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).
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