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Hyperinsulinemia rapidly increases human muscle microvascular perfusion but fails to increase muscle insulin clearance: evidence that a saturable process mediates muscle insulin uptake.

University of Virginia Health System, Charlottesville, Virginia

Correspondence: ebm2n{at}virginia.edu

Objective: Insulin's transport from the central circulation into muscle is rate-limiting for the stimulation of glucose metabolism. By recruiting muscle microvasculature, insulin may promote its own movement into muscle interstitium. We tested whether in humans, as in the rat, insulin exerts an early action to recruit microvasculature within skeletal muscle. We further hypothesized that expansion of muscle's microvascular volume (MV) would enhance muscle insulin clearance.

Research Design and Methods: MV, total blood flow, and muscle insulin and glucose uptake (forearm balance method) were measured in 14 lean, healthy volunteers before and during a 2-hr hyperinsulinemic (1 mU/kg/min) euglycemic clamp. MV was measured using contrast enhanced ultrasound (CEU).

Results: Forearm muscle MV increased within 20 min of insulin infusion (p<0.01), whereas an effect to increase total forearm flow was not observed until 100 min. Forearm insulin uptake increased with physiologic hyperinsulinemia (15± 3 and 87 ± 13 fM/min/100 ml) basal vs. last 40 min of clamp p<0.001). However, the extraction fraction and clearance of insulin declined (p=0.02, for each), indicating saturability of muscle insulin uptake at physiologic hyperinsulinemia.

Conclusion: Skeletal muscle contributes to peripheral insulin clearance both in the basal state and with physiologic hyperinsulinemia. Insulin promptly expands human muscle MV but only slowly increases blood flow. Despite increased MV available for insulin uptake, muscle insulin clearance decreases significantly. These findings are consistent with the presence of a saturable transport mechanism facilitating the transendothelial transport of insulin into human muscle.

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