Insulin, Insulin Resistance, and Platelet Signaling in Diabetes

Abstract

Insulin resistance and the metabolic syndrome are associated with a prothrombotic state that contributes to the pathogenesis and progression of the vascular complications of type 2 diabetes. Development of the disease is also linked to the loss of the direct antiplatelet effect of insulin and platelets obtained from patients with diabetes who are hyperreactive (i.e., demonstrate increased adhesiveness and exaggerated aggregation and thrombus generation). Conditions linked to insulin resistance and development of type 2 diabetes are generally associated with redox stress within the vasculature that, in turn, affects platelet function. There are numerous platelet signaling events that are sensitive to changes in the vascular balance of nitric oxide (NO) and oxygen-derived free radical generation; however, recent studies have highlighted the link among platelet hyperreactivity and oxidative modifications in Ca2+-ATPase activity and Ca2+ homeostasis, altered surface expression of glycoprotein receptors and adhesive proteins on the platelet surface, and increased binding of fibrinogen (rev. in (1). ### Effects of insulin on platelet function A direct antiplatelet effect of insulin has been demonstrated by many groups; although we and others have observed an insulin-induced attenuation of the thrombin-induced Ca2+ response and platelet aggregation as well as the release of ADP (2,3), reports from groups assessing the same responses are inconsistent. Part of the controversy may be attributed to the fact that responses to insulin are highly heterogeneous; indeed, clear populations of “responders” and “nonresponders” have been identified in several studies (3,4) and can be related to numerous factors including physical condition (5). Studies in which an effect of insulin has been documented and that were aimed at addressing the molecular mechanisms that underlie the antiaggregatory effects of insulin have not yet managed to completely clarify the events involved. Thus, although insulin has been reported to stimulate the AMP-activated protein kinase …