Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice
Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice
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DOI：
10.1172/jci32601
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发表时间：
2008-02-01
影响因子：
15.9
通讯作者：
Rieusset, Jennifer
中科院分区：
文献类型：
--
作者：
Bonnard, Charlotte;Durand, Annie;Rieusset, Jennifer
骨骼肌中的线粒体功能障碍与2型糖尿病的发展有关。然而，这些变化是胰岛素抵抗的原因还是结果尚不清楚。我们研究了高脂高糖饮食小鼠在胰岛素抵抗和糖尿病进展过程中肌肉线粒体的结构和功能。虽然1个月的高脂肪、高蔗糖饮食喂养足以诱导葡萄糖耐受不良，但小鼠在此阶段没有表现出线粒体功能障碍的证据。然而，延长的饮食干预诱导糖尿病状态，我们观察到肌肉组织中线粒体生物发生、结构和功能的改变。我们评估了氧化应激在这些线粒体异常发展中的作用，发现饮食诱导的糖尿病小鼠骨骼肌中ROS产生增加。此外，ROS的产生与高血糖链脲佐菌素治疗的小鼠肌肉中的线粒体改变有关，并且正常化的抗氧化剂或抗氧化剂治疗降低了肌肉ROS的产生并恢复了线粒体的完整性。葡萄糖或脂质诱导的ROS产生导致体外肌细胞线粒体的改变，这些影响被抗氧化剂治疗所阻断。这些数据表明，线粒体的改变并不先于胰岛素抵抗的发病，并导致增加的ROS生产在肌肉中的饮食诱导的糖尿病小鼠。
Mitochondrial dysfunction in skeletal muscle has been implicated in the development of type 2 diabetes. However, whether these changes are a cause or a consequence of insulin resistance is not clear. We investigated the structure and function of muscle mitochondria during the development of insulin resistance and progression to diabetes in mice fed a high-fat, high-sucrose diet. Although 1 month of high-fat, high-sucrose diet feeding was sufficient to induce glucose intolerance, mice showed no evidence of mitochondrial dysfunction at this stage. However, an extended diet intervention induced a diabetic state in which we observed altered mitochondrial biogenesis, structure, and function in muscle tissue. We assessed the role of oxidative stress in the development of these mitochondrial abnormalities and found that diet-induced diabetic mice had an increase in ROS production in skeletal muscle. In addition, ROS production was associated with mitochondrial alterations in the muscle of hyperglycemic streptozotocin-treated mice, and normalization of glycemia or antioxidant treatment decreased muscle ROS production and restored mitochondrial integrity. Glucose- or lipid-induced ROS production resulted in mitochondrial alterations in muscle cells in vitro, and these effects were blocked by antioxidant treatment. These data suggest that mitochondrial alterations do not precede the onset of insulin resistance and result from increased ROS production in muscle in diet-induced diabetic mice.