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Type 2 diabetes
Type 2 diabetes
Type 2 diabetes
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Type 2 diabetes
Other namesDiabetes mellitus type 2;
adult-onset diabetes;[1]
non-insulin-dependent diabetes mellitus (NIDDM)[1]
A blue circle is the universal symbol of diabetes.[2]
Pronunciation
SpecialtyEndocrinology
SymptomsIncreased thirst, frequent urination, unexplained weight loss, increased hunger[3]
ComplicationsHyperosmolar hyperglycemic state, diabetic ketoacidosis, heart disease, stroke, diabetic retinopathy, kidney failure, lower-limb amputations[1][4][5]
Usual onsetMiddle or older age[6]
DurationLong term[6]
CausesObesity, lack of exercise, genetics[1][6]
Diagnostic methodBlood test[3]
PreventionMaintaining normal weight, exercising, healthy diet[1]
TreatmentDietary changes, exercise, diabetes medication such as metformin and insulin, bariatric surgery[1][7][8][9]
Prognosis10 year shorter life expectancy[10]
Frequency392 million (2015)[11]

Diabetes mellitus type 2, commonly known as type 2 diabetes (T2D), and formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin.[6] Common symptoms include increased thirst, frequent urination, fatigue and unexplained weight loss.[3] Other symptoms include increased hunger, having a sensation of pins and needles, and sores (wounds) that heal slowly.[3] Symptoms often develop slowly.[6] Long-term complications from high blood sugar include heart disease, stroke, diabetic retinopathy, which can result in blindness, kidney failure, and poor blood flow in the lower limbs, which may lead to amputations.[1] A sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.[4][5]

Type 2 diabetes primarily occurs as a result of obesity and lack of exercise.[1] Some people are genetically more at risk than others.[6] Type 2 diabetes makes up about 90% of cases of diabetes, with the other 10% due primarily to type 1 diabetes and gestational diabetes.[1]

Diagnosis of diabetes is by blood tests such as fasting plasma glucose, oral glucose tolerance test, or glycated hemoglobin (A1c).[3]

Type 2 diabetes is largely preventable by staying at a normal weight, exercising regularly, and eating a healthy diet (high in fruits and vegetables and low in sugar and saturated fat).[1]

Treatment involves exercise and dietary changes.[1] If blood sugar levels are not adequately lowered, the medication metformin is typically recommended.[7][12] Many people may eventually also require insulin injections.[9] In those on insulin, routinely checking blood sugar levels (such as through a continuous glucose monitor) is advised; however, this may not be needed in those who are not on insulin therapy.[13] Bariatric surgery often improves diabetes in those who are obese.[8][14]

Rates of type 2 diabetes have increased markedly since 1960 in parallel with obesity.[15] As of 2015, there were approximately 392 million people diagnosed with the disease compared to around 30 million in 1985.[11][16] Typically, it begins in middle or older age,[6] although rates of type 2 diabetes are increasing in young people.[17][18] Type 2 diabetes is associated with a ten-year-shorter life expectancy.[10] Diabetes was one of the first diseases ever described, dating back to an Egyptian manuscript from c. 1500 BCE.[19] Type 1 and type 2 diabetes were identified as separate conditions in 400–500 CE with type 1 associated with youth and type 2 with being overweight.[20] The importance of insulin in the disease was determined in the 1920s.[21]

Signs and symptoms

[edit]
Overview of the most significant symptoms of diabetes

The classic symptoms of diabetes are frequent urination (polyuria), increased thirst (polydipsia), increased hunger (polyphagia), and weight loss.[22] Other symptoms that are commonly present at diagnosis include a history of blurred vision, itchiness, peripheral neuropathy, recurrent vaginal infections, and fatigue.[23] Other symptoms may include loss of taste.[24] Many people, however, have no symptoms during the first few years and are diagnosed on routine testing.[23] A small number of people with type 2 diabetes can develop a hyperosmolar hyperglycemic state (a condition of very high blood sugar associated with a decreased level of consciousness and low blood pressure).[23]

Complications

[edit]
Main article: Complications of diabetes

Type 2 diabetes is typically a chronic disease associated with a ten-year-shorter life expectancy.[10][25] This is partly due to a number of complications with which it is associated, including: two to four times the risk of cardiovascular disease, including ischemic heart disease and stroke; a 20-fold increase in lower limb amputations, and increased rates of hospitalizations.[10] In the developed world, and increasingly elsewhere, type 2 diabetes is the largest cause of nontraumatic blindness and kidney failure.[26] It has also been associated with an increased risk of cognitive dysfunction and dementia through disease processes such as Alzheimer's disease and vascular dementia.[27] Other complications include hyperpigmentation of skin (acanthosis nigricans), sexual dysfunction, diabetic ketoacidosis, and frequent infections.[22][28][29] There is also an association between type 2 diabetes and mild hearing loss.[30]

Causes

[edit]

The development of type 2 diabetes is caused by a combination of lifestyle and genetic factors.[26][31] While some of these factors are under personal control, such as diet and obesity, other factors are not, such as increasing age, female sex, and genetics.[10] Generous consumption of alcohol is also a risk factor.[32] Obesity is more common in women than men in many parts of Africa.[33] The nutritional status of a mother during fetal development may also play a role.[34]

Lifestyle

[edit]
Main article: Lifestyle causes of type 2 diabetes

Lifestyle factors are important to the development of type 2 diabetes, including obesity and being overweight (defined by a body mass index of greater than 25), lack of physical activity, poor diet, psychological stress, and urbanization.[10][35] Excess body fat is associated with 30% of cases in those of Chinese and Japanese descent, 60–80% of cases in those of European and African descent, and 100% of cases in Pima Indians and Pacific Islanders.[23] Among those who are not obese, a high waist–hip ratio is often present.[23] Smoking appears to increase the risk of type 2 diabetes.[36] Lack of sleep has also been linked to type 2 diabetes.[37] Laboratory studies have linked short-term sleep deprivations to changes in glucose metabolism, nervous system activity, or hormonal factors that may lead to diabetes.[37]

Dietary factors also influence the risk of developing type 2 diabetes. Consumption of sugar-sweetened drinks in excess is associated with an increased risk.[38][39] The type of fats in the diet are important, with saturated fat and trans fatty acids increasing the risk, and polyunsaturated and monounsaturated fat decreasing the risk.[31] Eating a lot of white rice appears to play a role in increasing risk.[40] A lack of exercise is believed to cause 7% of cases.[41] Sedentary lifestyle is another risk factor.[42] Persistent organic pollutants may also play a role.[43]

Genetics

[edit]
Main articles: Genetic causes of type 2 diabetes and Epigenetics of diabetes type 2

Most cases of diabetes involve many genes, with each being a small contributor to an increased probability of becoming a type 2 diabetic.[10] The proportion of diabetes that is inherited is estimated at 72%.[44] More than 36 genes and 80 single nucleotide polymorphisms (SNPs) had been found that contribute to the risk of type 2 diabetes.[45][46] All of these genes together still only account for 10% of the total heritable component of the disease.[45] The TCF7L2 allele, for example, increases the risk of developing diabetes by 1.5 times and is the greatest risk of the common genetic variants.[23] Most of the genes linked to diabetes are involved in pancreatic beta cell functions.[23]

There are a number of rare cases of diabetes that arise due to an abnormality in a single gene (known as monogenic forms of diabetes or "other specific types of diabetes").[10][23] These include maturity onset diabetes of the young (MODY), Donohue syndrome, and Rabson–Mendenhall syndrome, among others.[10] Maturity onset diabetes of the young constitute 1–5% of all cases of diabetes in young people.[47]

Epigenetic regulation may have a role in type 2 diabetes.[48]

Medical conditions

[edit]

There are a number of medications and other health problems that can predispose to diabetes.[49] Some of the medications include: glucocorticoids, thiazides, beta blockers, atypical antipsychotics,[50] and statins.[51] Those who have previously had gestational diabetes are at a higher risk of developing type 2 diabetes.[22] Other health problems that are associated include: acromegaly, Cushing's syndrome, hyperthyroidism, pheochromocytoma, and certain cancers such as glucagonomas.[49] Individuals with cancer may be at a higher risk of mortality if they also have diabetes.[52] Testosterone deficiency is also associated with type 2 diabetes.[53][54] Eating disorders may also interact with type 2 diabetes, with bulimia nervosa increasing the risk and anorexia nervosa decreasing it.[55]

Pathophysiology

[edit]
Hyperbolic relationship between insulin sensitivity and beta cell function showing dynamical compensation in "healthy" insulin resistance (transition from A to B) and the evolution of type 2 diabetes mellitus (transition from A to C).
Hyperbolic relationship between insulin sensitivity and beta cell function showing dynamical compensation in "healthy" insulin resistance (transition from A to B) and the evolution of type 2 diabetes mellitus (transition from A to C). Disposition metrics integrate beta cell function and insulin sensitivity in a way so that the results remain constant across dynamical compensation. Changed from Cobelli et al. 2007, Hannon et al. 2018 and Dietrich et al. 2024[56][57][58]

Type 2 diabetes is due to insufficient insulin production from beta cells in the setting of insulin resistance.[23] Insulin resistance, which is the inability of cells to respond adequately to normal levels of insulin, occurs primarily within the muscles, liver, and fat tissue.[59] In the liver, insulin normally suppresses glucose release. However, in the setting of insulin resistance, the liver inappropriately releases glucose into the blood.[10] The proportion of insulin resistance versus beta cell dysfunction differs among individuals, with some having primarily insulin resistance and only a minor defect in insulin secretion and others with slight insulin resistance and primarily a lack of insulin secretion.[23]

Other potentially important mechanisms associated with type 2 diabetes and insulin resistance include: increased breakdown of lipids within fat cells, resistance to and lack of incretin, high glucagon levels in the blood, increased retention of salt and water by the kidneys, and inappropriate regulation of metabolism by the central nervous system.[10] However, not all people with insulin resistance develop diabetes since an impairment of insulin secretion by pancreatic beta cells is also required.[23]

In the early stages of insulin resistance, the mass of beta cells expands, increasing the output of insulin to compensate for the insulin insensitivity, so that the disposition index remains constant.[60] But when type 2 diabetes has become manifest, the person will have lost about half of their beta cells.[60]

The causes of the aging-related insulin resistance seen in obesity and in type 2 diabetes are uncertain. Effects of intracellular lipid metabolism and ATP production in liver and muscle cells may contribute to insulin resistance.[61]

Diagnosis

[edit]
WHO diabetes diagnostic criteria[62][63]  edit
Condition 2-hour glucose Fasting glucose HbA1c
Unit mmol/L mg/dL mmol/L mg/dL mmol/mol DCCT %
Normal < 7.8 < 140 < 6.1 < 110 < 42 < 6.0
Impaired fasting glycaemia < 7.8 < 140 6.1–7.0 110–125 42–46 6.0–6.4
Impaired glucose tolerance ≥ 7.8 ≥ 140 < 7.0 < 126 42–46 6.0–6.4
Diabetes mellitus ≥ 11.1 ≥ 200 ≥ 7.0 ≥ 126 ≥ 48 ≥ 6.5

The World Health Organization definition of diabetes (both type 1 and type 2) is for a single raised glucose reading with symptoms, or for raised glucose readings on two separate dates, of either:[64]

  • fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dL)
or

A random blood sugar of greater than 11.1 mmol/L (200 mg/dL) in association with typical symptoms[22] or a glycated hemoglobin (HbA1c) of ≥ 48 mmol/mol (≥ 6.5 DCCT %) is another method of diagnosing diabetes.[10] In 2009, an International Expert Committee that included representatives of the American Diabetes Association (ADA), the International Diabetes Federation (IDF), and the European Association for the Study of Diabetes (EASD) recommended that a HbA1c threshold of ≥ 48 mmol/mol (≥ 6.5 DCCT %) should be used to diagnose diabetes.[65] This recommendation was adopted by the American Diabetes Association in 2010.[66] Positive tests should be repeated unless the person presents with typical symptoms and blood sugar >11.1 mmol/L (>200 mg/dL).[65]

ADA diabetes diagnostic criteria[67]  
Diabetes mellitus Prediabetes
HbA1c ≥ 6.5% (≥ 48 mmol/mol) 5.7–6.4% (39–47 mmol/mol)
Fasting glucose ≥ 126 mg/dL 100–125 mg/dL
2h glucose ≥ 200 mg/dL 140–199 mg/dL
Random glucose with classic symptoms ≥ 200 mg/dL Not available

Threshold for diagnosis of diabetes is based on the relationship between results of glucose tolerance tests, fasting glucose or HbA1c and complications such as retinal problems.[10] A fasting or random blood sugar is preferred over the glucose tolerance test, as they are more convenient for people.[10] HbA1c has the advantages that fasting is not required and results are more stable but has the disadvantage that the test is more costly than measurement of blood glucose.[68] It is estimated that 20% of people with diabetes in the United States do not realize that they have the disease.[10]

Type 2 diabetes is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency.[69] This is in contrast to type 1 diabetes in which there is an absolute insulin deficiency due to destruction of islet cells in the pancreas and gestational diabetes that is a new onset of high blood sugars associated with pregnancy.[23] Type 1 and type 2 diabetes can typically be distinguished based on the presenting circumstances.[65] If the diagnosis is in doubt antibody testing may be useful to confirm type 1 diabetes and C-peptide levels may be useful to confirm type 2 diabetes,[70] with C-peptide levels normal or high in type 2 diabetes, but low in type 1 diabetes.[71]

Screening

[edit]

The United States Preventive Services Task Force (USPSTF) recommended in 2021 screening for type 2 diabetes in adults aged 35 to 70 years old who are overweight (i.e. BMI over 25) or have obesity.[72] For people of Asian descent, screening is recommended if they have a BMI over 23.[72] Screening at an earlier age may be considered in people with a family history of diabetes; some ethnic groups, including Hispanics, African Americans, and Native Americans; a history of gestational diabetes; polycystic ovary syndrome.[72] Screening can be repeated every 3 years.[72]

According to the US Preventive Services Task Force in a recommendation statement, screening for diabetes in people without risk factors or symptoms is not recommended.[72] However, the American Diabetes Association (ADA) recommended in 2024 screening in all adults from the age of 35 years.[67] ADA also recommends screening in adults of all ages with a BMI over 25 (or over 23 in Asian Americans) with another risk factor: first-degree relative with diabetes, ethnicity at high risk for diabetes, blood pressure ≥130/80 mmHg or on therapy for hypertension, history of cardiovascular disease, physical inactivity, polycystic ovary syndrome or severe obesity.[67] ADA recommends repeat screening every 3 years at minimum.[67] ADA recommends yearly tests in people with prediabetes.[67] People with previous gestational diabetes or pancreatitis are also recommended screening.[67]

There is no evidence that screening changes the risk of death and any benefit of screening on adverse effects, incidence of type 2 diabetes, HbA1c or socioeconomic effects are not clear.[73][74]

In the UK, NICE guidelines suggest taking action to prevent diabetes for people with a body mass index (BMI) of 30 or more.[75] For people of Black African, African-Caribbean, South Asian and Chinese descent the recommendation to start prevention starts at the BMI of 27,5.[75] A study based on a large sample of people in England suggest even lower BMIs for certain ethnic groups for the start of prevention, for example 24 in South Asian and 21 in Bangladeshi populations.[76][77]

Prevention

[edit]
Main article: Prevention of type 2 diabetes

Onset of type 2 diabetes can be delayed or prevented through proper nutrition and regular exercise.[78][79] Intensive lifestyle measures may reduce the risk by over half.[26][80] The benefit of exercise occurs regardless of the person's initial weight or subsequent weight loss.[81] High levels of physical activity reduce the risk of diabetes by about 28%.[82] Evidence for the benefit of dietary changes alone, however, is limited,[79] with some evidence for a diet high in green leafy vegetables[83] and some for limiting the intake of sugary drinks.[84] There is an association between higher intake of sugar-sweetened fruit juice and diabetes, but no evidence of an association with 100% fruit juice.[85] A 2019 review found evidence of benefit from dietary fiber.[86]

A 2017 review found that, long term, lifestyle changes decreased the risk by 28%, while medication does not reduce risk after withdrawal.[87] While low vitamin D levels are associated with an increased risk of diabetes, correcting the levels by supplementing vitamin D3 does not improve that risk.[88]

In those with prediabetes, diet in combination with physical activity delays or reduces the risk of type 2 diabetes, according to a 2017 Cochrane review.[79] In those with prediabetes, metformin may delay or reduce the risk of developing type 2 diabetes compared to diet and exercise or a placebo intervention, but not compared to intensive diet and exercise, and there was not enough data on outcomes such as mortality and diabetic complications and health-related quality of life, according to a 2019 Cochrane review.[89] In those with prediabetes, alpha-glucosidase inhibitors such as acarbose may delay or reduce the risk of type 2 diabetes when compared to placebo, however there was no conclusive evidence that acarbose improved cardiovascular mortality or cardiovascular events, according to a 2018 Cochrane review.[90] In those with prediabetes, pioglitazone may delay or reduce the risk of developing type 2 diabetes compared to placebo or no intervention, but no difference was seen compared to metformin, and data were missing on mortality and complications and quality of life, according to a 2020 Cochrane review.[91] In those with prediabetes, there was insufficient data to draw any conclusions on whether SGLT2 inhibitors may delay or reduce the risk of developing type 2 diabetes, according to a 2016 Cochrane review.[92]

Management

[edit]
Further information: Diabetes management

Management of type 2 diabetes focuses on lifestyle interventions, lowering other cardiovascular risk factors, and maintaining blood glucose levels in the normal range.[26] Self-monitoring of blood glucose for people with newly diagnosed type 2 diabetes may be used in combination with education,[93] although the benefit of self-monitoring in those not using multi-dose insulin is questionable.[26] In those who do not want to measure blood levels, measuring urine levels may be done.[94] Managing other cardiovascular risk factors, such as hypertension, high cholesterol, and microalbuminuria, improves a person's life expectancy.[26] Decreasing the systolic blood pressure to less than 140 mmHg is associated with a lower risk of death and better outcomes.[95] Intensive blood pressure management (less than 130/80 mmHg) as opposed to standard blood pressure management (less than 140–160 mmHg systolic to 85–100 mmHg diastolic) results in a slight decrease in stroke risk but no effect on overall risk of death.[96]

Intensive blood sugar lowering (HbA1c < 6%) as opposed to standard blood sugar lowering (HbA1c of 7–7.9%) does not appear to change mortality.[97][98] The goal of treatment is typically an HbA1c of 7 to 8% or a fasting glucose of less than 7.2 mmol/L (130 mg/dL); however these goals may be changed after professional clinical consultation, taking into account particular risks of hypoglycemia and life expectancy.[99][100] Hypoglycemia is associated with adverse outcomes in older people with type 2 diabetes.[101] Despite guidelines recommending that intensive blood sugar control be based on balancing immediate harms with long-term benefits, many people – for example people with a life expectancy of less than nine years who will not benefit, are over-treated.[102]

It is recommended that all people with type 2 diabetes get regular eye examinations.[23] There is moderate evidence suggesting that treating gum disease by scaling and root planing results in an improvement in blood sugar levels for people with diabetes.[103]

Lifestyle

[edit]

Exercise

[edit]

A proper diet and regular exercise are foundations of diabetic care,[22] with one review indicating that a greater amount of exercise improved outcomes.[104] Regular exercise may improve blood sugar control, decrease body fat content, and decrease blood lipid levels.[105]

Diet

[edit]
Further information: Diet in diabetes

Calorie restriction to promote weight loss is generally recommended.[106] Around 80 percent of obese people with type 2 diabetes achieve complete remission with no need for medication if they sustain a weight loss of at least 15 kilograms (33 lb),[107][108] but most patients are not able to achieve or sustain significant weight loss.[109] Even modest weight loss can produce significant improvements in glycemic control and reduce the need for medication.[110]

Several diets may be effective such as the DASH diet, Mediterranean diet, low-fat diet, or monitored carbohydrate diets such as a low carbohydrate diet.[111][112][113] Other recommendations include emphasizing intake of fruits, vegetables, reduced saturated fat and low-fat dairy products, and with a macronutrient intake tailored to the individual, to distribute calories and carbohydrates throughout the day.[111][114] A 2021 review showed that consumption of tree nuts (walnuts, almonds, and hazelnuts) reduced fasting blood glucose in diabetic people.[115] As of 2015, there is insufficient data to recommend nonnutritive sweeteners, which may help reduce caloric intake.[116] An elevated intake of microbiota-accessible carbohydrates can help reducing the effects of T2D.[117] Viscous fiber supplements may be useful in those with diabetes.[118]

Culturally appropriate education may help people with type 2 diabetes control their blood sugar levels for up to 24 months.[119] There is not enough evidence to determine if lifestyle interventions affect mortality in those who already have type 2 diabetes.[80]

Stress management

[edit]

Although psychological stress is recognized as a risk factor for type 2 diabetes,[10] the effect of stress management interventions on disease progression are not established.[120] A Cochrane review is under way to assess the effects of mindfulness‐based interventions for adults with type 2 diabetes.[121]

Medications

[edit]

Blood sugar control

[edit]
See also: Diabetes medication

There are several classes of diabetes medications available. Metformin is generally recommended as a first line treatment as there is some evidence that it decreases mortality;[7][26][122] however, this conclusion is questioned.[123] Metformin should not be used in those with severe kidney or liver problems.[22] The American Diabetes Association and European Association for the Study of Diabetes recommend using a GLP-1 receptor agonist or SGLT2 inhibitor as the first-line treatment in patients who have or are at high risk for atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease.[124][125] The higher cost of these drugs compared to metformin has limited their use.[109][126][127]

Other classes of medications include: sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists.[125] A 2018 review found that SGLT2 inhibitors and GLP-1 agonists, but not DPP-4 inhibitors, were associated with lower mortality than placebo or no treatment.[128] Rosiglitazone, a thiazolidinedione, has not been found to improve long-term outcomes even though it improves blood sugar levels.[129] Additionally it is associated with increased rates of heart disease and death.[130]

Injections of insulin may either be added to oral medication or used alone.[26] Most people do not initially need insulin.[23] When it is used, a long-acting formulation is typically added at night, with oral medications being continued.[22][26] Doses are then increased to effect (blood sugar levels being well controlled).[26] When nightly insulin is insufficient, twice daily insulin may achieve better control.[22] The long acting insulins glargine and detemir are equally safe and effective,[131] and do not appear much better than NPH insulin, but as they are significantly more expensive, they are not cost effective as of 2010.[132] In those who are pregnant, insulin is generally the treatment of choice.[22]

Blood pressure lowering

[edit]

Many international guidelines recommend blood pressure treatment targets that are lower than 140/90 mmHg for people with diabetes.[133] However, there is only limited evidence regarding what the lower targets should be. A 2016 systematic review found potential harm to treating to targets lower than 140 mmHg,[134] and a subsequent review in 2019 found no evidence of additional benefit from blood pressure lowering to between 130 and 140 mmHg, although there was an increased risk of adverse events.[135] 2023 European Society of Cardiology guidelines recommend systolic blood pressure lowering to 130 mmHg in most people with diabetes.[136]

