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Type 2 diabetes

Type 2 diabetes (T2D), 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] Symptoms may also include increased hunger, having a sensation of pins and needles, and sores (wounds) that do not heal.[3] Often symptoms come on slowly.[6] Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations.[1] The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.[4][5]

Type 2 diabetes

Diabetes mellitus type 2;
adult-onset diabetes;[1]
noninsulin-dependent diabetes mellitus (NIDDM)

Middle or older age[6]

Long term[6]

Obesity, lack of exercise, genetics[1][6]

Maintaining normal weight, exercising, healthy diet[1]

10 year shorter life expectancy[10]

392 million (2015)[11]

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] In type 1 diabetes there is a lower total level of insulin to control blood glucose, due to an autoimmune induced loss of insulin-producing beta cells in the pancreas.[12][13] 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 fats).[1] Treatment involves exercise and dietary changes.[1] If blood sugar levels are not adequately lowered, the medication metformin is typically recommended.[7][14] 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.[15] Bariatric surgery often improves diabetes in those who are obese.[8][16]


Rates of type 2 diabetes have increased markedly since 1960 in parallel with obesity.[17] As of 2015 there were approximately 392 million people diagnosed with the disease compared to around 30 million in 1985.[11][18] Typically it begins in middle or older age,[6] although rates of type 2 diabetes are increasing in young people.[19][20] 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.[21] The importance of insulin in the disease was determined in the 1920s.[22]

Pathophysiology

Type 2 diabetes is due to insufficient insulin production from beta cells in the setting of insulin resistance.[13] 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.[56] 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.[13]


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.[13]


In the early stages of insulin resistance, the mass of beta cells expands, increasing the output of insulin to compensate for the insulin insensitivity.[57] But when type 2 diabetes has become manifest, a type 2 diabetic will have lost about half of their beta cells.[57] Fatty acids in the beta cells activate FOXO1, resulting in apoptosis of the beta cells.[57]


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.[58] New evidence also points to a role of a brain region called the hypothalamus in the development of insulin resistance. A gene called Dusp8 is linked with an increased risk for diabetes.[59] This gene codes for a protein that regulates neuronal signaling in the hypothalamus. Also, infusions into the hypothalamus of a hormone called leptin normalize blood glucose and diminish insulin resistance in diabetic animals.[60] Activation of hypothalamic cells by leptin has an important role in maintaining normal levels of blood glucose. Thus, both the endocrine cells of the pancreas AND cells in the hypothalamus may have a role in the etiology of type 2 diabetes.


Hypothalamic cells regulate blood glucose via projections to the autonomic nervous system. Autonomic innervation of liver and muscle cells stimulates an increased uptake of glucose. In diabetic humans, the control of blood glucose by the autonomic nervous system is abnormal.[61] Leptin-sensitive, glucose regulating neurons become resistant to leptin during aging or during exposure to a high-fat diet. These leptin-resistant neurons fail to restrain food intake, obesity, and blood glucose. The reasons for this lowered responsiveness to leptin are uncertain and are part of the puzzle of the causes of type 2 diabetes.[62]


Blood glucose levels can also be normalized in diabetic rodents by a single intrahypothalamic infusion of Fibroblast Growth Factor 1 (FGF1), an effect that persists for months even in severely diabetic animals. This remarkable cure of diabetes is accomplished by a stimulation of accessory brain cells called astrocytes.[63][64] Hypothalamic astrocytes that produce Fatty Acid Binding Protein 7 (FABP7) are targets of FGF1; these cells are also in close contact with leptin-sensitive neurons, influence their function, and regulate leptin sensitivity.[65][66] An abnormal function of FABP7+ astrocytes thus may contribute to the resistance to leptin and insulin that appear during aging and during exposure to high-fat diets.


During aging, FABP7+ astrocytes develop cytoplasmic granules derived from degenerating mitochondria. This mitochondrial degeneration is partly due to the oxidative stress of the heightened amounts of fatty acids that are taken up by these cells and oxidized within mitochondria.[67][68] A pathological degeneration of mitochondria in these cells may compromise their normal functions and contribute to abnormalities in the control of blood glucose by the hypothalamus.

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

The World Health Organization definition of diabetes (both type 1 and type 2) is for a single raised glucose reading with symptoms, otherwise raised values on two occasions, of either:[71]


A random blood sugar of greater than 11.1 mmol/L (200 mg/dL) in association with typical symptoms[23] 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 threshold of ≥ 48 mmol/mol (≥ 6.5 DCCT %) should be used to diagnose diabetes.[72] This recommendation was adopted by the American Diabetes Association in 2010.[73] Positive tests should be repeated unless the person presents with typical symptoms and blood sugars >11.1 mmol/L (>200 mg/dL).[72]


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.[75] 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.[76] 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.[13] Type 1 and type 2 diabetes can typically be distinguished based on the presenting circumstances.[72] 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,[77] with C-peptide levels normal or high in type 2 diabetes, but low in type 1 diabetes.[78]

Screening

Universal screening for diabetes in people without risk factors or symptoms is not recommended.[79][80] Screening is recommended by the World Health Organization, the United States Preventive Services Task Force (USPSTF), and the American Diabetes Association for high-risk adults.[81][82][83] Risk factors considered by the USPSTF include adults over 35 years old who are overweight or have obesity and adults without symptoms whose blood pressure is greater than 135/80 mmHg.[84][81] For those whose blood pressure is less, the evidence is insufficient to recommend for or against screening.[84] The American Diabetes Society recommends screening for adults with a body mass index (BMI) over 25.[83] For people of Asian descent, screening is recommended if they have a BMI over 23.[83] Other high risk groups include people with a first degree relative with diabetes; some ethnic groups, including Hispanics, African-Americans, and Native-Americans; a history of gestational diabetes; polycystic ovary syndrome; excess weight; and conditions associated with metabolic syndrome.[23] 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.[80][85]


In the UK, NICE guidelines suggest taking action to prevent diabetes for people with a body mass index (BMI) of 30 or more.[86] For people of Black African, African-Caribbean, South Asian and Chinese descent the recommendation to start prevention starts at the BMI of 27,5.[86] 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.[87][88]

Research

Researchers developed the Diabetes Severity Score (DISSCO), a tool that might better than the standard blood test at identify if a person's condition is declining.[167][168] It uses a computer algorithm to analyse data from anonymised electronic patient records and produces a score based on 34 indicators.[169][170]

Kahn CR, Ferris HA, O'Neill BT (2020). "Pathophysiology of Type 1 Diabetes Mellitus". Williams Textbook of Endocrinology (14 ed.). Elsevier. pp. 1349–1370.

International Diabetes Federation (2021). (PDF) (10 ed.). International Diabetes Federation. ISBN 978-2-930229-98-0. Retrieved 18 March 2022.

IDF Diabetes Atlas

IDF Diabetes Atlas 2015

Archived 2010-02-21 at the Wayback Machine

National Diabetes Information Clearinghouse

Centers for Disease Control (Endocrine pathology)

ADA's Standards of Medical Care in Diabetes 2019