Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism.
Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism.
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DOI：
10.1152/ajpcell.00311.2006
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发表时间：
2007-02
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影响因子：
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通讯作者：
J. Thyfault;M. Cree;D. Zheng;Jennifer Zwetsloot;E. Tapscott;T. Koves;O. Ilkayeva;R. Wolfe;D. Muoio-D
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文献类型：
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作者：
J. Thyfault;M. Cree;D. Zheng;Jennifer Zwetsloot;E. Tapscott;T. Koves;O. Ilkayeva;R. Wolfe;D. Muoio-D
急性运动可以逆转肌肉胰岛素抵抗，但其作用机制尚不清楚。通过使用后肢灌注模型，我们发现急性收缩使肥胖Zucker大鼠肌肉中胰岛素刺激的葡萄糖摄取恢复到瘦对照组的水平。以前的报告表明，肥胖相关的胰岛素抵抗源于脂质供应过剩和组织中有毒脂质中间体的积累，这些脂质中间体损害胰岛素信号传导。我们推断，收缩可能激活肌内脂质的水解和氧化，从而减轻“脂毒性”并引发肌肉增强胰岛素作用。事实上，对尿道衍生的酰基-肉毒碱酯的分析表明，收缩引起β-氧化通量和线粒体氧化的强烈增加。正如预测的那样，收缩降低了肌内三酰甘油含量，然而，二酰甘油和长链酰基辅酶A，脂质中间体假定触发胰岛素抵抗，要么不变或增加。在肥胖动物的肌肉中，胰岛素刺激的胰岛素受体和胰岛素受体底物-1的酪氨酸磷酸化在收缩后仍然受损，而下游信号蛋白AS 160的磷酸化部分恢复。这些结果表明，急性运动使糖尿病肌肉绕过胰岛素信号转导的上游缺陷，通过机制，更紧密地耦合到增加线粒体能量代谢比降低二酰基甘油和长链酰基辅酶A。
Acute exercise can reverse muscle insulin resistance, but the mechanism(s) of action are unknown. With the use of a hindlimb perfusion model, we have found that acute contraction restores insulin-stimulated glucose uptake in muscle of obese Zucker rats to levels witnessed in lean controls. Previous reports have suggested that obesity-related insulin resistance stems from lipid oversupply and tissue accumulation of toxic lipid intermediates that impair insulin signaling. We reasoned that contraction might activate hydrolysis and oxidation of intramuscular lipids, thus alleviating "lipotoxicity" and priming the muscle for enhanced insulin action. Indeed, analysis of mitochondrial-derived acyl-carnitine esters suggested that contraction caused robust increases in beta-oxidative flux and mitochondrial oxidation. As predicted, contraction decreased intramuscular triacylglycerol content; however, diacylglycerol and long chain acyl-CoAs, lipid intermediates presumed to trigger insulin resistance, were either unchanged or increased. In muscles from obese animals, insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 remained impaired after contraction, whereas phosphorylation of the downstream signaling protein, AS160, was partially restored. These results suggest that acute exercise enables diabetic muscle to circumvent upstream defects in insulin signal transduction via mechanisms that are more tightly coupled to increased mitochondrial energy metabolism than the lowering of diacylglycerol and long chain acyl-CoA.