Possible involvement of insulin and oxidative stress in vascular dysfunction of diabetic mellitus

Abstract

Macro- and microvascular disease states currently represent the principal causes of morbidity and mortality in patients with type I or type II diabetes mellitus. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in various beds in different animal models of diabetes and in humans with type I or type II diabetes. The principal mediators of diabetes-associated vascular dysfunction are increases in glucose, oxidized low-density lipoprotein, endothelin-1, angiotensin II, insulin, or growth factors. An accumulating body of evidence indicates that abnormal production of oxidative stress may be one of several factors contributing to vascular dysfunction in diabetes. It is possible that in diabetic states, hyperinsulinemia initiates oxidant stress, leading to vascular dysfunction at a later stage. We and others have demonstrated that in models of hyperinsulinemia and hyperglycemia, · NO production and/or · NO responsiveness are impaired in aortic strips. Several recent studies have shown that the formation of nitrotyrosine and/or peroxynitrite impairs vascular · NO responsiveness and · NO production. Our findings suggest that the coexistence of a high insulin level and an established diabetic state may lead to the excessive generation of peroxynitrite, and that this may in turn trigger an impairment of endothelium-dependent relaxation via a decrease in sarcoendo plasmic reticulum Ca2+ ATPase function. This review summarizes the results of our recent studies on the involvement of insulin and oxidative stress in the blood vessels of diabetic animals. © 2008 The Pharmaceutical Society of Japan.