Application of New Pathogenesis on the Drug Treatment of Diabetes

Kim, Young Seol

Abstract

Patients with type 2 diabetes mellitus are associated with insulin resistance and/or impaired insulin secretion. Previous observations indicate that patients with type 2 diabetes tend to have an impaired insulin response after a glycemic load. Recently it has been reported that hyperglycemia after a glucose load is itself a risk factor for the development of cardiovascular complications in the absence of elevated fasting plasma glucose. There are several points to be addressed for the application of new pathogenesis to diabetes treatment. One of them is the association between postprandial hyperglycemia and mortality from cardiovascular diseases. For the management of postprandial hyperglycemia inhibitors ofglucosidase and rapidacting insulin secretagogues have beneficial effects. Alphaglucosidase inhibitors in combination with diet therapy ameliorate insulin resistance and reduce the blood sugar level. A rapidly acting insulin secretagogue, such as repaglinide, lowers postprandial glucose levels without asignificant gain of body weight. These drugs may protect pancreaticcells from postprandial glucose toxicity and prevent the progression of diabetes. Both metformin and thiazolidinedione derivative (TZDs) improve insulin resistance, the major pathogenetic background of type 2 diabetes, and decrease blood glucose levels without stimulating, insulin secretion. Metformin inhibits glucose output from the liver, while TZDs increase glucose utilization in the peripheral tissues. In addition, it has been indicated that these agents ameliorate the metabolic syndrome beyond lowering the glucose level. Molecular targets for these agents have recentl been revealed ; AMPactivated protein kinase for metfOrnin and adiponectin, while PPAR for TZDs that induce gene expression of adipocyte glycerol kinase and adiponectin. Insulin-sensitizing agents are clinically useful for obese diabetic patients with insulin resistance. However, periodical examinations are necessary to avoid serious adverse effects such as lactic acidosis, although rare, by metformin and liver injury by TZDs. The advantage of insulin therapy for type 2 diabetic patients is still controversial. However, in many intervention studies, the intensive insulin therapy provided promising effects on preventing cardiovascular diseases. Moreover, insulin has been shown to stimulate nitric oxide production by cultured endothelial cells and to suppress the expression of intercellular adhesion molecule1 at least in vitro. In view of this antiinflammatory effect, longterm insulin therapy may potentially have an antiatherogenic effect.