Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents
Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents
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DOI：
10.1172/jci25151
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发表时间：
2005-12-01
影响因子：
15.9
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Morino, K;Petersen, KF;Shulman, GI
为了进一步探讨线粒体功能障碍和胰岛素抵抗的本质，发生在2型糖尿病父母的年轻、瘦弱、血糖正常、胰岛素抵抗的后代（IR后代）的肌肉中，我们测量了线粒体。在高胰岛素-正血糖钳夹之前和期间从这些个体获得的肌肉活检样本中的电子显微镜含量和胰岛素信号。胰岛素刺激的肌肉葡萄糖摄取率在IR后代中比对照组低约60%，并且通过H-1磁共振波谱评估，与细胞内脂质含量增加约60%相关。IR后代的肌肉线粒体密度降低了38%。这些变化与IR后代中IRS-1 Ser312和IRS-1 Ser636磷酸化增加50%以及胰岛素刺激的Akt激活减少约60%相关。这些数据提供了对可能导致2型糖尿病发展的早期缺陷的新见解，并支持了线粒体含量减少导致线粒体功能下降的假设，线粒体功能下降使IR后代更易发生细胞内脂质积累，进而激活丝氨酸激酶级联，导致胰岛素信号传导和肌肉作用的缺陷。
To further explore the nature of the mitochondrial dysfunction and insulin resistance that occur in the muscle of young, lean, normoglycemic, insulin-resistant offspring of parents with type 2 diabetes (IR offspring), we measured mitochondrial. content by electron microscopy and insulin signaling in muscle biopsy samples obtained from these individuals before and during a hyperinsulinemic-euglycemic clamp. The rate of insulin-stimulated muscle glucose uptake was approximately 60% lower in the IR offspring than the control subjects and was associated with an approximately 60% increase in the intramyocellular lipid content as assessed by H-1 magnetic resonance spectroscopy. Muscle mitochondrial density was 38% lower in the IR offspring. These changes were associated with a 50% increase in IRS-1 Ser312 and IRS-1 Ser636 phosphorylation and an approximately 60% reduction in insulin-stimulated Akt activation in the IR offspring. These data provide new insights into the earliest defects that may be responsible for the development of type 2 diabetes and support the hypothesis that reductions in mitochondrial content result in decreased mitochondrial function, which predisposes IR offspring to intramyocellular lipid accumulation, which in turn activates a serine kinase cascade that leads to defects in insulin signaling and action in muscle.