Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance
Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance
复制标题
IRTKS 作为胰岛素受体适配器的缺陷导致胰岛素抵抗
DOI：
10.1038/cr.2013.99
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发表时间：
2013-11-01
期刊：
影响因子：
44.1
通讯作者：
Han, Ze-Guang
中科院分区：
文献类型：
--
作者：
Huang, Li-Yu;Wang, Yu-Ping;Han, Ze-Guang
IRTKS编码IRSp 53/MIM同源结构域家族的成员，其已被证明在质膜突起的形成中起重要作用。虽然IRTKS的磷酸化反应发生在胰岛素刺激，这种蛋白在胰岛素信号转导中的作用仍然未知。在这里，我们表明，IRTKS缺陷小鼠表现出胰岛素抵抗，包括高血糖症，高胰岛素血症，葡萄糖耐受不良，胰岛素敏感性下降，并增加肝脏葡萄糖的生产。异位IRTKS的给药可以改善IRTKS缺陷和糖尿病小鼠的胰岛素抵抗。与此同时，IRTKS的表达水平在糖尿病小鼠模型中显著降低。此外，在这些受试者中还观察到IRTKS启动子的DNA超甲基化。我们还发现IRTKS作为胰岛素受体（IR）的一个适配子，通过调节IR的磷酸化来调节IR-IRS 1-PI 3 K-AKT信号通路，这些发现为我们对胰岛素信号通路和胰岛素抵抗的理解提供了新的视角。
IRTKS encodes a member of the IRSp53/MIM homology domain family, which has been shown to play an important role in the formation of plasma membrane protrusions. Although the phosphorylation of IRTKS occurs in response to insulin stimulation, the role of this protein in insulin signaling remains unknown. Here we show that IRTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production. The administration of ectopic IRTKS can ameliorate the insulin resistance of IRTKS-deficient and diabetic mice. In parallel, the expression level of IRTKS was significantly decreased in diabetic mouse model. Furthermore, DNA hypermethylation of the IRTKS promoter was also observed in these subjects. We also show that IRTKS, as an adaptor of the insulin receptor (IR), modulates IR-IRS1-PI3K-AKT signaling via regulating the phosphorylation of IR. These findings add new insights into our understanding of insulin signaling and resistance.