in understanding the general prevalence of the condition.
Blood glucose targets for diabetes management are generally categorized as follows: a range of 140–180 mg/dL (7.8–10.0 mmol/L) is preferable for most patients, while a lower range of 110–140 mg/dL (6.1–7.8 mmol/L) may be suitable for selected individuals; targets above 180 mg/dL (10.0 mmol/L) or below 110 mg/dL (6.1 mmol/L) are not recommended.
Lower $\mathrm{HbA_{1c}}$ levels are associated with a reduced risk of nephropathy, as shown in studies like the UKPDS, which found that microvascular risk remained lower even after $\mathrm{HbA_{1c}}$ levels became similar between intensively and conventionally managed groups, indicating a "metabolic memory" effect. In the ADVANCE study, intensive glucose management achieving an $\mathrm{HbA_{1c}}$ of $48\mathrm{mmol/mol}$ ($6.5\%$) led to significant risk reductions in new-onset moderately elevated albuminuria, severely increased albuminuria, and ESKD over five years. Similarly, the ACCORD study showed reductions in albuminuria progression and ESKD with intensive management, although in participants with existing CKD, intensive glucose control increased all-cause and cardiovascular mortality. This suggests that while tight glucose control offers kidney benefits, it may increase mortality risk, particularly in those with long-standing type 2 diabetes, supporting a less tight $\mathrm{HbA_{1c}}$ target in such individuals.
Advanced insulin delivery technologies, such as predictive low glucose suspend pumps and real-time continuous glucose monitoring (RT-CGM), have significantly improved in recent years, offering potential benefits in reducing HbA1c levels, fear of hypoglycemia, and improving quality of life. Sensor-augmented pump therapy has shown advantages in reducing fear of hypoglycemia in adults and parents of children with type 1 diabetes, as well as improving treatment satisfaction. However, these devices are costly and require consistent use, which can be challenging for many users. Studies have shown that improvement in HbA1c is associated with more frequent sensor use, though overall sensor use tends to decline over time. While such technologies may be particularly beneficial for individuals with recurrent severe hypoglycemia, clinical trials have found no significant advantage of insulin pumps and RT-CGM over multiple daily injections and standard fingerprick monitoring in reducing severe hypoglycemia or fear of hypoglycemia, although pumps do offer greater treatment satisfaction.
MODY (Maturity-Onset Diabetes of the Young) should be considered in patients diagnosed with diabetes before 25 years of age who do not clearly fit the phenotypes of either type 1 or type 2 diabetes and who have a strong family history of diabetes. These patients may often be effectively managed without injected insulin, making differentiation from apparent type 1 diabetes particularly important.
In individuals without diabetes, decreasing blood glucose levels enhance lipolysis due to reduced insulin secretion, leading to an increase in free fatty acids (FFA) that can stabilize or elevate glucose concentrations; however, hypoglycemia resulting from exogenous hyperinsulinism inhibits lipolysis and compromises counter-regulatory mechanisms.
Some miRNAs, including hepatic miR-424-5p, miR-15b, miR-195, and others, show specificity against proximal insulin signaling components during metabolic challenges in various tissues, which may impact insulin signaling and contribute to diabetes-related pathology.
Insulin signalling begins with autophosphorylation of the insulin receptor at multiple tyrosine residues, enabling the recruitment and activation of insulin receptor substrates (IRS) proteins, which subsequently activate phosphatidylinositol-3-kinase (PI3K) and AKT to regulate glucose uptake and metabolism, as well as protein and lipid metabolism. In diabetes, dysfunction in this pathway can lead to impaired glucose regulation. In the liver, insulin normally inhibits glucose production and promotes lipogenesis; in adipose tissue, it suppresses lipolysis and enhances glucose influx; and in muscle, it inhibits autophagy while promoting protein synthesis and glucose uptake, all of which are critical for maintaining metabolic homeostasis.
Tight glycemic control in patients with type 2 diabetes mellitus (T2DM), particularly those with established cardiovascular disease, has been evaluated in several clinical trials including the ACCORD, ADVANCE, and VADT studies. These trials investigated the impact of intensive glucose-lowering strategies on cardiovascular outcomes and found that tight blood glucose control had minimal effect on macrovascular complications. Initial findings from the DCCT in type 1 diabetes and the UKPDS in type 2 diabetes suggested limited cardiovascular benefits from intensive glycemic control, a conclusion reinforced by more recent trials. The ACCORD trial, in particular, raised concerns by suggesting a potential for adverse cardiovascular effects associated with tight glucose control.
