Metabolic and vascular effects of the thiazolidinedione troglitazone

Type 2 diabetes affects more than 16 million people in the U.S. and some 200 million people around the world, Besides causing disabling microvascular complications like retinopathy, nephropathy, and neuropathy, the disease is also associated with accelerated atherosclerosis and premature cardiovascular morbidity and mortality. This increased incidence of atherosclerotic disease (myocardial infarction, stroke, and peripheral vascular disease) is intricately associated with insulin resistance, which is a major pathophysiologic abnormality in type 2 diabetes. There is growing evidence that the insulin resistance of type 2 diabetes contributes to the metabolic abnormalities of hyperglycemia, hyperinsulinemia, dyslipidemia, hypertension, and hype which lead to accelerated cardiovascular morbidity and mortality. Collectively, this constellation of abnormalities has been termed the "cardiovascular dysmetabolic syndrome." Thiazolidinediones are oral antidiabetic agents that are "insulin sensitizers" and exert direct effects on the mechanisms of insulin resistance. Troglitazone is the first of these compounds to be available for use in humans. Its mechanism of action involves direct insulinomimetic effects as well as insulin-sensitizing actions, through binding to intracellular nuclear receptors (peroxisome proliferator-activator receptor-gamma) and regulation of expression of numerous genes that affect glucose and lipid metabolism. Troglitazone not only results in improved insulin sensitivity and glycemic control with reduced insulin requirements, but also has favorable effects on other components of cardiovascular dysmetabolic syndrome, including hypertension and dyslipidemia. These insulin sensitizing effects have the potential to prevent or delay premature atherosclerotic cardiovascular disease, morbidity, and death.