In people with diabetes and hypertension and either albuminuria or chronic kidney disease, an inhibitor of the renin-angiotensin system (such as an ACE inhibitor or angiotensin receptor blocker) to reduce the risks of progression of kidney disease and present cardiovascular events.[137] There is some evidence that angiotensin converting enzyme inhibitors (ACEIs) are superior to other inhibitors of the renin-angiotensin system such as angiotensin receptor blockers (ARBs),[138] or aliskiren in preventing cardiovascular disease.[139] Although a 2016 review found similar effects of ACEIs and ARBs on major cardiovascular and renal outcomes.[140] There is no evidence that combining ACEIs and ARBs provides additional benefits.[140]

Other

[edit]

The use of statins in diabetes to prevent cardiovascular disease should be considered after evaluating the person's total risk for cardiovascular disease.[141]

The use of aspirin (acetylsalicylic acid) to prevent cardiovascular disease in diabetes is controversial.[141] Aspirin is recommended in people with previous cardiovascular disease, however routine use of aspirin has not been found to improve outcomes in uncomplicated diabetes.[142] Aspirin as primary prevention may have greater risk than benefit, but could be considered in people aged 50 to 70 with another significant cardiovascular risk factor and low risk of bleeding after information about possible risks and benefits as part of shared-decision making.[141]

Vitamin D supplementation to people with type 2 diabetes may improve markers of insulin resistance and HbA1c.[143]

Sharing their electronic health records with people who have type 2 diabetes helps them to reduce their blood sugar levels. It is a way of helping people understand their own health condition and involving them actively in its management.[144][145]

Surgery

[edit]

Weight loss surgery in those who are obese is an effective measure to treat diabetes.[146] Many are able to maintain normal blood sugar levels with little or no medication following surgery[147] and long-term mortality is decreased.[148] There however is some short-term mortality risk of less than 1% from the surgery.[149] The body mass index cutoffs for when surgery is appropriate are not yet clear.[148] It is recommended that this option be considered in those who are unable to get both their weight and blood sugar under control.[150][151]

Epidemiology

[edit]
Further information: Epidemiology of diabetes
Prevalence of total diabetes by age and Global Burden of Disease super-region in 2021

The International Diabetes Federation estimates nearly 537 million people lived with diabetes worldwide in 2021,[152] 90–95% of whom have type 2 diabetes.[153] Diabetes is common both in the developed and the developing world.[10]

Some ethnic groups such as South Asians, Pacific Islanders, Latinos, and Native Americans are at particularly high risk of developing type 2 diabetes.[22] Type 2 diabetes in normal weight individuals represents 60 to 80 percent of all cases in some Asian countries. The mechanism causing diabetes in non-obese individuals is poorly understood.[154][155][156]

Rates of diabetes in 1985 were estimated at 30 million, increasing to 135 million in 1995 and 217 million in 2005.[16] This increase is believed to be primarily due to the global population aging, a decrease in exercise, and increasing rates of obesity.[16] Traditionally considered a disease of adults, type 2 diabetes is increasingly diagnosed in children in parallel with rising obesity rates.[10] The five countries with the greatest number of people with diabetes as of 2000 are India having 31.7 million, China 20.8 million, the United States 17.7 million, Indonesia 8.4 million, and Japan 6.8 million.[157] It is recognized as a global epidemic by the World Health Organization.[1]

History

[edit]
Further information: History of diabetes

Diabetes is one of the first diseases described[19] with an Egyptian manuscript from c. 1500 BCE mentioning "too great emptying of the urine."[20][158] The first described cases are believed to be of type 1 diabetes.[20] Indian physicians around the same time identified the disease and classified it as madhumeha or honey urine noting that the urine would attract ants.[20] The term "diabetes" or "to pass through" was first used in 230 BCE by the Greek Apollonius Memphites.[20] The disease was rare during the time of the Roman Empire with Galen commenting that he had only seen two cases during his career.[20]

Type 1 and type 2 diabetes were identified as separate conditions for the first time by the Indian physicians Sushruta and Charaka in 400–500 CE with type 1 associated with youth and type 2 with being overweight.[20] Effective treatment was not developed until the early part of the 20th century when the Canadians Frederick Banting and Charles Best discovered insulin in 1921 and 1922.[20] This was followed by the development of the longer acting NPH insulin in the 1940s.[20]

In 1916, Elliot Joslin proposed that in people with diabetes, periods of fasting are helpful.[159] Subsequent research has supported this, and weight loss is a first line treatment in type 2 diabetes.[159]

Research

[edit]

In 2020, Diabetes Severity Score (DISSCO) was developed which is a tool that could be better than HbA1c identify if a person's condition is declining.[25][160] It uses a computer algorithm to analyze data from anonymized electronic patient records and produces a score based on 34 indicators.[161][160]

Stem cells

[edit]
See also: Type 1 diabetes § Stem cells, and Diabetes management § Stem cells

In April 2024 scientists reported the first case of reversion of type 2 diabetes by use of stem cells in a 59-year-old man treated in 2021 who has since remained insulin-free.[162][163] Replication in more patients and evidence over longer periods would be needed before considering this treatment as a possible cure.

References

[edit]
[edit]
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Type 2 diabetes

View on Grokipedia
from Grokipedia
Type 2 diabetes is a chronic in which the body becomes resistant to the effects of —a produced by the that regulates blood glucose levels—or fails to produce enough insulin, resulting in elevated blood sugar () that can damage organs and tissues over time. It is the most prevalent form of worldwide, comprising over 95% of all diabetes cases, and develops gradually, often remaining undiagnosed for years due to subtle or absent early symptoms. The condition arises from a combination of and lifestyle factors, including or , physical inactivity, and poor diet, which contribute to in muscle, fat, and liver cells. Risk factors include being over age 45, having a , belonging to certain ethnic groups such as African American, Hispanic/Latino, American Indian, or Alaska Native populations, and a history of or . Globally, affected 830 million adults in 2022—up from 200 million in 1990—with type 2 accounting for the vast majority and leading to 1.6 million direct deaths in 2021, primarily from cardiovascular complications. Common symptoms, when present, include increased thirst and urination, unexplained , , , and slow-healing sores, though many individuals experience none until complications arise. In the United States, approximately 38 million people (about 1 in 10) have , with 90-95% diagnosed with type 2, and rates are rising among children, adolescents, and young adults due to increasing . Type 2 diabetes can often be prevented or delayed through interventions, such as achieving and maintaining a healthy weight (e.g., losing 5-7% of body weight), engaging in at least 150 minutes of moderate per week, and adopting a balanced diet rich in fruits, , and whole grains while limiting sugars and refined carbohydrates. Management is individualized based on patient factors such as comorbidities, obesity status, and organ health, as emphasized in the American Diabetes Association's Standards of Care in Diabetes—2026. Metformin remains a common first-line therapy for most patients without contraindications. GLP-1 receptor agonists (e.g., semaglutide) and dual GIP/GLP-1 receptor agonists (e.g., tirzepatide) are strongly recommended and often preferred for many patients, particularly those with obesity, cardiovascular disease, heart failure, chronic kidney disease, or metabolic dysfunction-associated steatotic liver disease, due to superior benefits in glycemic control, weight loss, and cardiorenal and hepatic protection, alongside ongoing blood glucose monitoring, insulin therapy when needed, and control of related conditions such as high blood pressure and cholesterol to reduce risks of heart disease, stroke, kidney failure, and nerve damage. With effective treatment, individuals with type 2 diabetes can lead long, healthy lives, though access to care remains a challenge, with 59% of adults worldwide untreated as of 2022.

Definition and Characteristics

Overview

Type 2 diabetes is a chronic characterized by persistent resulting from in peripheral tissues and a relative deficiency in insulin from pancreatic beta cells. This condition arises when the body's cells, particularly in muscle and adipose tissues, fail to respond adequately to insulin, leading to elevated glucose levels despite initial compensatory increases in insulin production. Over time, the pancreatic beta cells become dysfunctional and exhausted, further impairing insulin and exacerbating the . The physiological hallmarks of type 2 diabetes include pronounced in and fat, where is diminished, alongside progressive beta-cell impairment that shifts from relative to more absolute insulin deficiency. These features distinguish the disorder as a dual defect in insulin action and secretion, often progressing silently for years before clinical detection. Globally, type 2 diabetes accounts for over 90% of all cases and affects approximately 830 million adults worldwide as of 2022, with continuing to rise due to aging populations and lifestyle factors. This makes it one of the most significant challenges, imposing substantial burdens on healthcare systems and economies. Historically termed non-insulin-dependent diabetes mellitus or adult-onset diabetes, the condition was reclassified as type 2 in the late to reflect its underlying mechanisms rather than treatment needs or age of onset. Increasing rates have led to its recognition in children and adolescents, challenging the prior adult-exclusive label.

Differentiation from Other Diabetes Types

Type 2 diabetes is primarily characterized by in peripheral tissues coupled with progressive beta-cell dysfunction, without the initial autoimmune destruction seen in , where autoantibodies target and destroy insulin-producing beta cells in the . In contrast, typically presents with rapid onset, often in younger individuals, leading to absolute insulin deficiency and immediate dependence on exogenous insulin. , on the other hand, arises specifically during pregnancy due to hormone-induced from the , such as , and generally resolves postpartum, though it shares genetic risk factors like variants in TCF7L2 with type 2 diabetes. Diagnostic challenges arise from overlaps, particularly in (LADA), which mimics type 2 diabetes in its slower adult onset and initial non-insulin dependence but involves gradual autoimmune beta-cell loss detectable by autoantibodies like GAD65, affecting about 5-10% of those initially diagnosed with type 2. Misclassification risks are higher in overweight adults without classic type 1 symptoms, potentially delaying appropriate therapy until insulin requirements emerge. Similarly, (MODY) can be mistaken for type 2 due to its non-autoimmune but differs as a monogenic disorder caused by single-gene mutations (e.g., or GCK), leading to early-onset beta-cell defects without . The spectrum of diabetes types highlights type 2 as polygenic, influenced by over 700 genetic loci that together explain approximately 20% of its , alongside environmental factors like , in contrast to the monogenic forms like MODY, which have near-100% in affected families. This polygenic nature underscores type 2's heterogeneity, sometimes overlapping with other categories, but distinguishes it from the high-penetrance mutations in MODY or the HLA-linked in type 1 and . Clinically, type 2 diabetes features a slower progression from , allowing potential reversal through substantial (e.g., 15% body weight reduction) that normalizes beta-cell function and reduces intraorgan fat, unlike type 1's irreversible beta-cell destruction necessitating lifelong insulin. carries a 15-70% lifetime of progressing to type 2 postpartum, emphasizing the need for ongoing screening, while and MODY may require tailored approaches, such as for certain MODY subtypes, rather than the broad lifestyle and metformin focus in type 2.

