Dissecting the role of insulin resistance in the metabolic syndrome.
Dissecting the role of insulin resistance in the metabolic syndrome.
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DOI：
10.1097/mol.0b013e32832b2024
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发表时间：
2009-06
影响因子：
4.4
通讯作者：
Biddinger SB
中科院分区：
文献类型：
--
作者：
Haas JT;Biddinger SB
二十多年前，胰岛素抵抗被认为在代谢综合征的发病机制中起核心作用。然而，这一点很难证明，导致该领域内存在很大争议。最近对胰岛素信号传导存在遗传缺陷的小鼠和人类的研究首次使我们能够剖析胰岛素抵抗可能导致的代谢综合征的哪些特征。具有胰岛素受体的肝脏特异性敲除（LIRKO）的小鼠显示肝脏胰岛素抗性可产生（1）高血糖症;（2）增加的Apob分泌和动脉粥样硬化;和（3）增加的胆汁胆固醇分泌和胆固醇结石。这些变化中的许多可能是由于转录因子FoxO 1的去抑制。然而，无论是LIRKO小鼠还是胰岛素受体突变的人，都不会发生与代谢综合征相关的高甘油三酯血症或肝脂肪变性。这些数据表明胰岛素抵抗在代谢综合征的发病机制中起中心作用，因为高血糖症、动脉粥样硬化和胆固醇结石都可以由胰岛素抵抗引起。然而，高脂血症和肝脂肪变性并不直接归因于胰岛素抵抗，而应被视为代谢综合征的不同病理特征。
Over twenty years ago, insulin resistance was postulated to play a central role in the pathogenesis of the metabolic syndrome. However, this has been difficult to prove, leading to a great deal of controversy within the field. Recent studies in mice and humans with genetic defects in insulin signaling have allowed us, for the first time, to dissect which features of the metabolic syndrome can be caused by insulin resistance. Mice with liver specific knockout of the insulin receptor (LIRKO) show that hepatic insulin resistance can produce (1) hyperglycemia; (2) increased Apob secretion and atherosclerosis; and (3) increased biliary cholesterol secretion and cholesterol gallstones. Many of these changes may be due to dis-inhibition of the transcription factor, FoxO1. Yet, neither LIRKO mice nor humans with insulin receptor mutations develop the hypertriglyceridemia or hepatic steatosis associated with the metabolic syndrome. These data point to a central role for insulin resistance in the pathogenesis of the metabolic syndrome, as hyperglycemia, atherosclerosis, and cholesterol gallstones can all be caused by insulin resistance. However, hypertriglyceridemia and hepatic steatosis are not due directly to insulin resistance, and should be considered pathogenically distinct features of the metabolic syndrome.