METABOLIC IMPAIRMENT PRECEDES INSULIN-RESISTANCE IN SKELETAL-MUSCLE DURING HIGH-FAT FEEDING IN RATS

To examine whether impairment of intracellular glucose metabolism prec edes insulin resistance, we determined the time courses of changes in insulin-stimulated glucose uptake, glycolysis, and glycogen synthesis during high-fat feeding in rats. Animals were fed with a high-fat (66. 5%) diet ad libitum for 0, 2, 4, 7, or 14 days (n = 10-11 in each grou p) after 5 days of a low-fat (12.5%) diet. Submaximal and maximal insu lin-stimulated glucose fluxes were estimated in whole body and individ ual skeletal muscles using the glucose clamp technique combined with D -[3-H-3]glucose infusion and 2-[1-C-14]deoxyglucose injection. Both su bmaximal and maximal insulin-stimulated glucose uptake in whole body d ecreased gradually with high-fat feeding, However, the decreases were minimal and not statistically significant during the initial few days (i.e., 2 and 4 days) of high-fat feeding (P > 0.05). In contrast, insu lin-stimulated whole-body glycolysis (both maximal and submaximal) sig nificantly decreased by similar to 30% with 2 days of high-fat feeding and remained suppressed thereafter (P < 0.05). Similar patterns of ch anges in insulin-stimulated glucose uptake and glycolysis were also ob served in skeletal muscle. Insulin-stimulated glycogen synthesis and g lucose-6-phosphate (G-6-P) concentrations in skeletal muscle increased significantly during the initial few days of high-fat feeding and gra dually returned to control levels by day 14, suggesting that increased G-6-P concentrations were responsible for increased glycogen synthesi s. Thus, suppression of insulin-stimulated glycolysis and a compensato ry increase in glycogen synthesis (presumably arising from the glucose -fatty acid cycle) preceded decreases in insulin-stimulated glucose up take in skeletal muscle during high-fat feeding. These findings sugges t that the insulin resistance may develop as a secondary response to i mpaired intracellular glucose metabolism.