Signs and Symptoms

Common Presentations

Type 2 diabetes often presents with an insidious onset, where symptoms develop gradually over years due to chronic hyperglycemia. The classic symptoms include polydipsia, or excessive thirst, resulting from dehydration caused by osmotic diuresis as the kidneys attempt to excrete excess glucose. Polyuria, or frequent urination, accompanies this process, leading to increased fluid loss and further thirst. Polyphagia, an increased appetite, arises as cells are deprived of glucose despite elevated blood levels, prompting the body to seek more energy sources. Unexplained weight loss occurs in some cases due to the caloric loss from glucosuria and reduced cellular uptake of nutrients. Fatigue is common, stemming from energy deficits at the cellular level and overall metabolic strain. Blurred vision results from osmotic changes in the lens of the eye induced by fluctuating blood glucose. Other common symptoms include slow-healing sores, frequent infections, numbness or tingling in the hands or feet, and areas of darkened skin (acanthosis nigricans), often in the armpits and neck. A significant proportion of individuals with type 2 diabetes remain for extended periods, with nearly half of all cases worldwide undiagnosed and often discovered incidentally during routine health screenings or evaluations for unrelated conditions. The presentation can vary by demographics; in adults, symptoms typically progress slowly over several years, whereas in youth-onset type 2 diabetes, the disease advances more rapidly. These symptoms can notably affect daily life, with —a component of —causing frequent nighttime awakenings and sleep disturbances that exacerbate . Additionally, persistent tiredness and reduced energy levels often diminish exercise tolerance, limiting physical activity and contributing to a cycle of sedentary behavior.

Acute Manifestations

The (HHS) represents a rare but life-threatening acute complication primarily associated with type 2 diabetes, characterized by extreme , severe , and neurological alterations without significant . This condition often develops insidiously over days to weeks, building on chronic symptoms such as from osmotic . Key diagnostic features include plasma glucose levels exceeding 600 mg/dL, serum osmolality greater than 320 mOsm/kg, and profound fluid deficits averaging 9 liters in adults, leading to symptoms like , , and altered mental status ranging from to . Triggers for HHS commonly include infections, which account for 50-60% of cases, such as urinary tract infections or , as well as certain medications like glucocorticoids or diuretics that exacerbate , and treatment non-compliance. Unlike (DKA), which predominantly affects and features significant due to insulin deficiency, HHS is for minimal or absent , attributed to residual insulin secretion in type 2 diabetes that suppresses and production. The mortality rate for HHS reaches up to 20%, approximately 10 times higher than that of DKA, largely due to delayed recognition, underlying comorbidities, and complications like or .

Complications

Microvascular Complications

Microvascular complications arise from damage to small blood vessels due to prolonged in type 2 diabetes, primarily affecting the eyes, kidneys, and nerves. These conditions collectively contribute to significant morbidity, with , nephropathy, and neuropathy representing the core triad. The underlying pathology involves and basement membrane thickening, driven by hyperglycemia-induced mechanisms such as the formation of (AGEs) and activation of the (sorbitol) pathway, which increase and . Diabetic retinopathy develops in approximately 25% of individuals with type 2 diabetes and progresses through stages beginning with non-proliferative retinopathy, characterized by microaneurysms, dot-and-blot hemorrhages, cotton-wool spots, and increased . As it advances to proliferative retinopathy, neovascularization occurs, leading to retinal ischemia, vitreous hemorrhage, tractional , and , which can severely impair vision. Without intervention, proliferative disease carries a high of blindness, with up to 50% of untreated cases resulting in vision loss within five years; however, timely treatments like photocoagulation can reduce this to about 5%. Screening through dilated fundoscopy is recommended annually for early detection, using tools such as slit-lamp biomicroscopy or indirect to identify subtle changes like microaneurysms. Diabetic nephropathy, also known as diabetic kidney disease, affects 30-40% of patients with type 2 diabetes and progresses from early glomerular hyperfiltration to chronic kidney disease characterized by declining glomerular filtration rate. Albuminuria serves as an early marker, with microalbuminuria (30-300 mg/day) detectable through urine albumin-to-creatinine ratio testing on at least two occasions separated by three months, indicating initial glomerular barrier damage. About 20% of those with microalbuminuria advance to overt proteinuria, and ultimately, 20-40% of affected individuals develop end-stage renal disease requiring dialysis or transplantation, making it the leading cause of kidney failure in many developed countries. Progression is accelerated by factors like hypertension but can be slowed with blood pressure and glycemic control. Diabetic neuropathy impacts roughly 50% of patients with type 2 diabetes over their lifetime, manifesting in peripheral and autonomic forms that stem from nerve ischemia and metabolic disturbances. , the most common subtype, often presents with distal symmetric sensory loss, paresthesia, burning pain, or numbness in a "stocking-glove" distribution, starting in the feet and progressing proximally, which increases risks of foot ulcers and amputations due to loss of protective sensation. affects visceral functions, leading to symptoms such as (delayed gastric emptying causing nausea and bloating) and (dizziness upon standing due to impaired regulation). relies on clinical history, neurological exams like monofilament testing for sensation, and quantitative sensory tests, with prevalence rising to over 66% in long-standing disease.

Macrovascular and Other Complications

Type 2 diabetes significantly accelerates in large blood vessels, promoting the development of macrovascular complications such as (CVD). This process involves , , and chronic inflammation, which damage arterial walls and lead to plaque buildup. Individuals with type 2 diabetes face approximately a twofold increased risk of (CVD) compared to those without, though this equivalence to post-myocardial infarction risk seen in older studies varies in modern contexts with better preventive care. Myocardial infarction is a primary concern, with people with type 2 diabetes without prior exhibiting elevated risks. In individuals with type 2 diabetes without prior , the risk of remains elevated, with incidence rates having decreased in recent decades due to improved therapies. risk is also elevated, with diabetes contributing to a 1.5- to 2-fold higher likelihood of cerebrovascular events through similar atherosclerotic mechanisms. (PAD) prevalence exceeds twofold in those with diabetes compared to the general population, often manifesting as reduced blood flow to the limbs and increasing the risk of critical limb ischemia. Hypertension synergizes with type 2 diabetes to exacerbate macrovascular risks, occurring twice as frequently in diabetic patients and amplifying through interactive effects of elevated glucose and insulin. Dyslipidemia further contributes, characterized by elevated triglycerides and low cholesterol, which are linked to and promote atherogenic plaque formation in large vessels. Beyond macrovascular issues, type 2 diabetes heightens susceptibility to infections due to immune dysregulation, conferring a 1.5- to 4-fold increased risk across various pathogens. This vulnerability is evident in ulcers, where infections complicate healing and lead to lower extremity amputations in approximately 20% of cases. is similarly intensified, with diabetes raising susceptibility threefold through bidirectional inflammatory pathways that worsen gum tissue destruction. Type 2 diabetes also impairs bone healing, increasing the risk of pseudarthrosis (non-union) following spinal fusion surgery, with affected patients facing significantly higher rates of fusion failure. Cognitive decline represents another systemic complication, as type 2 diabetes is associated with accelerated aging and a higher incidence of . Mechanisms include macrovascular damage and chronic , resulting in gray matter atrophy that advances normal aging by about 26%. A bidirectional association exists between type 2 diabetes and depression, with approximately 10% to 20% of diabetic patients experiencing depression—more than twice the rate in the general —and depression similarly elevating diabetes risk.

Causes and Risk Factors

Genetic Contributions

Type 2 diabetes is a polygenic disorder influenced by the cumulative effects of numerous genetic variants, each contributing modestly to disease susceptibility. Genome-wide association studies (GWAS) have identified over 1,200 independent genetic loci associated with type 2 diabetes risk, primarily affecting beta-cell function, insulin secretion, and related metabolic pathways. Among these, the TCF7L2 gene harbors the strongest association, with the common intronic variant rs7903146 increasing risk by approximately 1.4-fold per risk allele and implicated in up to 20% of cases across populations. Other notable loci include SLC30A8, involved in zinc transport for insulin granule formation, and PAM, which influences peptide processing in beta cells. These variants collectively explain about 20% of the genetic heritability, with polygenic risk scores integrating them to predict individual susceptibility more accurately than single loci. Heritability estimates from twin and family studies underscore the substantial genetic component of type 2 diabetes, ranging from 40% to 80%, with a of over 34,000 twin pairs reporting 72% (95% CI: 61-78%). Familial clustering is evident, as individuals with a first-degree relative affected by type 2 diabetes face a 2- to 6-fold elevated , with hazard ratios of 2.72 for any first-degree family history and up to 5.14 for biparental involvement. This pattern reflects shared rather than solely environmental factors, though interacts with to amplify overall . While type 2 diabetes is predominantly polygenic, rare monogenic forms such as maturity-onset diabetes of the young (MODY) can mimic it and lead to misclassification, comprising up to 6% of apparent type 2 cases but often remaining undiagnosed for over a decade. MODY subtypes, like those caused by mutations in HNF1A or GCK, present with non-insulin-dependent hyperglycemia in non-obese individuals, typically before age 25, and are distinguished by autosomal dominant inheritance without autoantibodies. Ethnic variations highlight ancestry-specific genetic contributions to type 2 diabetes susceptibility. South Asian populations carry higher polygenic scores for beta-cell dysfunction (e.g., insulin deficiency endotype) and lipodystrophy-related traits, leading to earlier onset at lower compared to Europeans. In African ancestry groups, including , risk is approximately twofold higher than in , driven by both shared loci like TCF7L2 and novel variants such as those in TGFB1, with GWAS identifying ancestry-enriched signals explaining additional heritability. These differences emphasize the need for diverse genomic studies to capture population-specific risk profiles.

Lifestyle and Environmental Factors

Obesity plays a central role in the development of type 2 diabetes, primarily through the accumulation of visceral , which consists of larger adipocytes in areas such as the and omentum. This ectopic fat deposition directly promotes by impairing glucose metabolism, independent of overall (BMI). Visceral fat also triggers chronic low-grade in , mediated by the infiltration of macrophages and the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which further exacerbate . Individuals with a BMI greater than 30 kg/m² face a substantially elevated risk, with meta-analyses indicating approximately a 3.5- to 7-fold increase compared to those with a BMI under 25 kg/m², though this varies by and ethnicity. Dietary patterns significantly contribute to type 2 diabetes , particularly those characterized by high consumption of refined carbohydrates, added sugars, s, and low , as seen in the Western diet. Refined carbohydrates and sugars, often from processed foods like , lead to rapid glycemic spikes, gut , and , promoting and . High intake induces and mitochondrial dysfunction in cells, impairing insulin sensitivity and contributing to . Low fiber intake reduces gut microbiota diversity, fostering chronic and poor glucose . Adherence to a Western dietary pattern is associated with a 20-50% higher of type 2 diabetes, largely due to these combined effects on energy balance and metabolic health. Physical inactivity and sedentary behavior independently elevate the risk of type 2 diabetes, even after accounting for . Prolonged sitting, such as more than 6 hours per day compared to less than 2 hours, is linked to a 1.58-fold increased (95% CI: 1.47-1.71), driven by reduced insulin sensitivity in muscle, adipose, and liver tissues. This association holds without adjustment for BMI, highlighting sedentariness as a distinct modifiable factor. Each additional 2.4 hours of daily sedentary time raises the risk by about 18%, underscoring the dose-dependent nature of this exposure. Environmental factors beyond personal behaviors also influence type 2 diabetes onset, including , , and sleep disruption. Urbanization often reduces , with low-walkable neighborhoods associated with higher diabetes prevalence; conversely, each standard deviation increase in neighborhood correlates with a 12% reduction. , particularly long-term exposure to (NO₂) and fine particulate matter (PM₂.₅), heightens through and , with estimates of 19% increased odds per 10 μg/m³ rise in NO₂. Sleep disruption, such as habitual durations under 6 hours per night, is linked to a 9% higher , possibly via altered glucose and increased hormones. These effects can interact with genetic predispositions to amplify overall susceptibility.

