The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action

Abstract

Evidence suggests that insulin delivery to skeletal muscle interstitium is the rate-limiting step in insulin-stimulated muscle glucose uptake and that this process is impaired by insulin resistance. In this review we examine the basis for the hypothesis that insulin acts on the vasculature at three discrete steps to enhance its own delivery to muscle: (1) relaxation of resistance vessels to increase total blood flow; (2) relaxation of pre-capillary arterioles to increase the microvascular exchange surface perfused within skeletal muscle (microvascular recruitment); and (3) the trans-endothelial transport (TET) of insulin. Insulin can relax resistance vessels and increase blood flow to skeletal muscle. However, there is controversy as to whether this occurs at physiological concentrations of, and exposure times to, insulin. The microvasculature is recruited more quickly and at lower insulin concentrations than are needed to increase total blood flow, a finding consistent with a physiological role for insulin in muscle insulin delivery. Microvascular recruitment is impaired by obesity, diabetes and nitric oxide synthase inhibitors. Insulin TET is a third potential site for regulating insulin delivery. This is underscored by the consistent finding that steady-state insulin concentrations in plasma are approximately twice those in muscle interstitium. Recent in vivo and in vitro findings suggest that insulin traverses the vascular endothelium via a trans-cellular, receptor-mediated pathway, and emerging data indicate that insulin acts on the endothelium to facilitate its own TET. Thus, muscle insulin delivery, which is rate-limiting for its metabolic action, is itself regulated by insulin at multiple steps. These findings highlight the need to further understand the role of the vascular actions of insulin in metabolic regulation.

AGE/RAGE as a Mediator of Insulin Resistance or Metabolic Syndrome: Another Aspect of Metabolic Memory?

“…[41][42][43][44] . Endothelial dysfunction could be profoundly associated with less insulin delivery to the skeletal muscle interstitium, leading to decreased insulin-stimulated glucose uptake by the skeletal muscle [45][46][47][48][49] , which is implicated in the pathogenesis of insulin resistance. More directly, the restriction of the AGE content in standard mouse diets was found to markedly improve insulin resistance in obese db/db (++) mice 50 .…”

Systemic inhibition of nitric oxide synthesis in non-diabetic individuals produces a significant deterioration in glucose tolerance by increasing insulin clearance and inhibiting insulin secretion

“…Both insulin and glucose promote NO synthesis in tissues (endothelium, beta cells, skeletal muscle, liver and brain) that participate in the maintenance of glucose homeostasis [1,2]. The reduced NO bioavailability that is often found in conditions of impaired glucose homeostasis is expected to involve most of these tissues since it is sustained by enhanced oxidative stress, a systemic process.…”

Insulin Resistance in SHR/NDmc-cp Rats Correlates with Enlarged Perivascular Adipocytes and Endothelial Cell Dysfunction in Skeletal Muscle

“…Recent studies have demonstrated that the transfer of insulin from blood to the interstitium of skeletal muscle is the rate-limiting step in insulin-dependent glucose uptake (32). Insulin induces NO-dependent vasodilatation in skeletal muscle (33) by activating IRS-2 through the phosphorylation of eNOS at Ser1177 in endothelial cells (34).…”