Interaction between insulin sensitivity and muscle perfusion on glucose uptake in human skeletal muscle: evidence for capillary recruitment

Insulin and glucose delivery (muscle perfusion) can modulate insulin-mediated glucose uptake. This study was undertaken to determine 1) to what extent insulin sensitivity modulates the effect of perfusion on glucose uptake and 2) whether this effect is achieved via capillary recruitment. We measured glucose disposal rates (GDRs) and leg muscle glucose uptake (LGU) in subjects exhibiting a wide range of insulin sensitivity, after 4 h of steady-state (SS) euglycemic hyperinsulinemia (>6,000 pmol/l) and subsequently after raising the rate of leg blood flow (LBF) 2-fold with a superimposed intrafemoral artery infusion of methacholine chloride (Mch), an endothelium-dependent vasodilator. LBF was determined by thermodilution: LGU = arteriovenous glucose difference (AVGdelta) x LBF. As a result of the 114+/-12% increase in LBF induced by Mch, the AVGdelta decreased 32+/-4%, and overall rates of LGU increased 40+/-5% (P < 0.05). We found a positive relationship between the Mch-modulated increase in LGU and insulin sensitivity (GDR) (r = 0.60, P < 0.02), suggesting that the most insulin-sensitive subjects had the greatest enhancement of LGU in response to augmentation of muscle perfusion. In separate groups of subjects, we also examined the relationship between muscle perfusion rate and glucose extraction (AVGdelta). Perfusion was either pharmacologically enhanced with Mch or reduced by intra-arterial infusion of the nitric oxide inhibitor N(G)-monomethyl-L-arginine during SS euglycemic hyperinsulinemia. Over the range of LBF, changes in AVGdelta were smaller than expected based on the noncapillary recruitment model of Renkin. Together, the data indicate that 1) muscle perfusion becomes more rate limiting to glucose uptake as insulin sensitivity increases and 2) insulin-mediated increments in muscle perfusion are accompanied by capillary recruitment. Thus, insulin-stimulated glucose uptake displays both permeability- and perfusion-limited glucose exchange properties.