Associated Medical Conditions

Type 2 diabetes is frequently associated with several endocrine and inflammatory conditions that independently elevate its risk through mechanisms such as and beta-cell impairment. These comorbidities often share pathophysiological pathways involving hormonal dysregulation and chronic inflammation, contributing to independent of lifestyle factors like . Polycystic ovary syndrome (PCOS) is a key endocrine disorder linked to type 2 diabetes, with present in 50–80% of affected women, regardless of body weight. This stems from defects in insulin signaling and is compounded by , leading to compensatory that exacerbates ovarian dysfunction and metabolic disturbances. Women with PCOS face a 3- to 10-fold higher risk of developing type 2 diabetes compared to the general population, with the elevated risk persisting even in non-obese individuals. Early screening for glucose intolerance is recommended in PCOS due to this heightened susceptibility. Cushing's syndrome and acromegaly, both characterized by excess counterregulatory hormones, significantly impair insulin action and increase type 2 diabetes risk. In , glucocorticoid excess induces peripheral by promoting , , and visceral fat accumulation, resulting in impaired glucose tolerance or diabetes in 20–45% of cases. Similarly, in , hypersecretion antagonizes insulin effects on glucose uptake and stimulates hepatic glucose production, leading to diabetes in 12–56% of patients. These hormonal imbalances create a prediabetic state that necessitates vigilant metabolic monitoring. Chronic inflammatory conditions, including non-alcoholic fatty liver disease (NAFLD) and , elevate type 2 diabetes risk through cytokine-mediated pathways. NAFLD, marked by hepatic steatosis and inflammation, is associated with a 2- to 5-fold increased incidence of type 2 diabetes, driven by insulin resistance in the liver and . Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) play a central role by inhibiting signaling and promoting beta-cell stress. similarly heightens risk, with patients showing a 20–30% increased likelihood of type 2 diabetes onset, attributable to from TNF-α and other cytokines that foster . These links underscore the need for integrated management of inflammation in at-risk individuals. A history of pancreatitis, whether acute or chronic, independently raises type 2 diabetes risk by causing direct beta-cell damage and reducing pancreatic insulin secretory capacity. episodes lead to islet cell inflammation and , with up to 20% of survivors developing diabetes within 5 years and cumulative rates reaching 40% over time. exacerbates this through progressive and loss of beta-cell mass, compounding the risk in the presence of other metabolic stressors. Post-pancreatitis often requires ongoing for type 2 diabetes progression.

Pathophysiology

Insulin Resistance Mechanisms

Insulin resistance represents the primary early pathophysiological defect in type 2 diabetes, characterized by diminished responsiveness of target tissues—primarily skeletal muscle, liver, and adipose tissue—to insulin's metabolic actions, leading to impaired glucose homeostasis. This defect manifests at the cellular level through disruptions in insulin signaling cascades, ectopic lipid accumulation, and altered adipokine secretion, collectively contributing to hyperglycemia. A central mechanism involves defective insulin signaling, particularly in the insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K) pathway in skeletal muscle and liver. In these tissues, reduced tyrosine phosphorylation of IRS-1 and subsequent PI3K activation impair the downstream Akt signaling, which is essential for metabolic effects such as glucose transporter 4 (GLUT4) translocation to the cell membrane in skeletal muscle. This failure in GLUT4 translocation markedly reduces insulin-stimulated glucose uptake, exacerbating postprandial hyperglycemia. In the liver, impaired signaling prevents insulin-mediated suppression of gluconeogenesis and glycogenolysis, promoting excessive hepatic glucose output. These defects are evident even in lean individuals with type 2 diabetes, highlighting their role independent of obesity. Lipid-induced insulin resistance further compounds these signaling impairments through ectopic fat deposition in non-adipose tissues like and liver. Accumulation of diacylglycerols (DAGs) and s, derived from excess free fatty acids, activates (PKC) isoforms, which serine-phosphorylate IRS-1, thereby inhibiting the PI3K/Akt pathway. , particularly C16 and C18 species, directly disrupt this signaling by promoting via nuclear factor-κB (NF-κB) activation and release from resident macrophages. This lipid-mediated and ceramide buildup create a vicious cycle, sustaining resistance and contributing to the progression of type 2 diabetes. Adipokine dysregulation from dysfunctional also plays a pivotal , with reduced of and development of resistance. Low circulating levels fail to enhance oxidation and suppress hepatic via activation of (AMPK), resulting in increased liver glucose production and worsened insulin sensitivity. Conversely, hyperleptinemia in induces resistance in the and peripheral tissues, impairing its anorexigenic effects while paradoxically promoting and hepatic through sustained signaling defects. These imbalances link visceral adiposity to systemic . Quantitatively, insulin resistance in type 2 diabetes leads to a profound 50-70% reduction in insulin sensitivity, particularly in glucose disposal, which precedes and precipitates β-cell compensation failure. This degree of impairment is observed across lean and obese individuals, underscoring its foundational role in disease onset.

Beta-Cell Dysfunction and Progression

In the early stages of type 2 diabetes, pancreatic beta cells respond to by increasing insulin secretion, often two- to threefold above normal levels, resulting in compensatory that initially maintains euglycemia. This hypersecretion, driven by heightened beta-cell responsiveness to glucose, represents an adaptive mechanism to overcome peripheral and hepatic , but it places chronic stress on the beta cells. As the disease progresses, beta cells primarily undergo , losing their specialized insulin-producing identity, with increased as a secondary contributor, leading to a substantial reduction in functional beta-cell mass—typically 40-60% loss over time. Key contributors include islet amyloid polypeptide deposition, which aggregates in the and impairs insulin secretion, and endoplasmic reticulum stress from chronic exposure to high glucose and lipids, triggering unfolded protein response pathways that promote cell death and . Recent research as of 2025 indicates that beta-cell may be reversible with early interventions, such as sustained . These processes culminate in beta-cell failure, where the cells can no longer sustain adequate insulin output despite ongoing demand. A critical aspect of this dysfunction is the loss of the incretin effect, characterized by a reduced response to (GLP-1), which normally amplifies postprandial insulin secretion by 50-70% in healthy individuals but drops to less than 20% in type 2 diabetes. This impairment arises from diminished GLP-1 secretion and beta-cell insensitivity, further blunting glucose-dependent insulin release after meals. The overall disease trajectory is encapsulated in the "ominous octet" model, which highlights beta-cell dysfunction alongside alpha-cell hyperglucagonemia—leading to excessive hepatic glucose production—and increased renal glucose reabsorption via sodium-glucose cotransporter 2, both exacerbating hyperglycemia. This multifaceted progression underscores the need for therapies targeting multiple defects to halt beta-cell decline.

Diagnosis

Diagnostic Criteria

The diagnosis of type 2 diabetes is established using standardized criteria from the (ADA) and the (WHO), which align on key thresholds for plasma glucose and (HbA1c) levels. These include a plasma glucose (FPG) of ≥126 mg/dL (≥7.0 mmol/L) after at least 8 hours of no caloric intake, a 2-hour plasma glucose of ≥200 mg/dL (≥11.1 mmol/L) during a 75-g oral (OGTT), a random plasma glucose of ≥200 mg/dL (≥11.1 mmol/L) in the presence of classic symptoms of (such as , , and unexplained ), or an HbA1c of ≥6.5% (≥48 mmol/mol) using a National Glycohemoglobin Standardization Program (NGSP)-certified standardized to the Diabetes Control and Complications Trial (DCCT) reference. In the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation (e.g., diabetic ketoacidosis or hyperosmolar hyperglycemic state), the diagnosis requires confirmation by repeat testing on a subsequent day using the same or an alternative method. Prediabetes, an intermediate state increasing the risk of progression to type 2 diabetes, is defined by an FPG of 100–125 mg/dL (5.6–6.9 mmol/L) or impaired fasting glucose (IFG) per ADA criteria (WHO uses 110–125 mg/dL or 6.1–6.9 mmol/L), a 2-hour OGTT value of 140–199 mg/dL (7.8–11.0 mmol/L) or impaired glucose tolerance (IGT), or an HbA1c of 5.7–6.4% (39–47 mmol/mol). The 2025 ADA Standards of Care emphasize limitations of point-of-care (POC) HbA1c testing for diagnosis, particularly in populations with conditions affecting turnover, such as , hemoglobinopathies, , , or HIV treatment, where results may be inaccurate (often reading lower in increased turnover or higher in reduced turnover). In such cases, plasma glucose-based tests are preferred over POC HbA1c, which should be restricted to U.S. Food and Drug Administration-approved devices in (CLIA)-certified laboratories.

Confirmatory Tests

The diagnosis of type 2 diabetes requires confirmation through specific laboratory tests that measure glycemia, typically involving at least two abnormal results from the same or different tests unless unequivocal with symptoms is present. The A1c (HbA1c) assay is a primary confirmatory test that reflects the average blood glucose concentration over the preceding 2 to 3 months by measuring the percentage of glycated due to chronic . It is standardized through the National Glycohemoglobin Standardization Program (NGSP), which ensures assay accuracy and comparability across laboratories by certifying methods traceable to an international reference. Advantages include no requirement for , good preanalytical stability, and low intraindividual variability, making it convenient for clinical use. However, limitations arise from conditions affecting erythrocyte turnover or structure, such as (e.g., or ), , or recent blood loss, which can lead to falsely elevated or reduced readings. In such cases, alternative tests are recommended to avoid misdiagnosis. The oral glucose tolerance test (OGTT) serves as another key confirmatory method, particularly useful for detecting impaired glucose tolerance. The standard protocol involves an 8- to 10-hour fast followed by ingestion of a 75-gram anhydrous glucose load dissolved in 250-300 mL of water over 5 minutes, with plasma glucose measured at baseline and 2 hours post-load. Prior preparation includes a 3-day diet with at least 150 grams of carbohydrates daily and normal physical activity to ensure reproducibility. It is considered the gold standard for identifying prediabetes due to its sensitivity in capturing postprandial glucose excursions that other tests may miss. Nonetheless, the test is cumbersome, requiring patient compliance with fasting, precise timing, and prolonged clinic visits, and it exhibits poor reproducibility, with up to 20% of results being nondiagnostic and necessitating repeats. Factors like acute illness or medications can further influence outcomes. Fasting plasma glucose (FPG) testing provides a straightforward confirmatory approach by measuring venous plasma glucose after at least 8 hours of , offering an assessment of basal glycemia. Its simplicity and widespread availability make it an inexpensive initial option in resource-limited settings. However, results can be influenced by recent meals if is incomplete, as well as by acute stressors like illness, , or , which elevate glucose through counter-regulatory release. High day-to-day variability also limits reliability, often requiring repeat testing for confirmation. To rule out type 1 diabetes and confirm type 2 classification, especially in adults with atypical features or requiring insulin early, C-peptide and autoantibody testing are employed. C-peptide measurement assesses endogenous insulin secretion, as it is cosecreted with insulin in equimolar amounts; low levels, particularly <200 pmol/L (<0.6 ng/mL), suggest absolute insulin deficiency and beta-cell failure typical of type 1 diabetes, while levels ≥600 pmol/L (≥1.8 ng/mL) indicate preserved endogenous insulin production consistent with type 2 diabetes. Levels of 200–600 pmol/L (0.6–1.8 ng/mL) are indeterminate and may represent type 1 diabetes, maturity-onset diabetes of the young (MODY), or longstanding type 2 diabetes with significant β-cell failure. Autoantibody tests, particularly for glutamic acid decarboxylase (GAD65), islet antigen-2 (IA-2), and zinc transporter 8 (ZnT8), detect autoimmune destruction; positive results indicate type 1 or latent autoimmune diabetes in adults (LADA), prompting reclassification from presumed type 2. These tests are not routine for all cases but are valuable when clinical overlap exists, with absence of autoantibodies reinforcing a type 2 diagnosis. Discordant results among HbA1c, OGTT, and FPG should prompt evaluation for interferences or alternative testing to meet diagnostic thresholds outlined in established criteria.

