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).
Findings from previous studies using cultured endothelial cells (3-5) have demonstrated a transfer process involving insulin binding to the insulin or (at high concentrations) the IGF-I receptor. Insulin uptake requires intact insulin signaling to endothelial nitric oxide synthase within the endothelial cell (6), and transendothelial insulin transport appears to involve a complex vesicular trafficking process (2). In vivo, the endothelial cells in rat muscle accumulate insulin and its transport is a saturable process, indicating a role for the insulin receptor in the transendothelial insulin transport (5,7) in muscle.
In humans, the contribution of impaired transendothelial insulin transport to insulin resistance can potentially be quantified by measurement of interstitial insulin concentrations in insulin-sensitive and -resistant conditions, as is done using microdialysis by Szendroedi et al. (8) in this issue of Diabetes. In the context of their data, it is important to consider both the strengths and limitations of current experimental approaches to the assessment of insulin access to muscle interstitium.
One approach uses arterial/venous (A/V) sampling coupled with measurements of limb plasma flow. Such balance measurements are widely used to study glucose, amino acid, and fat metabolism. Surprisingly, although this can provide direct continuous sampling of muscle insulin uptake, a careful kinetic study in control versus insulin-resistant subjects has not been done. Both older and more recent data suggest that in healthy individuals the single pass extraction ratio of insulin across forearm skeletal muscle is 10-15% (9,10). The clearance of insulin declines when the plasma insulin concentration is raised, suggesting that the transfer process is saturable...