The age-adjusted prevalence of diabetes in the United States varies significantly among ethnic groups, with higher rates observed in Hispanic and Black American populations compared to white Americans. In 1991, the prevalence was 6% in white Americans, 9% in Cubans, 10% in Black Americans, 13% in Mexican Americans, and 13% in Puerto Ricans. These disparities have persisted over time, with reports showing that between 1987 and 1996, the 7–8-year incidence of type 2 diabetes tripled in both Mexican Americans and non-Hispanic white Americans, though the absolute rate remained twice as high in Mexican Americans. Type 2 diabetes is also notably more common among older Puerto Ricans (38%) and Dominicans (35%) compared to non-Hispanic white Americans (23%). Economic disadvantage may contribute significantly to the higher prevalence of type 2 diabetes among African American women.
FGF21 gene therapy using AAV vectors demonstrates therapeutic efficacy in treating type 2 diabetes and obesity by recapitulating the benefits of pharmacological FGF21 analogues while overcoming challenges like treatment adherence and immunogenic reactions, supporting its future clinical application for diabetes and related comorbidities.
High heel wedge footwear can increase forefoot plantar pressures, which may contribute to foot complications in individuals with diabetes.
Incretin-based therapies offer benefits in diabetes management beyond glucose control, primarily through anti-inflammatory and anti-oxidative stress effects. While exenatide showed no improvement in certain neuropathy measures compared to glargine in a pilot study, a recent randomized controlled trial found that once-weekly exenatide, combined with pioglitazone or basal bolus insulin, reduced HbA1c by approximately 3% (33 mmol/mol) and promoted corneal nerve regeneration, despite an average weight gain of about 4 kg.
After exercise, individuals with diabetes require carbohydrate intake to replenish glycogen stores in the muscle and liver, along with protein for muscle repair and synthesis. Without adequate intake, there is an increased risk of hypoglycaemia in the following hours and fatigue during subsequent exercise sessions. It is recommended that individuals consume snacks containing approximately 1g/kg body weight of carbohydrate and 0.3g/kg of protein, taken alongside insulin to enhance glycogen storage in muscles and liver. To manage this effectively, a third of the normal insulin-to-carbohydrate ratio is initially recommended.
UK people with diabetes who travel to warmer climates for spiritual pilgrimages may face increased health risks due to prolonged exposure to heat, long-distance walking, and crowded environments, which can exacerbate diabetes management and increase susceptibility to infections, particularly those associated with the countries of origin.
To avoid fetal and maternal complications, it is essential to achieve blood glucose concentrations as close to normal as possible without inducing hypoglycemia. Nutritional therapy should assist in achieving recommended fasting blood glucose values of 60–90 mg/dL (3.3–5.0 mmol/L) and postprandial values below 120 mg/dL (6.7 mmol/L). Women with known type 1 diabetes mellitus (T1DM) as well as those who develop gestational diabetes during pregnancy require detailed dietary counseling as an essential part of therapy. Energy intake should be adequate to support appropriate weight gain, with normal-weight women requiring an additional 70–240 kcal/day in the first and second trimesters and 300 kcal/day in the third trimester, while obese pregnant women should have a lower additional calorie intake, though total daily energy should not fall below 1600 kcal/day.
Severe chest pain and hypertension in a 75-year-old man with recent-onset type 2 diabetes treated with a sulfonylurea were associated with a blood glucose level of 27 mmol/l on admission, and the condition was linked to a phaeochromocytoma of the right adrenal, which was identified through imaging techniques including computed tomography, scanning with ${}^{131}$I-metaiodobenzylguanidine, and positron emission tomography with 18F-fluorodeoxyglucose, and following laparoscopic removal of the tumour, both diabetes and hypertension resolved.
The autoimmune destruction of pancreatic beta cells, characterized by mononuclear infiltration known as insulitis and involving autoreactive CD8+ T lymphocytes, plays a central role in the disease process. Both humoral and cellular immune pathways contribute to this condition, with islet autoantibodies appearing before insulitis and serving as markers of developing islet autoimmunity rather than a direct result of it. In genetically susceptible individuals, the induction of islet autoimmunity and the presence of autoantibodies against specific islet cell antigens can precede the onset of clinical symptoms by months to several years.
