A high-fat diet influences insulin-stimulated posttransport muscle glucose metabolism in rats

Because of a failure to detect significant quantities of intracellular glucose, it has been generally accepted that transport rather than phosphorylation is the rate-limiting process of muscle glucose metabolism under most (but not all) physiological conditions. Here, we have measured tissue free levels of the glucose analog 2-deoxy-d-glucose (2DG) in red quadriceps muscle of rats fed a high-fat diet (59% of energy from fat) for 3 weeks, to identify the barrier to insulin-stimulated glucose uptake previously seen in such animals. Measurements were performed on pentobarbital-anesthetized rats following exogenous infusion of radiolabeled 2DG. A glucose clamp was used to maintain plasma insulin at high physiological levels (≈ 120 mU/L). Three other treatment groups representing normal insulin action (chow-fed), extreme glucose uptake (maximal insulin stimulation + hyperglycemia), and insulin resistance with elevated free intracellular glucose (epinephrine infusion) were also studied for comparison. In chow-fed animals, no muscle free 2DG was detected, confirming transport as the rate-limiting process. In fat-fed animals, a significant elevation in muscle free 2DG was observed (P < .01 v) chow-fed controls). The elevation was similar in magnitude to that in epinephrine-infused rats, and implied a limitation of insulin action at a posttransport step. This result was confirmed with a more complex modeling analysis. We conclude that posttransport steps influence insulin-stimulated in vivo muscle glucose metabolism in long-term high-fat—fed rats.