Metabolic Inflexibility Revisited—Muscle Substrate Oxidation Is Mechanistically Dissociated from Muscle Insulin Resistance in Rats

Abstract

The Metabolic Inflexibility Hypothesis and Randle Hypothesis posit that alterations in muscle glucose and fat oxidation are key factors in the pathogenesis of obesity (lipid)-associated skeletal muscle insulin resistance. In order to test these hypotheses we used a stable isotope tracer ([U-13C]glucose) to measure the ratio of pyruvate dehydrogenase flux and citrate synthase flux (VPDH/VCS), a highly tissue-specific index for the proportional contribution of glucose oxidation to total mitochondrial oxidation in vivo. We found that insulin resistant rats fed a high fat diet (HFD) for 4 weeks did not have altered substrate (VPDH/VCS) oxidation in soleus muscle in the fasting state (5.8%±2.5% vs. 2.6%±1.0%). Hyperinsulinemic-euglycemic clamps increased relative glucose oxidation in both normal and insulin resistant rats, although this increase was blunted in insulin resistant rats (51.6±4.9% vs. 33.3±4.5%, p<0.05), which could be mostly attributed to an impairment in insulin-stimulated muscle glucose transport flux (124.4±18.7 vs. 69.3±11.3 nmol/(g•minute), p<0.05). Additionally, we found that an acute infusion of lipid during a clamp in normal rats significantly reduced relative glucose oxidation in soleus muscle (49.0±3.6% vs. 26.7±2.7%, p<0.001) without any effects on insulin-stimulated peripheral glucose metabolism (27.2±1.4 vs. 24.3±1.5 mg/(kg•minute), NS) or muscle glucose transport (143.8±22.4 vs. 138.1±18.3 nmol/(g•minute), NS). Conclusion: These data show that basal substrate preference in muscle is not altered in insulin resistant rats and that acute modulation of substrate oxidation in normal rats does not affect muscle insulin sensitivity, therefore challenging the Metabolic Inflexibility Hypothesis and Randle Hypothesis in the pathogenesis of lipid-induced muscle insulin resistance. Disclosure J.D. Song: None. R.J. Perry: None. A. Munk: None. Y. Zhang: None. D. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..