Hyperinsulinemia Rapidly Increases Human Muscle Microvascular Perfusion but Fails to Increase Muscle Insulin Clearance Evidence That a Saturable Process Mediates Muscle Insulin Uptake Emma M. Eggleston, Linda A. Jahn, and Eugene J. Barrett OBJECTIVE— Transport of insulin 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 the microvascular volume of muscle would enhance muscle insulin clearance. RESEARCH DESIGN AND METHODS— Microvascular vol- ume, total blood flow, and muscle insulin and glucose uptake (forearm balance method) were measured in 14 lean, healthy volunteers before and during a 2-h hyperinsulinemic-euglycemic clamp (1 mU  kg -1  min -1 ). Microvascular volume was mea- sured using contrast-enhanced ultrasound. RESULTS— Forearm muscle microvascular volume 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 physiological hyperinsu- linemia (15  3 and 87  13 fmol  min -1  100 ml -1 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 physiological hyperinsu- linemia. CONCLUSIONS— Skeletal muscle contributes to peripheral insulin clearance both in the basal state and with physiological hyperinsulinemia. Insulin promptly expands human muscle mi- crovascular volume but only slowly increases blood flow. De- spite increased microvascular volume 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. Diabetes 56:2958–2963, 2007 A number of studies have demonstrated that insulin enhances skeletal muscle blood flow and suggest that changes in muscle perfusion play a role in regulating muscle glucose dis- posal (1,2). The potential importance of muscle perfusion for the delivery of insulin to muscle is underscored by studies demonstrating that in muscle, glucose metabolism correlates more strongly with interstitial than with plasma insulin levels (3,4) and by considerable evidence that the transendothelial transport of insulin is rate limiting for its action on muscle glucose metabolism (3,5–7). Studies using lymphatic sampling or microdialysis to quantify interstitial insulin concentrations consistently demon- strate 1) a significant time delay between increases in interstitial versus arterial insulin concentrations (3,6,8) and 2) the presence of a persistent (approximately two- fold) concentration gradient between interstitial and plasma insulin concentrations both basally (3,9,10) and during steady-state hyperinsulinemia (3,7,9,11). The large majority of muscle endothelial surface area resides in capillaries and precapillary arterioles. How- ever, only 25% of skeletal muscle microvasculature is perfused at rest. Expanding the microvascular surface area perfused within muscle would proportionately increase the opportunity for insulin and glucose ex- change across the skeletal muscle bed. Our laboratory has demonstrated that insulin increases capillary perfu- sion within muscle by recruiting microvasculature (12– 14). This recruitment appears to be due to relaxation of terminal arterioles, which, like the relaxation of resis- tance vessels by insulin, is sensitive to inhibition of nitric oxide synthase and is diminished by insulin resistance (15,16). In the rat, insulin increases micro- vascular perfusion within 10 –15 min. This increase temporally precedes changes in both glucose utilization and total blood flow (14) and suggests that insulin actively regulates its own delivery to the capillary endothelium. However, the time course for insulin- mediated microvascular recruitment in humans is not known. In the current study, we used contrast-enhanced ultra- sound (CEU) to ascertain whether in humans, as in the rat, insulin exerts an early action to recruit microvasculature within skeletal muscle. We further hypothesized that if insulin did expand the microvascular volume available for perfusion within skeletal muscle, enhanced muscle insulin From the University of Virginia Health System, Charlottesville, Virginia. Address correspondence and reprint requests to Emma M. Eggleston, University of Virginia Health System, P.O. Box 801410, 450 Ray C. Hunt Dr., Charlottesville, VA 22908. E-mail: ebm2n@virginia.edu. Received for publication 18 May 2007 and accepted in revised form 23 August 2007. Published ahead of print at http://diabetes.diabetesjournals.org on 24 Au- gust 2007. DOI: 10.2337/db07-0670. CEU, contrast-enhanced ultrasound; MBV, microvascular blood volume. © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. ORIGINAL ARTICLE 2958 DIABETES, VOL. 56, DECEMBER 2007