Skeletal Muscle Vascular Function: A Counterbalance of Insulin Action.

Insulin is a vasoactive hormone that regulates vascular homeostasis by maintaining balance of endothelial derived nitric oxide (NO) and the potent vasoconstrictor, endothein-1 (ET-1). Although there is general agreement that insulin resistance and the associated compensatory hyperinsulinemia disturb this balance, the vascular consequences for hyperinsulinemia in isolation from insulin resistance are still unclear. Presently, there is no simple answer for this question, especially in a background of mixed reports examining the effects of experimental hyperinsulinemia on endothelial mediated vasodilation. There is also a lack of consistency between clinical and mechanistic studies in regards to the vascular outcomes of hyperinsulinemia. Understanding the mechanisms by which hyperinsulinemia induces vascular dysfunction is essential in advancing treatment and prevention of obesity and insulin resistance-related vascular complications. Thus, herein, we review key human and animal literature addressing the effects of hyperinsulinemia on vascular function, at both the clinical and cellular levels. Further, we give special attention to the vasoregulatory effects of hyperinsulinemia on skeletal muscle, the largest insulin-dependent organ in the body. This review will also characterize the differential vascular effects of hyperinsulinemia on large conduit vessels versus small resistance microvessels and the dramatic effects of key experimental variables such as insulin dose, duration of exposure, and underlying insulin sensitivity in an effort to unravel potential sources of discrepancies in the literature. At the cellular level, we provide an overview of insulin signaling events governing vascular tone. Finally, we hypothesize a role for hyperinsulinemia and insulin resistance in the development of cardiovascular disease (CVD).