type 2 diabetes type 2 diabetes type 2 diabetes, 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, and unexplained weight loss. symptoms may also include increased hunger, feeling tired, and sores (wounds) that do not heal. often symptoms come on slowly. 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. the sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon. type 2 diabetesother namesdiabetes mellitus type 2;adult-onset diabetes;noninsulin-dependent diabetes mellitus (niddm)a blue circle is the universal symbol of diabetespronunciation/daɪəbiːtəs/ specialtyendocrinologysymptomsincreased thirst, frequent urination, unexplained weight loss, increased hungercomplicationshyperosmolar hyperglycemic state, diabetic ketoacidosis, heart disease, strokes, diabetic retinopathy, kidney failure, amputationsusual onsetmiddle or older agedurationlong termcausesobesity, lack of exercise, geneticsdiagnostic methodblood testpreventionmaintaining normal weight, exercising, healthy diettreatmentdietary changes, metformin, insulin, bariatric surgeryprognosis10 year shorter life expectancyfrequency392 million (2015) 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. 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. 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 a normal weight, exercising regularly, and eating a healthy diet (high in fruits and vegetables and low in sugar and saturated fats). 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 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 c. 1500 bce. the importance of insulin in the disease was determined in the 1920s. signs and symptoms 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. 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 main article: complications of diabetes 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, 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. 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, with one proposed mechanism being that of dna methylation. the intestinal bacteria prevotella copri and bacteroides vulgatus have been connected with type 2 diabetes. lifestyle 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. 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. a 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 fats 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. persistent organic pollutants may also play a role. genetics main article: genetic causes of type 2 diabetes 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. epigenetics epigenetic regulation occurs at multiple levels including (1) direct methylation of cytosine and adenine residues in dna, (2) covalent modification of histone proteins in chromatin, and (3) action of non coding micrornas (for other examples, see wikipedia article “epigenetics”). on november 17-19, 2017, the american diabetes association held a research symposium entitled “epigenetics and epigenomics: implications for diabetes and obesity.” as a result of this symposium, an overview of the state of the field was presented in which it was noted that over 1,000 research articles have been published that address the intersection of diabetes and epigenetics or epigenomics. the current state of knowledge in this field is addressed the wikipedia article “epigenetics of diabetes type 2.” 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. but when type 2 diabetes has become manifest, a type 2 diabetic will have lost about half of their beta cells. fatty acids in the beta cells activate foxo1, resulting in apoptosis of the 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. new evidence also points to a role of a brain region called the hypothalamus in the development of insulin resistance. for one thing, a gene called dusp8 is linked with an increased risk for diabetes. 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. 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. 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. 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. 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. 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. a