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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor
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Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor

机译：高胰岛素血症导致GLUT4葡萄糖转运蛋白和FoxO1转录因子的胰岛素调节不耦合

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Insulin resistance is a component of the metabolic syndrome and Type 2 diabetes. It has been recently shown that in liver insulin resistance is not complete. This so-called selective insulin resistance is characterized by defective insulin inhibition of hepatic glucose output while insulin-induced lipogenesis is maintained. How this occurs and whether uncoupled insulin action develops in other tissues is unknown. Here we show in a model of chronic hyperinsulinemia that adipocytes develop selective insulin resistance in which translocation of the GLUT4 glucose transporter to the cell surface is blunted yet nuclear exclusion of the FoxOI transcription factor is preserved, rendering uncoupled insulin-controlled carbohydrate and lipid metabolisms. We found that in adipocytes FoxOI nuclear exclusion has a lower half-maximal insulin dose than GLUT4 translocation, and it is because of this inherent greater sensitivity that control of FoxOI by physiological insulin concentrations is maintained in adipocytes with compromised insulin signaling. Pharmacological and genetic interventions revealed that insulin regulates GLUT4 and FoxOI through the PI3-kinase isoform p11 Oα, although FoxOI showed higher sensitivity to p110α activity than GLUT4. Transient down-regulation and overexpression of Akt isoforms in adipocytes demonstrated that insulin-activated PI3-kinase signals to GLUT4 primarily through Akt2 kinase, whereas Akt1 and Akt2 signal to FoxO1. We propose that the lower threshold of insulin activity for FoxO1's nuclear exclusion is in part due to its regulation by both Akt isoforms. Identification.of uncoupled insulin action in adipocytes suggests this condition might be a general phenomenon of insulin target tissues contributing to insulin resistance's pathophysiology.
机译：胰岛素抵抗是代谢综合征和2型糖尿病的组成部分。最近已经表明，肝脏中胰岛素抵抗还不完全。这种所谓的选择性胰岛素抵抗的特征在于，在维持胰岛素诱导的脂肪生成的同时，胰岛素抑制肝葡萄糖输出的缺陷。这是如何发生的以及在其他组织中是否会产生未偶联的胰岛素作用尚不清楚。在这里，我们在慢性高胰岛素血症模型中显示，脂肪细胞发展出选择性的胰岛素抵抗，其中GLUT4葡萄糖转运蛋白向细胞表面的转运变钝，但保留了FoxOI转录因子的核排斥，从而使胰岛素控制的碳水化合物和脂质代谢解偶联。我们发现，在脂肪细胞中，FoxOI核排斥的半数最大胰岛素剂量低于GLUT4易位，并且由于这种固有的更高的敏感性，在胰岛素信号受损的脂肪细胞中，通过生理胰岛素浓度对FoxOI的控制得以维持。药理和遗传学干预表明，尽管FoxOI对p110α活性的敏感性高于GLUT4，但胰岛素通过PI3-激酶同工型p11Oα调节GLUT4和FoxOI。脂肪细胞中Akt亚型的瞬时下调和过度表达表明，胰岛素激活的PI3激酶主要通过Akt2激酶传递给GLUT4，而Akt1和Akt2传递给FoxO1。我们认为，对于FoxO1的核排斥，胰岛素活性的较低阈值部分是由于其受两种Akt亚型的调节。脂肪细胞中未偶联的胰岛素作用的鉴定表明，这种情况可能是胰岛素靶组织引起胰岛素抵抗的病理生理的普遍现象。

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    Eva Gonzalez; Emily Flier; Dorothee Molle; Domenico Accili; Timothy E. McGraw;

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    Biochemistry Department, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065;

    Biochemistry Department, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065;

    Biochemistry Department, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065;

    Columbia University College of Physicians and Surgeons, New York, NY 10032;

    Biochemistry Department, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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