Metabolic inflexibility of insulin resistant liver

Abstract

Insulin resistance (IR) in muscle is characterized by dysfunctional glucose and mitochondrial fluxes and impaired capacity to switch between glucose and fat oxidation, hastening lipid accretion. We tested whether similar metabolic pathology accompanies hepatic IR and hypothesized that IR impairs the flexibility of mitochondrial metabolism in liver. Wistar rats fed either 10 or 45% fat calories for 13–15 wks were subjected to hyperinsulinemic euglycemic clamps. Glucose, amino acid (AA) and lipid metabolism were profiled with stable isotope based LC-MS/MS and 2H/13C NMR isotopomer analysis during the fed to fasted transition or a lipid challenge. High fat diet induced hepatic IR did not induce alterations in glucose, AA or mitochondrial fluxes of fat oxidation even though modulation of plasma lipid metabolites and AAs by insulin was impaired. However, an i.v. lipid challenge elevated plasma fatty acids 4–5 fold, but failed to induce mitochondrial metabolism in insulin resistant livers, mainly due to the impaired induction of hepatic TCA cycle. In conclusion, metabolic alterations need not manifest during certain stages of hepatic IR; however the metabolic inflexibility to oxidize lipid through mitochondrial pathways of fat oxidation, especially the hepatic TCA cycle may be intrinsic to early hepatic IR and further, central to the progress of IR to diabetes. Support: NIH RO1DK078184 (SCB), ADA 7-09-BS-24 (SCB)