Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance
Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance
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DOI：
10.1128/mcb.24.17.7435-7443.2004
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发表时间：
2004-09-01
影响因子：
5.3
通讯作者：
Rui, LY
中科院分区：
文献类型：
--
作者：
Duan, CJ;Yang, HY;Rui, LY
胰岛素通过结合和激活胰岛素受体调节葡萄糖稳态，胰岛素反应缺陷（胰岛素抵抗）诱发2型糖尿病。SH2- b是Src同源2 （SH2）和pleckstrin同源结构域的衔接蛋白，在胰岛素应答中通过其SH2结构域与胰岛素受体结合；然而，其生理作用尚不清楚。我们发现SH2-B在肝脏、骨骼肌和脂肪中表达。SH2-B的全身性缺失会损害肝脏、骨骼肌和脂肪中的胰岛素受体激活和信号传导，包括胰岛素受体底物1 （IRS1）和IRS2的酪氨酸磷酸化以及磷脂酰肌醇3-激酶/Akt和Erk1/2通路的激活。因此，SH2-B-/-敲除小鼠出现年龄依赖性高胰岛素血症、高血糖症和葡萄糖耐受不良。此外，SH2- b在培养细胞中以SH2结构域依赖的方式直接增强胰岛素受体的自磷酸化和IRS1和IRS2的酪氨酸磷酸化。我们的数据表明SH2-B是胰岛素受体激活的生理增强剂，在衰老过程中维持正常的胰岛素敏感性和葡萄糖稳态所必需的。
Insulin regulates glucose homeostasis by binding and activating the insulin receptor, and defects in insulin responses (insulin resistance) induce type 2 diabetes. SH2-B, an Src homology 2 (SH2) and pleckstrin homology domain-containing adaptor protein, binds via its SH2 domain to insulin receptor in response to insulin; however, its physiological role remains unclear. Here we show that SH2-B was expressed in the liver, skeletal muscle, and fat. Systemic deletion of SH2-B impaired insulin receptor activation and signaling in the liver, skeletal muscle, and fat, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and IRS2 and activation of the phosphatidylinositol 3-kinase/Akt and the Erk1/2 pathways. Consequently, SH2-B-/- knockout mice developed age-dependent hyperinsulinemia, hyperglycemia, and glucose intolerance. Moreover, SH2-B directly enhanced autophosphorylation of insulin receptor and tyrosine phosphorylation of IRS1 and IRS2 in an SH2 domain-dependent manner in cultured cells. Our data suggest that SH2-B is a physiological enhancer of insulin receptor activation and is required for maintaining normal insulin sensitivity and glucose homeostasis during aging.