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Type 2 DM is one of the most commonly seen genetic disorders, yet its exact mode of inheritance has remained elusive and is likely to be polygenic. The rate of concordance is high in identical twins, but is much lower in non-identical dizygotic twins. Patients with type 2 DM show an increased frequency of diabetes in other family members compared with the non-diabetic population. Only a small proportion of patients (< 3%) with type 2 DM have a monogenic disorder. No unequivocal, reproducible associations with type 2 diabetes have been found for candidate genes studied so far. Furthermore, no genome scans in type 2 DM have identified any region with an effect as large as the HLA region in type 1 DM.

It has long been recognized that the hyperglycemia of type 2 DM results from a defect in both insulin secretion and insulin action

Pathogenesis of type 2 DM

Subjects with type 2 DM exhibit abnormalities in glucose homeostasis owing to impaired insulin secretion, insulin resistance in muscle, liver and adipocytes and abnormalities of splanchnic glucose uptake.

Insulin secretion in type 2 DM

Impaired insulin secretion is a universal finding in patients with type 2 diabetes. In the early stages of type 2 DM insulin resistance can be compensated for by an increase in insulin secretion leading to normal glucose tolerance. With increasing insulin resistance, the fasting plasma glucose will rise, accompanied by an increase in fasting plasma insulin levels, until a fasting plasma glucose level is reached when the p-cell is unable to maintain its elevated rate of insulin secretion at which point the fasting plasma insulin declines sharply. Hepatic glucose production will begin to rise. When fasting plasma glucose reaches high levels, the plasma insulin response to a glucose challenge is markedly blunted. Although fasting insulin levels remain elevated, postprandial insulin and C-peptide secretory rates are decreased. This natural history of type 2 diabetes starting from normal glucose tolerance, followed by insulin resistance, compensatory hyperinsulinemia and then by progression to impaired glucose tolerance and overt diabetes has been documented in a variety of populations.

Type 2 DM is characterized by loss of the firstphase insulin response to an intravenous glucose load, although this abnormality may be acquired secondary to glucotoxicity. Loss of the first-phase insulin response is important as this early quick insulin secretion primes insulin target tissues, especially the liver.

There may be multiple possible causes of the impaired insulin secretion in type 2 DM with several abnormalities having been shown to disturb the delicate balance between islet neogenesis and apoptosis. Studies in first-degree relatives of patients with type 2 diabetes and in twins have provided strong evidence for the genetic basis of abnormal p-cell function. Acquired defects in type 2 diabetes may lead to impairment of insulin secretion. Clinical studies in man, and animal studies, have supported the concept of glucotoxicity, whereby an elevation in plasma glucose levels, in the presence of a reduced p-cell mass, can lead to a major impairment in insulin secretion. Lipotoxicity has also been implicated as an acquired cause of impaired p-cell function. Patients with type 2 DM exhibit a reduced response of the incretin glucagon-like peptide (GLP)-1 in response to oral glucose, while GLP-1 administration enhances the postprandial insulin secretory response and may restore near-normal glycemia.

Amyloid deposits (islet amyloid polypeptide (IAPP)) or amylin in the pancreas are frequently observed in patients with type 2 diabetes and have been implicated as a cause of progressive p-cell failure. However, definitive evidence that amylin contributes to p-cell dysfunction in humans is lacking.

Insulin resistance in type 2 DM

Insulin resistance is a characteristic feature of both lean and obese individuals with type 2 diabetes. As indicated above, in the fasting state, plasma insulin levels are increased in patients with type 2 diabetes. Since hyperinsulinemia is a potent inhibitor of hepatic glucose production and an excessive rate of hepatic glucose production is the major abnormality responsible for the elevated fasting plasma glucose in type 2 diabetes, it follows that there must be hepatic resistance to the action of insulin. The liver is also resistant to the inhibitory effect of hyperglycemia on hepatic glucose output. Most of the increase in hepatic glucose production can be accounted for by an increase in hepatic gluconeogenesis.

Muscle is the major site of insulin-stimulated glucose disposal in humans. Muscle represents the primary site of insulin resistance in type 2 diabetic subjects leading to a marked blunting of glucose uptake into peripheral muscle. In contrast, splanchnic tissues, like the brain, are relatively insensitive to insulin with respect to stimulation of glucose uptake. Following glucose ingestion both impaired suppression of hepatic glucose production and decreased muscle glucose uptake are responsible for the observed glucose intolerance leading to hyperglycemia.

There is a dynamic relationship between insulin resistance and impaired insulin secretion. Insulin resistance is an early and characteristic feature of type 2 diabetes in high-risk populations. Overt diabetes develops only when the p-cells are unable to increase sufficiently their insulin output to compensate for the defect in insulin action (insulin resistance).

Insulin resistance in type 2 diabetes is primarily due to post-binding defects in insulin action. Diminished insulin binding is modest and secondary to down-regulation of the insulin receptor by chronic hyperglycemia. Post-binding defects that have been recognized include reduced insulin receptor tyrosine kinase activity, insulin signal transduction abnormalities, decreased glucose transport, diminished glucose phosphorylation and impaired glycogen synthase activity. Quantitatively, impaired glycogen synthesis represents the major abnormality responsible for insulin resistance in type 2 diabetic patients.

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