CONTRIBUTION OF MUSCLE AND LIVER TO GLUCOSE-FATTY ACID CYCLE IN HUMANS

To examine the influence of elevated free fatty acid (FFA) levels on h epatic glucose production (HGP) and oxidative and nonoxidative pathway s of glucose metabolism, 12 healthy subjects participated in two eugly cemic insulin-clamp studies performed with and without infusion of Int ralipid plus heparin. To elucidate the role of skeletal muscle in this putative interaction, we performed muscle biopsies for the measuremen t of activities of glycogen synthase (GS), pyruvate dehydrogenase (PDH ), and carnitine palmitoyltransferase (CPT). Infusion of Intralipid pl us heparin caused an increase in plasma FFA concentrations and rate of lipid oxidation (measured by indirect calorimetry) that was not inhib ited by insulin. Suppression of HGP by insulin was impaired by elevate d plasma FFA levels. Furthermore, the increase in plasma FFA was assoc iated with a 20% reduction in total glucose metabolism (P < 0.01), whi ch was completely accounted for by a reduction in the rate of glucose oxidation. Although the fractional activity of GS was increased by ins ulin, elevation of plasma FFA had no influence on this key enzyme of g lycogen synthesis. In addition, the activities of PDH and CPT were uni nfluenced by the elevation of FFA, suggesting that oxidative processes in skeletal muscle were not a major target for the operative glucose- fatty acid cycle under the current conditions. Taken together, the dat a indicate that the interaction between FFA and glucose metabolism als o involves impaired suppression of HGP by insulin.