Screening

At-Risk Population Guidelines

Guidelines for screening individuals at risk for type 2 diabetes emphasize early identification in populations with elevated susceptibility, primarily guided by age, (BMI), and additional risk factors. According to the 2025 (ADA) Standards of Care, all adults aged 35 years and older should undergo screening, reflecting an adjustment from prior recommendations to address increasing incidence in younger middle-aged adults. For adults under 35 years, screening is recommended if they have or (BMI ≥25 kg/m²) accompanied by one or more risk factors, such as or conditions like (PCOS). This approach prioritizes those whose lifestyle and environmental factors, including , heighten susceptibility to . High-risk ethnic groups warrant targeted screening due to disproportionate prevalence rates. The ADA identifies African American, , American Indian, Alaska Native, Asian American, and populations as particularly vulnerable, recommending screening for those with BMI ≥25 kg/m² (or ≥23 kg/m² for Asian Americans) and additional risks like family history of diabetes. Individuals with a first-degree relative with type 2 diabetes face approximately a twofold increased risk, further justifying inclusion in at-risk criteria regardless of age or BMI thresholds. or itself amplifies these risks across groups, with BMI serving as a key proxy for metabolic vulnerability. Women with a history of gestational diabetes mellitus (GDM) are at substantially elevated risk for developing type 2 diabetes postpartum. The ADA advises screening women with GDM history within 4–12 weeks after delivery using a 75-g oral (OGTT), followed by periodic reassessment every 1–3 years, as up to 50% may progress to type 2 diabetes within 10 years. A history of delivering a macrosomic (birth weight ≥9 lb or 4 kg) is a general for type 2 diabetes but is not a specific indication for postpartum screening per ADA guidelines. In response to the rising incidence of pediatric type 2 diabetes, the ADA guidelines reinforce screening for aged 10 years or older (or at onset if earlier) who have (BMI ≥95th percentile for age and sex) and at least one additional , such as family history or belonging to a high-risk ethnic group. This update underscores the need to address pediatric cases amid increasing rates among children. Internationally, organizations like the recommend risk-based screening without fixed age thresholds, focusing on high-risk populations globally.

Screening Protocols

Screening for type 2 diabetes typically involves testing with hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), or a 2-hour 75-g oral glucose tolerance test (OGTT), with HbA1c often preferred due to its convenience as a non-fasting measure that reflects average glycemia over the prior 2-3 months. For adults identified in at-risk populations, such as those who are or obese with additional risk factors like family history or high-risk , screening is recommended beginning at age 35 years or earlier if risks are present, with repeat testing every 3 years if results are normal; more frequent screening, such as annually, is advised for individuals with or multiple risk factors to detect progression early. The OGTT is particularly recommended in specific scenarios where its greater sensitivity for detecting impaired glucose tolerance is beneficial, such as during for mellitus screening at 24-28 weeks gestation using a 75-g load, or for postpartum screening in women with a history of , ideally performed 4-12 weeks after delivery to identify persistent dysglycemia before it progresses to overt type 2 diabetes. Following this initial postpartum test, lifelong screening every 1-3 years is suggested, depending on results, to monitor for type 2 diabetes development. Community-based screening approaches emphasize opportunistic testing in settings during routine visits, as this facilitates immediate follow-up and referral, though implementation can be challenged by barriers such as limited access in low-resource settings, including rural areas or underserved populations where healthcare infrastructure may be inadequate. Large-scale community programs are generally not recommended without established systems for confirmatory testing and management to avoid diagnostic uncertainty. Early screening has demonstrated cost-effectiveness by reducing the incidence of major microvascular complications when is identified and managed promptly; recent analyses (as of 2024) indicate incremental cost-effectiveness ratios around $32,000 per gained for opportunistic approaches.

Prevention

Lifestyle-Based Strategies

Lifestyle-based strategies for preventing or delaying the onset of type 2 diabetes primarily involve sustainable behavioral changes targeting modifiable risk factors such as and . These approaches emphasize achieving and maintaining a modest through and increased , as demonstrated in large-scale clinical trials. In the Diabetes Prevention Program (DPP), a landmark involving over 3,000 adults with , participants in the intensive lifestyle intervention arm achieved an average 5-7% body weight reduction through a combination of dietary modifications and exercise, resulting in a 58% relative reduction in the incidence of type 2 diabetes compared to the group over nearly three years. This intervention highlights how even modest can significantly improve insulin sensitivity and lower diabetes risk in high-risk individuals. Dietary shifts play a central role in these strategies by promoting nutrient-dense foods that stabilize blood glucose levels and support . Adopting a Mediterranean-style diet, rich in whole grains, , fruits, nuts, and healthy fats while limiting refined sugars and processed carbohydrates, has been associated with a 30% lower of developing type 2 diabetes in large cohort studies. Similarly, low-glycemic index diets, which prioritize foods like , non-starchy , and whole grains that cause slower rises in blood sugar, help reduce insulin demand and may prevent progression to diabetes in prediabetic individuals. Increasing intake of nuts, such as almonds or walnuts, provides fiber and healthy fats that enhance and improve glycemic control, while reducing added sugars limits excessive caloric intake and hepatic fat accumulation, both key contributors to . These patterns not only aid in but also foster long-term metabolic . Regular is another cornerstone, with evidence supporting at least 150 minutes per week of moderate-intensity , such as brisk walking or , combined with resistance training two to three times weekly. This regimen enhances insulin sensitivity by increasing in muscles independent of insulin and promoting fat loss, thereby reducing risk by up to 58% when paired with dietary changes, as seen in the DPP. improves and mitochondrial function in , while resistance training builds lean mass to further boost metabolic rate. Guidelines from the recommend this level of activity for prediabetic adults to delay or prevent type 2 diabetes onset. Behavioral support mechanisms are essential for initiating and sustaining these changes, addressing common barriers like and formation. Structured counseling, as implemented in the DPP through individual and group sessions with lifestyle coaches, significantly improves adherence to diet and exercise goals, contributing to the observed risk reduction. Digital tools, including mobile apps for tracking , dietary intake, and progress, have shown promise in enhancing engagement; for instance, app-based interventions in programs can improve outcomes by providing real-time feedback and reminders. However, long-term adherence remains challenging, with studies indicating that only about 50% of participants maintain beyond four years without ongoing support, underscoring the need for community-based or reinforcement strategies.

Pharmacological and Early Interventions

Pharmacological interventions play a key role in preventing the progression from to type 2 diabetes, particularly in high-risk individuals. Metformin is recommended as a first-line for adults with and a (BMI) of 35 kg/m² or greater, those under 60 years of age, or with a history of , based on guidelines from the . In the Diabetes Prevention Program Outcomes Study (DPPOS), long-term follow-up demonstrated that metformin reduced the incidence of type 2 diabetes by 31% compared to over more than two decades, with sustained benefits in and glycemic control. Other (GLP-1) receptor agonists, such as , are considered for high-risk obese individuals with to further mitigate progression. In the SCALE trial, 3.0 mg administered for three years alongside diet and exercise reduced the risk of developing type 2 diabetes by 79% in participants with , primarily through significant and improved insulin sensitivity. These agents are particularly beneficial in obese populations, where they promote sustained weight reduction and delay diabetes onset. Early interventions targeting modifiable risk factors also show promise in deficient or severely obese populations. supplementation in individuals with and has been associated with a 15% reduction in risk, with a three-year absolute risk reduction of 3.3%, as evidenced by pooled analyses of randomized trials focusing on insufficient populations. For those with severe obesity (BMI ≥40 kg/m²) and , achieves remission rates of 30-60% over four years, with higher initial rates (up to 82% at one year) that stabilize long-term through substantial and metabolic improvements. Emerging evidence from 2025 highlights precision tools, including AI-driven models, to predict responders to preventive interventions in . These tools analyze genetic, metabolic, and lifestyle data to identify individuals likely to benefit from targeted therapies like metformin or GLP-1 agonists, enabling personalized prevention strategies that address heterogeneity in prediabetes progression. Such approaches complement lifestyle-based strategies by optimizing resource allocation for high-benefit cases.

Management

Type 2 diabetes is a chronic condition that cannot be fully cured, though remission—defined as achieving and maintaining HbA1c below 6.5% without glucose-lowering medications for at least three months—is achievable in some cases through significant weight loss (typically 10-15 kg or more), which primarily reduces ectopic fat accumulation in the liver and pancreas to restore insulin sensitivity and beta-cell function, low-carbohydrate diets, regular exercise, and bariatric surgery. Sustaining remission requires ongoing lifestyle maintenance to prevent relapse, with treatment individualized and consultation with an endocrinologist recommended.

Lifestyle Modifications

Lifestyle modifications form the cornerstone of managing type 2 diabetes, focusing on sustainable behavioral changes to improve glycemic control, promote , and enhance overall health outcomes in diagnosed individuals. These interventions, often delivered through diabetes self-management education and support (DSMES), emphasize individualized approaches tailored to personal preferences, cultural factors, and health status to foster long-term adherence and potentially sustain remission. Building on strategies used in prevention, these modifications adapt to ongoing needs post-diagnosis for continuous control. Dietary therapy involves personalized medical nutrition therapy (MNT) plans developed by registered nutritionists, incorporating techniques such as counting to manage postprandial glucose excursions and plant-based eating patterns to reduce saturated fats and improve insulin sensitivity. Aiming for a 500–750 kcal daily energy deficit supports gradual , typically targeting 3–7% of body weight in or obese adults to enhance metabolic health without risking . These strategies can lower HbA1c by 0.3–2.0%, depending on adherence and baseline levels. Physical activity programs recommend at least 150 minutes per week of moderate-to-vigorous , spread over at least three days, combined with resistance training two to three times weekly, including (HIIT) for those able to tolerate it. These structured efforts target 7–10% weight reduction, which correlates with HbA1c improvements of 0.5–1%, alongside benefits to and ; lifestyle changes typically show obvious effects on insulin resistance in 3-6 months, while complete reversal may take months to years depending on individual baseline. Individualization accounts for comorbidities, starting with supervised sessions to build confidence and safety. Adequate of 7–9 hours per night is essential, as poor disrupts glucose ; screening and counseling on are recommended to mitigate these effects. through mindfulness-based practices, such as , helps lower levels, thereby reducing stress-induced and improving glycemic control. Multidisciplinary teams, including educators, psychologists, and digital coaching apps, support adherence, with tools shown to further decrease HbA1c by about 0.3%; however, long-term retention in such programs averages around 50%, highlighting the need for ongoing motivation strategies.

