The Vascular Contribution to Insulin Resistance: Promise, Proof, and Pitfalls

Abstract

Insulin resistance is a potent and highly prevalent risk factor for diabetes and cardiovascular disease. A landmark compartmental analysis of human insulin kinetics (that led to the development of the euglycemic insulin clamp) identified insulin’s slow transit from plasma to muscle as a rate-limiting step for insulin-mediated glucose disposal (1). This first step of insulin-stimulated glucose uptake, i.e., insulin’s crossing from plasma to muscle interstitium, is governed by vascular endothelium. Accumulating evidence supports a contribution of endothelial insulin transport to insulin resistance (2). The insulin receptor can mediate transendothelial insulin transport (3), and mice lacking insulin receptor substrate 2 specifically in vascular endothelium are insulin resistant. Nevertheless, the regulation of muscle transendothelial insulin transfer, especially in humans, is poorly understood (2) (Fig. 1). FIG. 1. Insulin (pentagons) enters the skeletal muscle capillary microvasculature where it can exchange between the plasma and the interstitium. This can be assessed by sampling A/V insulin and quantifying blood flow (white stars) or by sampling lymphatic insulin (black star). Alternatively, a microdialysis catheter introduced into muscle is used for sampling (a typical catheter is ∼30× larger than the capillary displayed). Plasma insulin concentrations both fasting and during steady-state hyperinsulinemia are estimated two- to threefold higher than interstitial. Insulin transits to the interstitium from plasma by binding with the insulin receptor on the endothelial cell, activating a signaling cascade that increases nitric oxide (NO) formation. Insulin crosses the vascular endothelium by a vesicular transport pathway and accesses the interstitium where most is removed by muscle through receptor-mediated endocytosis …