Insulin resistance and its treatment by thiazolidinediones

Insulin resistance is a change in physiologic regulation such that a fixed dose of insulin causes less of an effect on glucose metabolism than occurs in normal individuals. The normal compensatory response to insulin resistan ce is an increase in insulin secretion that results in hyperinsulinemia. If the hyperinsulinemia is sufficient to overcome the insulin resistance, glu cose regulation remains normal; if not, type 2 diabetes ensues. Associated with insulin resistance, however, is a cluster of other metabolic abnormali ties involving body fat distribution, lipid metabolism, thrombosis and fibr inolysis, blood pressure regulation, and endothelial cell function. This cl uster of abnormalities is referred to as the insulin resistance syndrome or the metabolic syndrome. II is causally related not only to the development of type 2 diabetes but also to cardiovascular disease. A major unresolved issue is whether there is a single underlying cause of this syndrome and, i f so, what might it be? Several promising hypotheses have been proposed. Th ere are some data to support the hypothesis that fetal malnutrition imprint s on metabolic regulatory processes that, in later adult life, predispose t o the development of the insulin resistance syndrome. Visceral obesity also has been a candidate for the cause of the syndrome. Whatever mechanism is ultimately found to be responsible, it will undoubtedly have both genetic a nd environmental components. Among the biochemical mediators that are likel y to be responsible for the interference with insulin's effects on intermed iary metabolism are free fatty acids and other products from adipose tissue . Recent data suggest that the substances stimulate serine phosphorylation of molecules involved in the initial steps of insulin action, thereby block ing the ability of these molecules to be tyrosine phosphorylated and initia te the subsequent steps of the insulin action cascade. The thiazolidinediones are a new class of agents that have been developed t o treat type 2 diabetic patients, These drugs act as peroxisome proliferato r-activated receptor gamma (PPAR gamma) agonists Following their binding to the receptor, the heterodimer molecule that contains the binding site is a ctivated. The activated complex binds to the response elements of specific genes that regulate molecules that effect insulin action and lipid metaboli sm These genes are either activated or inhibited. Specifically, the thiazol idinediones improve insulin action and decrease insulin resistance. The exa ct mechanism by which these agents decrease insulin resistance is not clear but they do decrease the elevated free fatty acid levels present in insuli n-resistant patients and they appear to change the body distribution of adi pose tissue. Treatment of insulin-resistant type 2 diabetic patients with t hiazolidinediones not only improves glycemic control and decreases insulin resistance, it also improves many of the abnormalities that are part of the insulin resistance syndrome.