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 demonstrate that alterations in mitochondrial substrate preference are not an essential step in the pathogenesis of muscle insulin resistance.

已假定肌肉线粒体底物偏好的改变在肌肉胰岛素抵抗的发病机制中起主要作用。为了检验这一假设，我们评估了肌肉中线粒体丙酮酸氧化 (V _PDH ) 与线粒体柠檬酸合酶通量 (V _CS ) 的比率。与这一假设相反，我们发现高脂肪饮食 (HFD) 喂养的胰岛素抵抗大鼠在禁食状态下没有表现出比目鱼肌或股四头肌的肌肉底物偏好 (V _PDH /V _CS )改变。此外，高胰岛素正常血糖 (HE) 钳夹增加了正常和胰岛素抵抗大鼠肌肉中的V _PDH / V _CS。然后我们检查了肌肉 V胰岛素敏感和胰岛素抵抗人类的_PDH /V _CS通量，并发现 V _PDH /V _{CS 的}相对比率相似，经过过夜禁食（~20%），并且在 HE 钳夹期间V _PDH /V _CS通量的类似增加. 总之，这些发现表明线粒体底物偏好的改变不是肌肉胰岛素抵抗发病机制中的必要步骤。