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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, hyperinsulinemic-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 (∼20%), and similar increases in V_PDH/V_CS fluxes during a HE clamp. Altogether, these findings …