Reduced expression of the murine p85α subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes
Reduced expression of the murine p85α subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes
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DOI：
10.1172/jci13305
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发表时间：
2002-01-01
影响因子：
15.9
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Mauvais-Jarvis, F;Ueki, K;Kahn, CR
胰岛素作用的一个关键成分是磷脂酰肌醇(PI)3-激酶。Pik3r1基因编码PI3-激酶的主要调节亚基p85pha及其剪接变异体。杂合性破坏Pik3r1改善了正常小鼠和因胰岛素受体和/或胰岛素受体底物-1(IRS1)基因杂合缺失而产生胰岛素抵抗的小鼠的胰岛素信号和葡萄糖稳态。P85的表达减少调节了该蛋白、PI3-激酶的p110催化亚基和IRS蛋白之间的分子平衡。因此，尽管p85α降低，但PI 3-激酶活性正常，胰岛素刺激的Akt活性增加，糖耐量和胰岛素敏感性得到改善。此外，Pik3r1杂合子可以保护遗传性胰岛素抵抗小鼠免受糖尿病的侵袭。这些数据表明，p85α水平的调节可能为2型糖尿病的治疗提供一个新的治疗靶点。
A critical component of insulin action is the enzyme phosphoinositide (PI) 3-kinase. The major regulatory subunits of PI 3-kinase, p85alpha and its splice variants, are encoded by the Pik3r1 gene. Heterozygous disruption of Pik3r1 improves insulin signaling and glucose homeostasis in normal mice and mice made insulin-resistant by heterozygous deletion of the Insulin receptor and/or insulin receptor substrate-1 (IRS1) genes. Reduced expression of p85 modulates the molecular balance between this protein, the p 110 catalytic subunit of PI 3-kinase, and the IRS proteins. Thus, despite the decrease in p85alpha, PI 3-kinase activation is normal, insulin-stimulated Akt activity is increased, and glucose tolerance and insulin sensitivity are improved. Furthermore, Pik3r1 heterozygosity protects mice with genetic insulin resistance from developing diabetes. These data suggest that regulation of p85alpha levels may provide a novel therapeutic target for the treatment of type 2 diabetes.