Vascular Endothelial Nitric Oxide, Insulin Signaling and Insulin Transport: A Delicate Balance

Abstract

Vascular endothelial dysfunction, characterized by a deficiency of bio-available nitric Oxide (NO), has been found to precede the development of type 2 diabetes and is significantly correlated with insulin resistance [1]. Vascular Endothelial Cells (ECs) have pleiotropic functions and regulate a large variety of cellular processes including coagulation, fibrinolysis, angiogenesis, adhesion and transmigration of inflammatory cells and vasculature hemodynamics. Another very important vascular endothelial function is providing a barrier that regulates entry of nutrients and hormones into the interstitium of peripheral tissues [2]. This is particularly true for skeletal muscle, a major site of fuel use, where its continuous vascular endothelium has well-developed junctional structures and abundant caveolae that provides a relatively tight diffusional barrier. This is in stark contrast to the discontinuous endothelium with gaps between ECs in liver. Muscle’s tight endothelium has constituted the structural basis for a strong argument that the transit of insulin from the vascular to the interstitial compartment within skeletal muscle is rate limiting for insulin’s metabolic action [2]. Most importantly, this rate-limiting step for peripheral insulin action is delayed in insulin-resistant obese subjects [3-5]. Current evidence indicates that insulin trans-endothelial transport (TET) is mediated by the molecular transcytotic machinery