PLASMA-FREE FATTY-ACIDS DECREASE INSULIN-STIMULATED SKELETAL-MUSCLE GLUCOSE-UPTAKE BY SUPPRESSING GLYCOLYSIS IN CONSCIOUS RATS

The effects of elevated plasma free fatty acid (FFA) levels on insulin -stimulated whole-body and skeletal muscle glucose transport, glucose uptake, glycolysis, and glycogen synthesis were studied in conscious r ats during hyperinsulinemic-euglycemic clamps with (n = 26) or without (n = 23) Intralipid and heparin infusion. Whole-body and skeletal mus cle glucose uptake, glycolysis, and glycogen synthesis were estimated using D-[3-H-3]glucose and 2-[C-14]deoxyglucose (study 1), and glucose transport activity was assessed by analyzing plasma kinetics of L-[C- 14]glucose and 3-O-[H-3]-methylglucose (study 2). Plasma FFA levels de creased during the clamps without intralipid but increased above basal during the clamps with Intralipid infusion (P < 0.01 for both). Eleva ted plasma FFA levels decreased insulin-stimulated whole-body glucose uptake by similar to 15% and similar to 20% during physiological and m aximal insulin clamps, respectively (P < 0.01). Similarly, insulin-sti mulated glucose uptake was also decreased in individual skeletal muscl es with Intralipid infusion (P < 0.05). The most profound effect of el evated plasma FFA levels was a 30-50% suppression of insulin-stimulate d glycolysis in whole body and individual skeletal muscles in both cla mps. In contrast, physiological insulin-stimulated glycogen synthesis was increased with elevated plasma. FFA levels in whole body and indiv idual skeletal muscles (P < 0.05). Glucose-6-phosphate (G-6-P) levels were increased in soleus and extensors digitorum longus (EDL) muscles with Intralipid infusion in both clamps (P < 0.05). Intralipid infusio n did not alter the time profiles of plasma L-glucose and 3-O-methylgl ucose after an intravenous injection during maximal insulin clamps, an d compartmental analysis indicated no significant effect of elevated F FA levels on glucose transport activity in insulin-sensitive tissues ( P > 0.05). Thus, elevated plasma FFA decreased insulin-stimulated gluc ose uptake in skeletal muscle by suppressing glycolysis and increasing G-6-P levels. These findings suggest that the classic glucose-fatty a cid cycle was the predominant mechanism underlying the inhibitory effe ct of FFA on skeletal muscle glucose uptake.