Rate-limiting steps for insulin-mediated glucose uptake into perfused rat hindlimb

To determine the glucose and insulin concentrations at which glucose transport is rate limiting for insulin-mediated glucose uptake and metabolism in muscle, glucose clearance was determined in the presence of glucose concentrations ranging from trace to 20 mM and in the absence or presence of insulin in the perfused rat hindlimb. In the absence of insulin and at submaximally stimulating insulin concentrations glucose clearance was constant up to 7 mM glucose and then decreased as the glucose concentration was raised. At maximally stimulating insulin concentrations glucose clearance was constant up to 2 mM glucose and then decreased. The decrease in glucose clearance between 2 and 7 mM glucose in the presence of maximally stimulating insulin concentrations could not be accounted for by competition among glucose molecules for the glucose transport system. The results suggest that at physiological glucose concentrations in the presence of maximally stimulating insulin concentrations the rate-limiting step for insulin-mediated glucose uptake and metabolism in muscle shifts from glucose transport to some step beyond transport.