MECHANISMS OF LIVER AND MUSCLE INSULIN-RESISTANCE INDUCED BY CHRONIC HIGH-FAT FEEDING

To elucidate cellular mechanisms of insulin resistance induced by exce ss dietary fat, we studied conscious chronically high-fat-fed (HFF) an d control chow diet-fed rats during euglycemic-hyperinsulinemic (560 p mol/l plasma insulin) clamps. Compared with chow diet feeding, fat fee ding significantly impaired insulin action (reduced whole body glucose disposal rate, reduced skeletal muscle glucose metabolism, and decrea sed insulin suppressibility of hepatic glucose production [HGP]). In H FF rats, hyperinsulinemia significantly suppressed circulating free fa tty acids but not the intracellular availability of fatty acid in skel etal muscle (long chain fatty acyl-CoA esters remained at 230% above c ontrol levels). In HFF animals, acute blockade of beta-oxidation using etomoxir increased insulin-stimulated muscle glucose uptake, via a se lective increase in the component directed to glycolysis, but did not reverse the defect in net glycogen synthesis or glycogen synthase. In clamp HFF animals, etomoxir did not significantly alter the reduced ab ility of insulin to suppress HGP, but induced substantial depletion of hepatic glycogen content. This implied that gluconeogenesis was reduc ed by inhibition of hepatic fatty acid oxidation and that an alternati ve mechanism was involved in the elevated HGP in HFF rats. Evidence wa s then obtained suggesting that this involves a reduction in hepatic g lucokinase (GK) activity and an inability of insulin to acutely lower glucose-6-phosphatase (G-6-Pase) activity. Overall, a 76% increase in the activity ratio G-6-Pase/GK was observed, which mould favor net hep atic glucose release and elevated HGP in HFF rats. Thus in the insulin -resistant HFF rat 1) acute hyperinsulinemia fails to quench elevated muscle and liver lipid availability, 2) elevated lipid oxidation oppos es insulin stimulation of muscle glucose oxidation (perhaps via the gl ucose-fatty acid cycle) and suppression of hepatic gluconeogenesis, an d 3) mechanisms of impaired insulin-stimulated glucose storage and HGP suppressibility are not dependent on concomitant Lipid oxidation; in the case of HGP we provide evidence for pivotal involvement of G-6-Pas e and GK in the regulation of HGP by insulin, independent of the gluco se source.