Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction
Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction
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DOI：
10.2337/db06-s002
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发表时间：
2006-12-01
期刊：
影响因子：
7.7
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
--
作者：
Morino, Katsutaro;Petersen, Kitt Falk;Shulman, Gerald I.
最近使用磁共振波谱的研究表明，由于胰岛素刺激的葡萄糖转运活性缺陷导致的胰岛素刺激的肌糖原合成减少是2型糖尿病发病机制的主要因素。胰岛素刺激的葡萄糖转运活性缺陷的分子机制可归因于肌细胞内脂质代谢产物（如脂肪酰辅酶A和二酰甘油）的增加，这反过来又激活丝氨酸/苏氨酸激酶级联，从而导致胰岛素信号转导缺陷（通过胰岛素受体底物（IRS）-1的Ser/Thr磷酸化）。在与非酒精性脂肪肝相关的肝胰岛素抵抗中也观察到类似的机制，这是2型糖尿病的常见特征，其中肝细胞二酰甘油含量增加激活蛋白激酶C-CRP，导致胰岛素刺激的IRS-2酪氨酸磷酸化减少。最近，磁共振波谱研究在健康瘦老年人和健康瘦胰岛素抵抗的后代的父母与2型糖尿病已经证明，线粒体功能降低可能使这些人易患肌细胞内脂质积累和胰岛素抵抗。进一步的分析发现，胰岛素抵抗后代中线粒体功能的降低主要归因于线粒体密度的降低。通过阐明胰岛素抵抗的细胞和分子机制，这些研究为2型糖尿病的治疗和预防提供了潜在的新靶点。
Recent studies using magnetic resonance spectroscopy have shown that decreased insulin-stimulated muscle glycogen synthesis due to a defect in insulin-stimulated glucose transport activity is a major factor in the pathogenesis of type 2 diabetes. The molecular mechanism underlying defective insulin-stimulated glucose transport activity can be attributed to increases in intramyocellular lipid metabolites such as fatty acyl CoAs and diacylglycerol, which in turn activate a serine/threonine kinase cascade, thus leading to defects in insulin signaling through Ser/Thr phosphorylation of insulin receptor substrate (IRS)-1. A similar mechanism is also observed in hepatic insulin resistance associated with nonalcoholic fatty liver, which is a common feature of type 2 diabetes, where increases in hepatocellular diacylglycerol content activate protein kinase C-epsilon, leading to reduced insulin-stimulated tyrosine phosphorylation of IRS-2. More recently, magnetic resonance spectroscopy studies in healthy lean elderly subjects and healthy lean insulin-resistant offspring of parents with type 2 diabetes have demonstrated that reduced mitochondrial function may predispose these individuals to intramyocellular lipid accumulation and insulin resistance. Further analysis has found that the reduction in mitochondrial function in the insulin-resistant offspring can be mostly attributed to reductions in mitochondrial density. By elucidating the cellular and molecular mechanisms responsible for insulin resistance, these studies provide potential new targets for the treatment and prevention of type 2 diabetes.