Diabetes foot ulcer management involves controlling blood glucose levels with insulin, managing infections with antibiotics, eliminating pressure on the affected area, administering anti-tetanus measures, ensuring adequate nutrition, and assessing kidney and cardiac function. Proper wound care includes debridement, dressing, and regular examination, with excision of all dead tissue and the use of non-irritant solutions like diluted hydrogen peroxide or iodine in cases of gross infection, while normal saline is preferred otherwise. Anesthesia is typically required during wound manipulation except in cases of an insensitive foot, and wide surgical incision and drainage are often necessary due to the frequent presence of deep infections. Diabetic feet may show minimal or no pain, and signs of infection may be absent early on, making the extent of tissue damage potentially greater than what appears clinically. Daily wound assessment and debridement are essential, and corrosive or detergent agents should be avoided.
The prevalence of previously diagnosed diabetes in patients with acute stroke ranges from 8% to 28%, and an additional 6% to 42% have unrecognized pre-existing dysglycemia. Plasma glucose levels at presentation are a major prognostic factor in acute stroke, with full functional recovery at 4 weeks observed only in those with blood glucose levels below 8 mmol/L. Individuals with elevated plasma glucose at presentation do not regain full function within this timeframe, although it remains unclear whether this is due to the metabolic stress response proportional to stroke severity or the direct negative impact of hyperglycemia on recovery from ischemic damage.
Growth hormone (GH) and insulin-like growth factor I (IGF-I) have been implicated in the development of diabetes-related microangiopathy, though no drugs targeting this axis are yet in clinical use. Transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF) are significant pathogenic factors in diabetic microangiopathy and have been extensively studied. The tumor necrosis factor (TNF) superfamily has also been increasingly linked to the pathogenesis of microvascular complications in diabetes.
At least 30% of diabetes patients are undetected, with studies showing that 11% of a Belgian outpatient population with one known cardiovascular risk factor had diabetes and 3% had impaired glucose tolerance (IGT). Prevalence rates in Sweden were 7.8% in men and 5.1% in women aged 35–79 years, with similar figures in a Finnish middle-aged population. The prevalence of diabetes can be significantly higher in high-risk groups, particularly those with coronary artery disease (CAD). In the Euro Heart Survey Diabetes and the Heart, 31% of patients admitted for acute and stable CAD had known diabetes, 12% had previously unknown diabetes, and 28% had IGT, while only 29% had normal glucose metabolism. Comparable findings were observed in populations with cerebral and peripheral vascular disease, highlighting that glucose abnormalities are common and often underestimated in cardiovascular disease patients due to insufficient diagnostic accuracy and incomplete assessment of glucometabolic status.
Glucose variability in diabetes can be quantified using standard metrics such as standard deviation (SD) and coefficient of variation (CV), with CV being more descriptive of hypoglycaemic excursions due to its relative nature to the mean. Over the past half-century, several diabetes-specific metrics have been developed, including the M-value, which uses a logarithmic transformation of glucose deviation from a preset value like 120 mg/dl (6.7 mmol/l). Among these, mean amplitude of glucose excursions (MAGE) is one of the most widely used, while the mean of daily differences (MODD) measures inter-day variability, and continuous overlapping net glycaemic action (CONGA) serves as a composite index reflecting both the magnitude and timing of glucose fluctuations over various time periods.
Young adults with type 1 diabetes are less fit than those without diabetes despite similar physical activity levels, potentially due to abnormalities in cardiac muscle and autonomic nerve function, reduced skeletal muscle size and power, and altered cardiac metabolism favoring non-esterified fatty acids over glucose. Supervised physical activity programs can improve fitness in individuals with type 1 diabetes, increasing VO₂ max by up to 27%.
Islet cell autoantibodies, including islet surface antibodies and autoantibodies against GAD65, IA-2, insulin, and ZnT8, play a key role in the identification and differentiation of type 1 diabetes mellitus (T1DM) from other forms of diabetes. These autoantibodies can appear months to years before clinical onset, often as early as the perinatal period, with multiple autoantibodies typically emerging within 6–12 months after the first appears. Persistent presence of single or multiple islet autoantibodies for 3–6 months is indicative of islet autoimmunity, which is highly associated with T1DM development, while transient and solitary autoantibodies are linked to a lower risk, potentially due to protective genetic factors such as HLA DR15-DQ6.
Amylin is a peptide co-secreted with insulin from pancreatic beta cells and has physiological effects such as delaying gastric emptying, suppressing post-meal glucagon secretion, and increasing satiety. Pramlintide, a synthetic amylin mimetic approved for insulin-treated individuals with type 1 or type 2 diabetes, offers benefits including improved glycemic control and mild weight loss, though it may cause transient nausea and hypoglycemia. Non-insulin parenteral therapies for diabetes include amylin mimetics and GLP-1 receptor activators, also known as incretin mimetics.
