Dissociation of Muscle Insulin Resistance from Alterations in Mitochondrial Substrate Preference.

Alterations in muscle mitochondrial substrate preference have been postulated to play a major role in the pathogenesis of muscle insulin resistance. In order to examine this hypothesis, we assessed the ratio of mitochondrial pyruvate oxidation (V-PDH) to rates of mitochondrial citrate synthase flux (V-CS) in muscle. Contrary to this hypothesis, we found that high-fat-diet (HFD)-fed insulin-resistant rats did not manifest altered muscle substrate preference (V-PDH/V-CS) in soleus or quadriceps muscles in the fasting state. Furthermore, hyperin-sulinemic-euglycemic (HE) clamps increased V-PDH/V-CS in both muscles in normal and insulin-resistant rats. We then examined the muscle V-PDH/V-CS flux in insulin-sensitive and insulin-resistant humans and found similar relative rates of V-PDH/V-CS, following an overnight fast (similar to 20%), and similar increases in V-PDH/V-CS fluxes during a HE clamp. Altogether, these findings demonstrate that alterations in mitochondrial substrate preference are not an essential step in the pathogenesis of muscle insulin resistance.