Four main elements characterize the pathophysiology of this disease;insulin resistance, cell dysfunction, dysregulated hepatic glucose production (HGP), and abnormal intestinal glucose absorption. In the preclinical phase, the pancreatic cells compensate for a genetically predetermined peripheral in-sulin resistance (in muscle and fat) by producing more insulin (hyperinsutinemia) to maintain euglycemia. Some patients are identified at this stage while they are clinically asymptomatic. With time, the cells gradually fail to compensate for the pro-gressive increase in insulin resistance (stage of impaired glucose tolerance), and eventually hyperglycemia becomes clinically manifest as diabetes mellitus. Insulin secretion is still present, but not in the hyperinsulinemic range, and the result is relative insulin deficiency. Classically, one notes early loss of the first phase of glucose-stimulated insulin secretion (peaking at 10 minutes), with subsequent gradual loss of the second phase (starting 30 minutes after glucose stimulus and peaking at 60 minutes. ). Other features of Q-cell dysfunction include dys-rhythmic pulsatile insulin secretion, defective glucose potentia-tion of nonglucose insulin secretagogues [ the incretins: glu-cose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)], increased proinsulinto-insulin ratio (from defective protease activity), accumulation of islet amy-loid polypeptide, increased glucagon secretion from islet cells, and "glucotoxicity. " Glucotoxicity refers to the effect of chronic hyperglycemia in decreasing insulin secretion (through impaired cell sensitivity) and insulin activity (by increasing insulin resistance and insulin receptor tyrosine kinase activity). Glucotoxicity is a function of the duration and magnitude of the hyperglycemia and contributes to the progressive worsen-ing of hyperglycemia. Elevated free fatty acid levels, the result of abnormal lipid metabolism in these patients, also have a tox-ic effect on cells (lipotoxicity) and contribute further to the failure of these cells.

Before the appearance of fasting hyperglycemia, in the latter stages of hyperinsulinemia, one can usually show an ab-normality in postprandial glucose metabolism (impaired glucose tolerance) that is not manifest clinically. The relative contri-butions of insulin resistance and insulin secretory defect to the pathogenesis in individual patients vary, with insulin resistance playing a dominant role in most patients who are obese (0¡«80 % to 90 % in the United States) and failure of insulin secre-tion being more important in patients of normal weight.

The third contributing factor to hyperglycemia in type 2 diabetes is the excessive HGP (25% to 50% higher than nor-mal) that results from inadequate suppression of hepatic gluco-neogenesis, as a result of resistance of the liver to the inhibito-ry effects of insulin. Postprandial HGP is markedly increased, with a variable increase in the basal rate. Within the diabetic liver, decreased glycogen synthesis and increased fat synthesis also occur.

Hyperglycemia, with or without autonomic nerve involve-ment, may contribute to gastric dysmotility (symptomatic or not) and alterations in the rate of glucose absorption (usually increased), with consequent exacerbation of hyperglycemia, which results in a vicious cycle.

Amylin, a peptide hormone cosecreted with insulin from the pancreatic cells, is thought to influence postprandial glycemic control by slowing the rate of gastric emptying and thus carbohydrate absorption and by supressing glucagon secre-tion. With cell destruction (type 1), atrophy or "exhaus-tion" (type 2), the secretion of insulin and of amylin declines.

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