Pharmacological Therapies

Pharmacological therapies for type 2 diabetes focus on achieving and maintaining glycemic targets while mitigating cardiovascular, renal, hepatic, and metabolic complications, with selections tailored to patient-specific factors such as comorbidities, obesity, renal function, and cost. There is no single "best" medication for type 2 diabetes, as the American Diabetes Association's Standards of Care in Diabetes—2026 emphasize individualized treatment based on patient factors like comorbidities, obesity, and organ health. The (ADA) Standards of Care in Diabetes—2026 recommend a person-centered approach, prioritizing agents with proven cardiorenal and hepatic benefits early in treatment, regardless of baseline HbA1c levels. Metformin remains a common first-line therapy for most adults with type 2 diabetes without contraindications due to its efficacy, safety profile, and affordability. As a biguanide, it primarily suppresses hepatic gluconeogenesis, reducing fasting glucose and HbA1c by 1-2%, while being weight-neutral and carrying a low risk of hypoglycemia. The United Kingdom Prospective Diabetes Study (UKPDS 34) showed that metformin-based intensive glucose control in overweight patients decreased the combined risk of diabetes-related complications, including myocardial infarction, by 32%. Gastrointestinal side effects, such as nausea, diarrhea, and abdominal discomfort, affect up to 25% of users initially but often diminish with extended-release formulations or dose titration; monitoring for vitamin B12 deficiency is advised with long-term use, and it is contraindicated if eGFR is below 30 mL/min/1.73 m². Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists, such as semaglutide and tirzepatide, are strongly recommended and often preferred for many patients, particularly those with obesity, cardiovascular disease, heart failure, chronic kidney disease, or metabolic dysfunction-associated steatotic liver disease (MASLD/MASH), due to superior benefits in glycemic control, weight loss, and cardiorenal and hepatic protection. These injectable or oral agents enhance glucose-dependent insulin secretion, inhibit glucagon release, delay gastric emptying, and promote satiety, yielding HbA1c reductions of 1-2% and weight loss of 5-15 kg or more over time. The SUSTAIN-6 trial demonstrated that once-weekly subcutaneous semaglutide reduced major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) by 26% in patients with type 2 diabetes and established cardiovascular disease. Common adverse effects include transient gastrointestinal symptoms like nausea and vomiting, occurring in 15-20% of users; weekly dosing improves adherence compared to daily options. The 2026 ADA guidelines highlight their role in early therapy for cardiovascular protection, weight management, and hepatic benefits. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, including empagliflozin, offer dual benefits for glycemic and cardiorenal outcomes through inhibition of renal glucose reabsorption, promoting glycosuria and natriuresis. This mechanism lowers HbA1c by 0.5-1%, reduces systolic blood pressure by 3-5 mmHg, and supports modest weight loss of 2-3 kg. The EMPA-REG OUTCOME trial reported that empagliflozin decreased the primary composite cardiovascular endpoint by 14% and cardiovascular mortality by 38% in patients with type 2 diabetes and atherosclerotic cardiovascular disease. Risks include genital mycotic infections (5-10% incidence) and a low but serious potential for euglycemic diabetic ketoacidosis, particularly in perioperative settings or with low-carbohydrate diets. The 2026 ADA standards expand recommendations for initiating SGLT2 inhibitors early in patients with heart failure, chronic kidney disease, or high cardiovascular risk, even at eGFR levels above 45 mL/min/1.73 m², to prevent progression of these conditions. Additional classes provide options for individualized regimens when first-line agents are insufficient. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin, augment endogenous incretin levels to modestly lower HbA1c by 0.5-0.8%, with weight neutrality and minimal hypoglycemia risk, though they offer limited cardiovascular benefits compared to GLP-1 agonists. Sulfonylureas, like glimepiride, stimulate pancreatic beta-cell insulin release for HbA1c reductions of 1-1.5%, but they increase hypoglycemia risk (up to 2-3 times higher than comparators) and promote weight gain of 1-3 kg. Insulin therapy progresses from basal regimens (e.g., once-daily glargine) to basal-bolus schemes as beta-cell function declines, providing robust HbA1c control (1.5-3.5% reductions) but requiring careful titration to avoid hypoglycemia and weight gain. Combination therapy with metformin, a sulfonylurea (such as glipizide), and insulin is a recognized approach when oral agents alone are insufficient for glycemic control, though it increases the risk of hypoglycemia. Current guidelines prefer adding basal insulin to oral agents over sliding scale insulin alone in outpatient settings, as sliding scale regimens are less effective and not routinely recommended for ongoing management. For patients on metformin plus a DPP-4 inhibitor with poor control, one possible oral escalation approach involves adding an SGLT2 inhibitor (or pioglitazone as an alternative if SGLT2 inhibitors are contraindicated), followed by the other agent if further intensification is needed, and then low-dose sulfonylurea or alpha-glucosidase inhibitor for quadruple oral therapy prior to considering injectables. The ADA 2026 algorithms advocate combination therapy from diagnosis if HbA1c exceeds the target by ≥1.5%, typically starting with metformin plus a GLP-1 receptor agonist (or dual GIP/GLP-1 receptor agonist) or SGLT2 inhibitor based on comorbidities—such as atherosclerotic cardiovascular disease, heart failure, chronic kidney disease, or MASLD/MASH—to maximize cardiorenal and hepatic protection. For example, dual therapy with metformin and an SGLT2 inhibitor is preferred in heart failure patients, while triple combinations may incorporate DPP-4 inhibitors or sulfonylureas if needed, with transitions to insulin for persistent hyperglycemia. Therapy is reassessed every 3-6 months, emphasizing de-intensification to minimize polypharmacy risks once targets are met. These pharmacological strategies complement lifestyle modifications to achieve holistic glycemic, cardiovascular, and weight management.

Surgical and Procedural Options

Surgical and procedural options represent a key intervention for managing type 2 diabetes in patients with who have not achieved adequate glycemic control through modifications or pharmacological therapies. These approaches, particularly bariatric surgeries, can lead to significant and sometimes sustained remission of diabetes by altering gastrointestinal anatomy and physiology. Bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) and (SG) are established procedures that promote and improve metabolic outcomes in individuals with type 2 diabetes. RYGB involves creating a small gastric pouch and rerouting the to bypass part of the and , while SG entails removing about 80% of the to form a tube-like structure. Studies report diabetes remission rates of 60-80% at one year post-surgery for both procedures, with RYGB often showing slightly higher rates (e.g., 57-65%) compared to SG (47-63%). Long-term durability is observed in 30-50% of cases, with complete remission rates around 31% at 10 years. The mechanisms underlying diabetes improvement following bariatric surgery extend beyond and include changes in gut hormone secretion, such as increased levels of (GLP-1), which enhances insulin secretion and suppresses . Caloric restriction contributes initially, but weight-independent effects, like altered signaling and intestinal , play a significant role in rapid glycemic normalization. These physiological shifts can occur within days of surgery, independent of substantial weight reduction. Endoscopic alternatives offer less invasive options for , with duodenal mucosal resurfacing (DMR) emerging as a promising procedure as of 2025. DMR uses hydrothermal to remove and regenerate the duodenal mucosa, targeting in the proximal intestine without altering anatomy. Clinical trials demonstrate an approximate 1% reduction in HbA1c at one year, alongside improvements in insulin sensitivity and hepatic steatosis. Eligibility for these interventions typically requires a (BMI) of ≥35 kg/m² with comorbidities like uncontrolled type 2 diabetes, though guidelines may extend to BMI ≥30 kg/m² for diabetes-specific indications. Risks include nutritional deficiencies, such as iron, , and calcium malabsorption, necessitating lifelong supplementation and monitoring. Other potential complications involve surgical site infections or, for , transient .

Prognosis

Outcome Predictors

Glycemic control is a primary predictor of outcomes in type 2 diabetes, with sustained HbA1c levels below 7% reducing the risk of microvascular complications by 25%. The Prospective Diabetes Study (UKPDS) established that early intensive glucose lowering, using or insulin, yields a legacy effect, conferring long-term benefits such as a 15% reduction in and a 13% decrease in all-cause mortality, even after glycemic differences between treatment groups diminished over time. These findings underscore the importance of achieving tight control early in the disease course to mitigate progression and improve survival. The burden of comorbidities strongly influences disease progression and cardiovascular event risk in type 2 diabetes. Duration of diabetes is a critical factor, with each additional 5 years of disease increasing the incidence of by approximately 17%. Coexisting and further elevate cardiovascular risk, as these conditions synergize with to promote and . Predictive models, such as the , integrate diabetes duration, , lipid profiles, and other variables to estimate 10-year risk, aiding in personalized assessment. Socioeconomic factors play a pivotal role in shaping outcomes for individuals with type 2 diabetes. Limited access to healthcare and lower levels are associated with poorer glycemic management and higher complication rates due to barriers in treatment adherence and implementation. Notably, adults with type 2 diabetes from low-income households face approximately twofold higher diabetes-related mortality compared to those from higher socioeconomic strata, reflecting disparities in resource availability and preventive care. Remission potential serves as an optimistic outcome predictor, particularly in early-stage type 2 diabetes responsive to . Achieving exceeding 15% of initial body weight through structured interventions correlates with sustained glycemic control and remission. The Remission Clinical Trial (DiRECT) demonstrated that such substantial weight reduction via a low-calorie diet led to remission in 36% of participants at 24 months, with durability directly tied to the magnitude of weight lost, highlighting reversal as a viable prognostic marker for select patients.

Long-Term Health Impacts

Type 2 diabetes significantly reduces overall , primarily due to its association with , with affected individuals experiencing an average reduction of 6 to 10 years compared to those without the condition. This shortfall is largely attributable to heightened risks of heart attacks, , and other cardiovascular events that accelerate mortality. For those with youth-onset type 2 diabetes, diagnosed before age 30, the impact is even more pronounced, potentially shortening life by 14 to 15 years or more, reflecting the cumulative burden of prolonged disease duration. The condition also imposes a substantial disability burden, particularly through complications like and , which impair daily functioning and independence. Neuropathy often leads to mobility issues, such as peripheral nerve damage causing pain, numbness, and balance problems that increase fall risk and limit . Vision loss from can severely affect , contributing to difficulties in reading, driving, and self-care, thereby fostering greater reliance on caregivers and reducing . Overall, people with type 2 diabetes face a 50% to 90% higher risk of compared to the general population, exacerbating morbidity over decades. Economically, type 2 diabetes entails high per-patient costs in the United States, averaging approximately $19,700 in annual medical expenditures as of 2022, with about $12,000 directly attributable to the disease and its management. Psychosocially, it is linked to elevated depression rates, ranging from 20% to 30% among patients—more than double the general population prevalence—due to chronic stress, symptom burden, and social isolation. These factors compound the long-term toll on mental health and financial stability. Influenced by predictors like glycemic control, these impacts can vary but underscore the need for sustained management. Recent data indicate positive shifts in outcomes through multifactorial interventions targeting blood sugar, , , and , which can extend life expectancy by up to 3 years as of 2024 and narrow gaps for well-managed cases. In patients achieving multiple targets, excess mortality risk is often eliminated, approaching that of non-diabetic individuals. These advances highlight the potential for improved with comprehensive care strategies.

