The vascular system controls the delivery of nutrients and hormones to muscle, and a number of hormones may act to regulate muscle metabolism and contractile performance by modulating blood flow to and within muscle. This review examines evidence that insulin has major hemodynamic effects to influence muscle metabolism. Whole body, isolated hindlimb perfusion studies and experiments with cell cultures suggest that the hemodynamic effects of insulin emanate from the vasculature itself and involve nitric oxide-dependent vasodilation at large and small vessels with the purpose of increasing access for insulin and nutrients to the interstitium and muscle cells. Recently developed techniques for detecting changes in microvascular flow, specifically capillary recruitment in muscle, indicate this to be a key site for early insulin action at physiological levels in rats and humans. In the absence of increases in bulk flow to muscle, insulin may act to switch flow from nonnutritive to the nutritive route. In addition, there is accumulating evidence to suggest that insulin resistance of muscle in vivo in terms of impaired glucose uptake could be partly due to impaired insulin-mediated capillary recruitment. Exercise training improves insulin-mediated capillary recruitment and glucose uptake by muscle.

We have reported that insulin exerts two vascular actions in muscle; it both increases blood flow and recruits capillaries. In parallel hyperinsulinemic-euglycemic clamp studies, we compared the insulin dose response of muscle microvascular recruitment and femoral blood flow as well as hindleg glucose uptake in fed, hooded Wistar and fasted Sprague-Dawley rats. Using insulin doses between 0 and 30 mU ؊1 ⅐ min ؊1 ⅐ kg ؊1 , we measured microvascular recruitment at 2 h by 1-methylxanthine (1-MX) metabolism or contrast-enhanced ultrasound (CEU), and muscle glucose uptake was measured by either arteriovenous differences or using 2-deoxyglucose. We also examined the time course for reversal of microvascular recruitment following cessation of a 3 mU ⅐ min ؊1 ⅐ kg ؊1 insulin infusion. In both groups, whether measured by 1-MX metabolism or CEU, microvascular recruitment was fully activated by physiologic hyperinsulinemia and occurred at lower insulin concentrations than those that stimulated glucose uptake or hindleg total blood flow. The latter processes were insulin dose dependent throughout the entire dose range studied. Upon stopping the insulin infusion, increases in microvascular volume persisted for 15-30 min after insulin concentrations returned to basal levels. We conclude that the precapillary arterioles that regulate microvascular recruitment are more insulin sensitive than resistance arterioles that regulate total flow. Diabetes 53: [447][448][449][450][451][452][453] 2004 B ased in part on their observation that glucose disposal and leg blood flow displayed similar dose responses to insulin, Baron and colleagues (1,2) proposed that insulin-induced changes in blood flow were one determinant of muscle glucose uptake. Others (3,4) suggested that insulin-induced changes in flow require higher concentrations and longer exposures to insulin than those required for glucose disposal. We reported previously that insulin recruits microvascular vessels in skeletal muscle separate from any effect on total flow (5) and have suggested that insulin's microvascular action contributes to its overall effect on nutrient and hormone delivery to muscle (6). The effects of insulin on both capillary recruitment (7) and larger resistance vessels that regulate total blood flow to muscle (8) are the result of insulin-induced nitric oxide-dependent relaxation processes. We recently reported that microvascular recruitment by physiologic insulin precedes the increase in rat hindlimb total muscle blood flow by as much as 90 min (9). To further compare insulin's actions on total flow and microvascular recruitment, we examined the dose-response characteristics of these two vascular responses. In addition, to further characterize insulin's microvascular action, we examined the time course for its reversal following insulin removal. Dose-response studies were conducted on ad libitum-fed and 24-h-fasted rats using two different methods to assess microvascular recruitment, hindlimb metabolism of 1-methylxanthine (1-MX) (5) and contrast-enha...

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