The diagnosis of diabetes, particularly in gestational contexts, involves methodological considerations such as the use of a single oral glucose tolerance test (OGTT) glucose value and the selection of a risk threshold, with some studies using an arbitrary 1.75 risk threshold. Clinical outcomes like birth weight, cord C-peptide, and neonatal skin folds exceeding the 90th percentile are associated with this diagnostic approach, although randomized controlled trials (RCTs) have shown only marginal benefits at these thresholds. Some researchers argue that a higher risk ratio of 2, as seen in observational studies, may be a more reliable threshold than 1.75, and this higher ratio could potentially be achieved by using a diagnostic criterion that includes both a high fasting glucose and another elevated glucose threshold.
SGLT-2 inhibitors were originally developed to lower glucose and were found to reduce the risk of cardiovascular disease, particularly heart failure hospitalization. These inhibitors were shown to prevent the development of heart failure in people with type 2 diabetes, as demonstrated in cardiovascular outcome trials such as DECLARE-TIMI 58, which evaluated dapagliflozin in 17,160 participants. A secondary analysis revealed that participants with a history of heart failure at baseline benefited the most from dapagliflozin, suggesting that SGLT-2 inhibitors may be beneficial for individuals with existing heart failure. This led to further clinical trials evaluating SGLT-2 inhibitors in people with a history of heart failure.
The prevalence of type 2 diabetes is rising globally, with approximately 537 million people affected in 2021, making it one of the most common non-communicable diseases. This increase is particularly notable in regions undergoing rapid economic development and urbanization, and the ageing population has further contributed to this trend. Additionally, the age of onset of diabetes is decreasing, leading to a growing number of young working-age individuals being affected. Risk factors for type 2 diabetes are often linked to a Westernized lifestyle and urbanization, though new environmental risk factors have also emerged. Regions with a high ratio of impaired glucose tolerance to diabetes are at an earlier stage of the epidemic and may benefit most from targeted preventive strategies.
Nerve conduction studies are used to assess the function of peripheral nerves and can help diagnose diabetic neuropathy, a common complication of diabetes that results from nerve damage due to prolonged high blood sugar levels.
Cold feet and dry feet are abnormalities associated with diabetes, often resulting from peripheral neuropathy or poor circulation due to long-term damage to nerves and blood vessels caused by elevated blood glucose levels.
In managing diabetes, treatment approaches may vary based on life expectancy and other factors such as poor appetite, weight loss, and anorexia, with non-insulin glucose-lowering therapies potentially being reduced or discontinued. Insulin treatment can be stopped in individuals with type 2 diabetes but must continue in those with type 1 diabetes. Maintaining appropriate blood glucose levels is crucial to prevent both hyperglycaemia and hypoglycaemia, which are associated with unpleasant symptoms, and insulin may be used with a palliative intent in certain cases.
Genetic overexpression or selective stimulation of PPAR δ improves insulin sensitivity, increases fatty acid oxidation, raises thermogenesis, and prevents weight gain. A selective PPAR δ agonist or a panPPAR agonist with tailored selectivity for PPAR α, γ, and δ may offer therapeutic benefits. Selective RXR modulators have been shown to reduce hyperglycemia in animal models, but often come with side effects such as hypertriglyceridemia and thyroid dysfunction. Some RXR agonists can reduce apoxitite, enhance mitochondrial uncoupling protein production, and decrease weight gain, leading to preclinical exploration of their combination with PPAR γ agonists.
Exogenous insulin injection is the primary treatment for correcting hyperglycemia in patients with type 1 diabetes mellitus (T1DM), allowing them to live nearly normal lives; however, complications often arise within 10–12 years of onset, even with proper metabolic control. Predicting T1DM offers a chance to implement preventive measures aimed at reducing or halting beta-cell destruction. Early identification of at-risk individuals can lead to timely, symptom-free diagnosis and prevent acute T1DM, which is critical for avoiding diabetic ketoacidosis (DKA)—a life-threatening condition frequently observed in children under four years old and linked to high morbidity and mortality.
Newer blood glucose monitoring devices can store and upload data to mobile devices or computers, allow reapplication of blood to the sample strip if the initial sample is insufficient, and require very small blood volumes. These features enable the use of smaller, thinner lancets, reducing discomfort and promoting regular testing. Advances in technology have also improved calibration and reduced errors caused by incorrect insertion of test strips, thereby lowering the risk of inaccurate readings.