Epidemiology

Global Burden and Prevalence

Type 2 diabetes represents the majority of diabetes cases globally, accounting for over 90% of the 589 million adults aged 20–79 years living with in 2024, or 11.1% of this population. Of these, an estimated 252 million cases are undiagnosed. This prevalence is projected to rise to 853 million by 2050, reflecting a significant escalation in the global scale of the condition. Regional variations highlight disparities in burden, with the highest prevalence in the at 17.6% in 2024, while records the lowest at 5.0%, though the latter region anticipates the steepest proportional increase of 142% by 2050 due to rapid and demographic shifts. The condition exerts profound strain on health systems, serving as a leading cause of blindness from and end-stage kidney failure from , contributing to over 2 million deaths in 2021 alone when combined with related and 3.4 million deaths in 2024. Economically, diabetes incurred a global health expenditure of $966 billion in 2021, surpassing $1 trillion in 2024 and underscoring its impact on resources and productivity. The global of type 2 diabetes has risen substantially since 2010, driven primarily by , aging, and factors, with the number of adults affected increasing from approximately 366 million in 2011 to 537 million in 2021, representing a roughly 47% rise in total cases. Age-standardized rates have also increased in many regions, with notable accelerations in low- and middle-income countries where the burden is growing most rapidly. This upward trend was further exacerbated by the , as infection with has been associated with a 60% higher of new-onset type 2 diabetes compared to non-infected individuals, particularly in the months following acute illness. Shifts in age distribution highlight emerging challenges, particularly among younger populations; the incidence of type 2 diabetes in children and adolescents has increased dramatically over the past two decades, with U.S. data showing a doubling of diagnoses from 9 per 100,000 youths in 2002–2003 to 17.9 per 100,000 in 2017–2018, largely attributed to rising rates. Globally, this trend is evident in high-risk groups, where youth-onset cases have surged exponentially, underscoring the need for early intervention strategies. Demographic disparities amplify these trends, with ethnic minorities facing 1.5 to 3 times higher prevalence rates than ; for instance, American Indian and Alaska Native adults have a diagnosed rate of 13.6%, nearly three times the rate for white adults. Geographic inequities also persist, as rural residents often experience 3–5% higher risk of new-onset type 2 compared to urban dwellers in certain U.S. regions, compounded by limited access to healthcare and higher levels. Projections indicate that low- and middle-income countries will shoulder the majority of the burden, with over 80% of the 853 million projected diabetes cases by 2050 occurring in these regions. This shift emphasizes the global south's disproportionate impact, where socioeconomic factors and underdiagnosis exacerbate inequities.

History

Early Recognition

The earliest known descriptions of a condition resembling diabetes mellitus appear in ancient medical texts, where excessive urination, or polyuria, was noted as a primary symptom. In ancient Egypt, the Ebers Papyrus, dating to approximately 1550 BCE, contains the first documented reference to this ailment, prescribing remedies for a disorder characterized by frequent and voluminous urination that "flows like a river." This observation, though lacking details on sweetness, laid foundational groundwork for recognizing metabolic disturbances involving fluid loss. Similarly, in ancient India, Ayurvedic texts such as the Sushruta Samhita, composed around 600 BCE, described madhumeha—literally "honey urine"—as a subtype of prameha (urinary disorders), highlighting not only polyuria and thirst but also the sweet taste of the urine due to its sugar content, which attracted ants and flies. Advancements in the 17th and 19th centuries shifted focus toward the physiological characteristics of the disease. In 1674, English physician , in his work Pharmaceutice Rationalis, differentiated diabetes from other polyuric conditions by tasting the urine and noting its "wonderfully sweet" quality, akin to honey or sugar, which he attributed to a failure in the body's processing of saccharine substances. This sensory observation marked a key step in identifying as a hallmark. Building on this, French physiologist Claude Bernard's experiments in the elucidated the pancreas's role; between 1849 and 1856, he demonstrated that pancreatic secretions aid carbohydrate digestion and that ligating pancreatic ducts led to atrophy and symptoms mimicking diabetes, including , thereby linking pancreatic dysfunction to the disease's . The 20th century brought clearer distinctions between diabetes subtypes, culminating in modern nomenclature. In 1936, British physician Harold Himsworth proposed the insulin resistance hypothesis in his seminal paper, classifying diabetes into "insulin-sensitive" (now type 1, prone to ketosis and requiring insulin) and "insulin-insensitive" (now type 2, characterized by resistance to insulin's effects despite adequate production), based on clinical responses to insulin therapy. This framework evolved terminologically in the mid-20th century, with "maturity-onset diabetes" emerging in the 1950s to describe the non-insulin-dependent form typically appearing in adults, contrasting with juvenile-onset cases. By the 1970s, amid growing evidence of etiological differences, the World Health Organization (WHO) formalized the classification in its reports, adopting "type 2 diabetes" to denote the insulin-resistant variant, a shift solidified in the 1980 WHO expert committee recommendations.

Key Developments in Understanding and Treatment

The discovery of insulin in 1921 by and Charles Best marked a pivotal advancement in , enabling the first effective treatment for severe and preventing fatalities from , though its application extended to type 2 diabetes as an injectable therapy for glycemic control. In the 1950s, the introduction of oral , beginning with in 1956, revolutionized treatment for type 2 diabetes by stimulating endogenous insulin secretion from pancreatic beta cells, offering a non-injectable alternative that improved patient adherence and accessibility. Metformin's revival in the 1990s, following its FDA approval in 1994, further transformed therapy; as a that reduces hepatic glucose production and enhances insulin sensitivity, it became a cornerstone due to its efficacy and low risk, with long-term benefits confirmed in subsequent studies. Landmark clinical trials in the late solidified evidence-based approaches. The Prospective Diabetes Study (UKPDS), reported in 1998, demonstrated that intensive glycemic control—targeting HbA1c below 7%—reduced microvascular complications by 25% in patients with type 2 diabetes, emphasizing the value of tight management with , insulin, or metformin despite initial macrovascular uncertainties. Similarly, the Diabetes Prevention Program (DPP) in 2002 showed that lifestyle interventions, including 7% and 150 minutes of weekly , prevented or delayed type 2 diabetes onset by 58% in high-risk individuals, outperforming metformin (31% reduction) and validating preventive strategies over pharmacological alone. Molecular insights deepened understanding of type 2 diabetes . The 1994 identification of , a hormone encoded by the ob that regulates balance and via hypothalamic signaling, highlighted adipose tissue's role in and obesity-related diabetes, though therapeutic applications proved limited due to leptin resistance in most patients. Building on hormone research, the recognition of (GLP-1)'s glucose-dependent insulin secretion and suppression led to the development of GLP-1 receptor agonists; , approved in 2005 as the first such agent, offered dual glycemic and weight-loss benefits, with subsequent drugs like expanding options for cardiovascular risk reduction. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, first approved in the early 2010s (dapagliflozin in Europe in 2012 and canagliflozin in the United States in 2013), promote glucose excretion via the kidneys and demonstrated cardiovascular and renal benefits in trials like EMPA-REG OUTCOME (2015). By 2025, the (ADA) Standards of Care incorporated SGLT2 inhibitors as a foundational for type 2 diabetes, prioritizing their use for cardiovascular and renal protection in patients with established or high-risk , atherosclerotic , or , independent of baseline glycemic control, based on robust trial evidence of reduced major adverse events.

Research

Emerging Pharmacological and Device Innovations

Recent advancements in pharmacological therapies for type 2 diabetes have focused on incretin-based agents that enhance glycemic control and promote substantial . Dual agonists targeting both glucose-dependent insulinotropic polypeptide (GIP) and (GLP-1) receptors, such as , have demonstrated superior efficacy in clinical trials, achieving up to 20.9% body weight reduction over 72 weeks in a dose-dependent manner among patients with type 2 diabetes. also significantly lowers HbA1c levels and improves metabolic outcomes compared to other GLP-1 agonists like . Building on these, triple agonists that additionally activate receptors, such as , are in phase 3 trials and show promising placebo-adjusted weight reductions in participants with type 2 diabetes, potentially offering enhanced energy expenditure and insulin sensitivity. Device innovations are expanding automated management options beyond type 1 diabetes, with closed-loop insulin delivery systems—often termed artificial pancreas—now being adapted for type 2 diabetes patients requiring insulin therapy. These hybrid systems integrate continuous glucose monitoring (CGM) with algorithm-driven insulin pumps to automate dosing, improving time in target glucose range in real-world settings over one year of use. A randomized crossover confirmed the feasibility of fully automated closed-loop systems in adults with type 2 diabetes, reducing without increasing risk. Furthermore, CGM devices enhanced by (AI) enable for glucose fluctuations, using multimodal data to forecast spikes and lows, thereby supporting proactive interventions in type 2 diabetes management. AI integration with CGM has shown potential to identify diabetes subtypes and personalize care through real-time . Efforts to develop disease-modifying therapies aim to preserve beta-cell function and address underlying . (AMPK) activators, which regulate cellular , are under investigation for their role in reducing beta-cell stress and improving insulin in type 2 diabetes; preclinical and early indicate they enhance in and promote beta-cell rest. Natural products and novel compounds targeting the AMPK pathway have demonstrated potential to mitigate and lipid dysregulation, key contributors to beta-cell dysfunction. Oral insulin formulations remain in development, with preclinical and phase 2 trials exploring their potential to control postprandial glucose and preserve beta-cell function in type 2 diabetes without injectable delivery. These approaches seek to slow disease progression by targeting beta-cell preservation. Non-pharmacological device-based innovations, such as duodenal mucosal resurfacing (DMR) via , represent a novel strategy for achieving glycemic remission in type 2 diabetes by resurfacing the duodenal lining to normalize nutrient sensing and insulin sensitivity. Clinical studies have reported sustained improvements in HbA1c and hepatic indices up to 24 months post-procedure, with some patients eliminating insulin use. In 2025 trials, DMR combined with GLP-1 agonists has shown enhanced weight maintenance and metabolic benefits three months after discontinuation of , addressing a gap in non-stem cell interventions for potential disease remission. Challenges include optimizing procedural safety and long-term durability, but DMR offers a minimally invasive alternative to traditional therapies.

Precision Medicine and Genetic Advances

Precision medicine in type 2 diabetes leverages genetic and data to tailor treatments, improving outcomes by accounting for individual variability in drug response and disease progression. has identified key genetic variants that influence therapeutic efficacy, enabling more selection. For instance, the TCF7L2 rs7903146 variant, a major genetic for type 2 diabetes, is associated with reduced glycemic response to metformin in newly diagnosed patients, with risk allele carriers showing poorer improvements in markers and HbA1c levels after treatment initiation. This finding supports for TCF7L2 to guide alternative therapies, such as or GLP-1 receptor agonists, in carriers to optimize glycemic control and minimize ineffective treatments. Biomarker-based tools further advance personalization by predicting responses to specific therapies, reducing reliance on trial-and-error approaches. Low beta-cell function markers, including C-peptide levels and islet autoantibodies, reliably forecast poor glycemic response to GLP-1 receptor agonists (GLP-1RAs), allowing clinicians to prioritize these agents for s with preserved beta-cell capacity. Recent pharmacogenomic studies have identified genetic variants that modulate GLP-1RA , with genome-wide association analyses revealing predictors for stratification. These low-cost clinical and genetic biomarkers, increasingly integrated into routine care as of 2025, facilitate cost-effective personalization without extensive sequencing. Gene therapy prospects offer transformative potential by directly addressing genetic underpinnings of type 2 diabetes. Preclinical models using CRISPR-Cas9 have successfully edited type 2 diabetes risk loci, such as TCF7L2, in human pancreatic lines to restore insulin secretion and mitigate impaired glucose-stimulated responses, demonstrating feasibility for correcting beta-cell dysfunction. Similarly, stem cell-derived s, generated from induced pluripotent stem cells, have entered early clinical stages, primarily for , with phase 1/2 trials showing insulin independence in select T1D patients; similar approaches are under preclinical investigation for type 2 diabetes to restore beta-cell function. These approaches hold promise for durable beta-cell replenishment, though challenges like immune rejection persist. Integration of and enhances precision through polygenic risk scores (PRS) for proactive intervention. AI-driven PRS models, incorporating thousands of genetic variants, accurately stratify type 2 diabetes risk across ancestries, enabling early lifestyle or pharmacological interventions that delay onset by identifying high-risk individuals years in advance. A 2025 multi-ancestry analysis of over 880,000 participants validated a PRS that predicts not only incidence but also complication risks, with context-dependent performance highlighting the need for population-specific tuning. However, equity concerns arise in diverse populations, as PRS derived primarily from European cohorts underperform in non-European groups, potentially exacerbating disparities without inclusive genomic data. Efforts to broaden ancestry representation in AI models are underway to ensure equitable application.

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