Limitations to basal and insulin-stimulated skeletal muscle glucose uptakein the high-fat-fed rat

Rats fed a high-fat diet display blunted insulin-stimulated skeletal muscle glucose uptake. It is not clear whether this is due solely to a defect in glucose transport, or if glucose delivery and phosphorylation are also impa ired. To determine this, rats were fed standard chow (control rats) or a hi gh-fat diet (HF rats) for 4 wk. Experiments were then performed on consciou s rats under basal conditions or during hyperinsulinemic euglycemic clamps. Rats received primed constant infusions of 3-O-methyl-[H-3] glucose (3-O-M G) and [1-C-14]mannitol. Total muscle glucose concentration and the steady- state ratio of intracellular to extracellular 3-O-MG concentration [which d istributes based on the transsarcolemmal glucose gradient (TSGG)] were used to calculate glucose concentrations at the inner and outer sarcolemmal sur faces ([G](im) and [G](om), respectively) in soleus. Total muscle glucose w as also measured in two fast-twitch muscles. Muscle glucose uptake was mark edly decreased in HF rats. In control rats, hyperinsulinemia resulted in a decrease in soleus TSGG compared with basal, due to increased [G](im). In H F rats during hyperinsulinemia, [G](im) also exceeded zero. Hyperinsulinemi a also decreased muscle glucose in HF rats, implicating impaired glucose de livery. In conclusion, defects in extracellular and intracellular component s of muscle glucose uptake are of major functional significance in this mod el of insulin resistance.