Type two 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. Common symptoms include increased thirst, frequent urination, fatigue and unexplained weight loss. Other symptoms include increased hunger, having a sensation of pins and needles, and sores (wounds) that heal slowly. Symptoms often develop slowly. 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. A sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.

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

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

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).

Treatment involves exercise and dietary changes. If blood sugar levels are not adequately lowered, the medication metformin is typically recommended. Many people may eventually also require insulin injections. 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. Bariatric surgery often improves diabetes in those who are obese.

Rates of type 2 diabetes have increased markedly since 1960 in parallel with obesity. As of 2015, there were approximately 392 million people diagnosed with the disease compared to around 30 million in 1985. Typically, it begins in middle or older age, although rates of type 2 diabetes are increasing in young people. Type 2 diabetes is associated with a ten-year-shorter life expectancy. Diabetes was one of the first diseases ever described, dating back to an Egyptian manuscript from   BCE. 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. The importance of insulin in the disease was determined in the 1920s.

Signs and symptoms

The classic symptoms of diabetes are frequent urination (polyuria), increased thirst ( polydipsia), increased hunger (polyphagia), and weight loss. Other symptoms that are commonly present at diagnosis include a history of blurred vision, itchiness, peripheral neuropathy, recurrent vaginal infections, and fatigue. Other symptoms may include loss of taste. Many people, however, have no symptoms during the first few years and are diagnosed on routine testing. 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).

Complications

Type 2 diabetes is typically a chronic disease associated with a ten-year-shorter life expectancy. 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. In the developed world, and increasingly elsewhere, type 2 diabetes is the largest cause of nontraumatic blindness and kidney failure. 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. Other complications include hyperpigmentation of skin ( acanthosis nigricans), sexual dysfunction, diabetic ketoacidosis, and frequent infections. There is also an association between type 2 diabetes and mild hearing loss.

Causes

The development of type 2 diabetes is caused by a combination of lifestyle and genetic factors. 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. Generous consumption of alcohol is also a risk factor. Obesity is more common in women than men in many parts of Africa. The nutritional status of a mother during fetal development may also play a role.

Lifestyle

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. 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. Among those who are not obese, a high waist–hip ratio is often present. Smoking appears to increase the risk of type 2 diabetes. Lack of sleep has also been linked to type 2 diabetes. Laboratory studies have linked short-term sleep deprivations to changes in glucose metabolism, nervous system activity, or hormonal factors that may lead to diabetes.

Dietary factors also influence the risk of developing type 2 diabetes. Consumption of sugar-sweetened drinks in excess is associated with an increased risk. 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. Eating a lot of white rice appears to play a role in increasing risk. A lack of exercise is believed to cause 7% of cases. Sedentary lifestyle is another risk factor. Persistent organic pollutants may also play a role.

Genetics

Most cases of diabetes involve many genes, with each being a small contributor to an increased probability of becoming a type 2 diabetic. The proportion of diabetes that is inherited is estimated at 72%. More than 36 genes and 80 single nucleotide polymorphisms (SNPs) had been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total heritable component of the disease. 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. Most of the genes linked to diabetes are involved in pancreatic beta cell functions.

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"). These include maturity onset diabetes of the young (MODY), Donohue syndrome, and Rabson–Mendenhall syndrome, among others. Maturity onset diabetes of the young constitute 1–5% of all cases of diabetes in young people.

Epigenetic regulation may have a role in type 2 diabetes.

Medical conditions

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

Pathophysiology

Type 2 diabetes is due to insufficient insulin production from beta cells in the setting of insulin resistance. 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. In the liver, insulin normally suppresses glucose release. However, in the setting of insulin resistance, the liver inappropriately releases glucose into the blood. 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.

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. However, not all people with insulin resistance develop diabetes since an impairment of insulin secretion by pancreatic beta cells is also required.

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. But when type 2 diabetes has become manifest, the person will have lost about half of their beta cells.

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.

Diagnosis

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:
* fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dL)
:or
* glucose tolerance test with two hours after the oral dose a plasma glucose ≥ 11.1 mmol/L (200 mg/dL)
A random blood sugar of greater than 11.1 mmol/L (200 mg/dL) in association with typical symptoms or a glycated hemoglobin (HbA_1c) of ≥ 48 mmol/mol (≥ 6.5 DCCT %) is another method of diagnosing diabetes. 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 HbA_1c threshold of ≥ 48 mmol/mol (≥ 6.5 DCCT %) should be used to diagnose diabetes. This recommendation was adopted by the American Diabetes Association in 2010. Positive tests should be repeated unless the person presents with typical symptoms and blood sugar >11.1 mmol/L (>200 mg/dL).

Threshold for diagnosis of diabetes is based on the relationship between results of glucose tolerance tests, fasting glucose or HbA_1c and complications such as retinal problems. A fasting or random blood sugar is preferred over the glucose tolerance test, as they are more convenient for people. HbA_1c 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. It is estimated that 20% of people with diabetes in the United States do not realize that they have the disease.

Type 2 diabetes is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. 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. Type 1 and type 2 diabetes can typically be distinguished based on the presenting circumstances. 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, with C-peptide levels normal or high in type 2 diabetes, but low in type 1 diabetes.

Screening

Universal screening for diabetes in people without risk factors or symptoms is not recommended.

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. For people of Asian descent, screening is recommended if they have a BMI over 23. 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. Screening can be repeated every 3 years.

The American Diabetes Association (ADA) recommended in 2024 screening in all adults from the age of 35 years. 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. ADA recommends repeat screening every 3 years at minimum. ADA recommends yearly tests in people with prediabetes. People with previous gestational diabetes or pancreatitis are also recommended screening.

There is no evidence that screening changes the risk of death and any benefit of screening on adverse effects, incidence of type 2 diabetes, HbA_1c or socioeconomic effects are not clear.

In the UK, NICE

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