Targeted Disruption of ROCK1 Causes Insulin Resistance in Vivo
Targeted Disruption of ROCK1 Causes Insulin Resistance in Vivo
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DOI：
10.1074/jbc.c900014200
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发表时间：
2009-05-01
影响因子：
4.8
通讯作者：
Kim, Young-Bum
中科院分区：
文献类型：
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作者：
Lee, Dae Ho;Shi, Jianjian;Kim, Young-Bum
胰岛素信号对正常的葡萄糖稳态至关重要。rho激酶（ROCK）异构体在培养的细胞系中参与胰岛素信号传导和葡萄糖代谢。为了研究ROCK1在体内调节全身葡萄糖稳态和胰岛素敏感性中的生理作用，我们研究了ROCK1全局破坏的小鼠。在这里，我们发现，在16 - 18周龄时，rock1缺陷小鼠表现出胰岛素抵抗，胰岛素注射后血糖水平下降失败。然而，在没有ROCK1的情况下，葡萄糖耐量正常。这些影响与肥胖的变化无关。有趣的是，ROCK1基因消融导致葡萄糖诱导的胰岛素分泌显著增加，导致高胰岛素血症。为了确定ROCK1缺失导致胰岛素抵抗的机制，我们测量了胰岛素激活磷脂酰肌醇3-激酶和骨骼肌多个远端通路的能力。胰岛素刺激下与IRS-1或磷酸酪氨酸相关的磷脂酰肌醇3-激酶活性也降低了40%，而骨骼肌中胰岛素受体酪氨酸磷酸化没有任何改变。同时，体外ROCK磷酸化的IRS-1丝氨酸632/635位点丝氨酸磷酸化也在这些小鼠中受损。胰岛素诱导的Akt、AS160、S6K和S6磷酸化也在骨骼肌中降低。这些数据表明，ROCK1缺乏通过损害骨骼肌中的胰岛素信号通路导致全身胰岛素抵抗。因此，我们的研究结果确定了ROCK1是体内葡萄糖稳态和胰岛素敏感性的新调节因子，这可能为肥胖和2型糖尿病的治疗提供新的方法。
Insulin signaling is essential for normal glucose homeostasis. Rho-kinase (ROCK) isoforms have been shown to participate in insulin signaling and glucose metabolism in cultured cell lines. To investigate the physiological role of ROCK1 in the regulation of whole body glucose homeostasis and insulin sensitivity in vivo, we studied mice with global disruption of ROCK1. Here we show that, at 16 - 18 weeks of age, ROCK1-deficient mice exhibited insulin resistance, as revealed by the failure of blood glucose levels to decrease after insulin injection. However, glucose tolerance was normal in the absence of ROCK1. These effects were independent of changes in adiposity. Interestingly, ROCK1 gene ablation caused a significant increase in glucose-induced insulin secretion, leading to hyperinsulinemia. To determine the mechanism(s) by which deletion of ROCK1 causes insulin resistance, we measured the ability of insulin to activate phosphatidylinositol 3-kinase and multiple distal pathways in skeletal muscle. Insulin-stimulated phosphatidylinositol 3-kinase activity associated with IRS-1 or phospho-tyrosine was also reduced similar to 40% without any alteration in tyrosine phosphorylation of insulin receptor in skeletal muscle. Concurrently, serine phosphorylation of IRS-1 at serine 632/635, which is phosphorylated by ROCK in vitro, was also impaired in these mice. Insulin-induced phosphorylation of Akt, AS160, S6K, and S6 was also decreased in skeletal muscle. These data suggest that ROCK1 deficiency causes systemic insulin resistance by impairing insulin signaling in skeletal muscle. Thus, our results identify ROCK1 as a novel regulator of glucose homeostasis and insulin sensitivity in vivo, which could lead to new treatment approaches for obesity and type 2 diabetes.