Complete failure of insulin-transmitted signaling, but not obesity-induced insulin resistance, impairs respiratory chain function in muscle
Complete failure of insulin-transmitted signaling, but not obesity-induced insulin resistance, impairs respiratory chain function in muscle
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DOI：
10.1007/s00109-012-0887-y
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发表时间：
2012-10-01
影响因子：
4.7
通讯作者：
Wiesner, R. J.
中科院分区：
文献类型：
--
作者：
Franko, A.;von Kleist-Retzow, J. C.;Wiesner, R. J.
线粒体功能障碍在胰岛素抵抗和2型糖尿病发展中的作用仍然存在争议。为了明确胰岛素受体（InsR）信号传导、胰岛素抵抗、高血糖、高脂血症和线粒体功能之间的关系，我们分析了四种不同小鼠模型中胰岛素敏感、慢氧化肌肉的线粒体性能。在肥胖但血糖正常的ob/ob小鼠以及肥胖但糖尿病小鼠在高脂饮食下，线粒体性能保持不变，即使肌细胞内二酰基甘油（DAG），三酰基甘油（TAG），和神经酰胺积累。相比之下，在肌肉特异性InsR敲除（MIRKO）和链脲佐菌素（STZ）治疗的低胰岛素血症，高血糖小鼠，线粒体呼吸链复合物和线粒体功能的水平显着降低。在STZ中，而不是在MIRKO小鼠中，这是由PGC-1 α表达减少介导的线粒体基因转录减少引起的。我们的结论是，线粒体功能障碍是没有因果关系参与肥胖相关的胰岛素抵抗的发病机制在血糖正常的条件下。然而，肥胖相关的2型糖尿病和DAG或TAG的积累与线粒体功能受损无关。相比之下，STZ治疗小鼠中观察到的慢性低胰岛素血症和高血糖症以及MIRKO小鼠肌肉中InsR缺乏导致线粒体功能障碍。我们假设，在临床研究中观察到的非糖尿病、肥胖或2型糖尿病、肥胖患者骨骼肌线粒体质量和/或性能降低必须由遗传易感性、身体活动不足或其他未知因素解释。
The role of mitochondrial dysfunction in the development of insulin resistance and type 2 diabetes remains controversial. In order to specifically define the relationship between insulin receptor (InsR) signaling, insulin resistance, hyperglycemia, hyperlipidemia and mitochondrial function, we analyzed mitochondrial performance of insulin-sensitive, slow-oxidative muscle in four different mouse models. In obese but normoglycemic ob/ob mice as well as in obese but diabetic mice under high-fat diet, mitochondrial performance remained unchanged even though intramyocellular diacylglycerols (DAGs), triacylglycerols (TAGs), and ceramides accumulated. In contrast, in muscle-specific InsR knockout (MIRKO) and streptozotocin (STZ)-treated hypoinsulinemic, hyperglycemic mice, levels of mitochondrial respiratory chain complexes and mitochondrial function were markedly reduced. In STZ, but not in MIRKO mice, this was caused by reduced transcription of mitochondrial genes mediated via decreased PGC-1 alpha expression. We conclude that mitochondrial dysfunction is not causally involved in the pathogenesis of obesity-associated insulin resistance under normoglycemic conditions. However, obesity-associated type 2 diabetes and accumulation of DAGs or TAGs is not associated with impaired mitochondrial function. In contrast, chronic hypoinsulinemia and hyperglycemia as seen in STZ-treated mice as well as InsR deficiency in muscle of MIRKO mice lead to mitochondrial dysfunction. We postulate that decreased mitochondrial mass and/or performance in skeletal muscle of non-diabetic, obese or type 2 diabetic, obese patients observed in clinical studies must be explained by genetic predisposition, physical inactivity, or other still unknown factors.