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/jci200213305
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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
胰岛素作用的关键成分是磷酸肌醇（PI）3-激酶。PI 3-激酶的主要调节亚基p85 α及其剪接变体由Pik 3r 1基因编码。Pik 3r 1的杂合破坏改善正常小鼠和通过胰岛素受体和/或胰岛素受体底物-1（IRS 1）基因的杂合缺失而产生胰岛素抵抗的小鼠中的胰岛素信号传导和葡萄糖稳态。p85表达减少调节该蛋白、PI 3-激酶的p110催化亚基和IRS蛋白之间的分子平衡。因此，尽管p85 α降低，PI 3-激酶激活是正常的，胰岛素刺激的Akt活性增加，葡萄糖耐量和胰岛素敏感性得到改善。此外，Pik 3r 1杂合性保护具有遗传性胰岛素抵抗的小鼠免于发展糖尿病。这些数据表明，p85 α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.