Dissection of the role of IRS family proteins in the growth and development of pancreatic β cells

胰岛素受体底物(IRS)1-1和IRS-2是胰岛素受体酪氨酸激酶和胰岛素样生长因子受体酪氨酸激酶的两种主要底物。小鼠有胰岛素抵抗的骨骼肌，但不会患糖尿病，因为β细胞能够经历增殖并分泌更多的胰岛素来补偿胰岛素抵抗。相比之下，Irs2^&lt；-/-&gt；小鼠患糖尿病是因为β-细胞因肥胖和肝脏中的胰岛素信号缺陷而导致的胰岛素抵抗而不能发生增殖。我们还通过与大鼠胰岛素II启动子(RIP)-Cre和irs2/loxP小鼠杂交，在β细胞和下丘脑中培育了缺失irs2的小鼠。来自两个实验室的条件性基因敲除小鼠通常表现出高血糖，伴随着β细胞质量减少和肥胖。在我们的动物中，我们将其命名为βHT-IRS2小鼠，β细胞的增殖显著降低。这些研究表明，胰岛素样生长因子-2在成年动物β细胞质量的调节中起着至关重要的作用。我们还发现，在高脂饮食喂养的野生型小鼠的胰岛中，β细胞的生长和Irs2的表达都有明显的诱导作用。由于我们观察到高脂饮食喂养的葡萄糖激酶(+/-)小鼠胰岛中Irs2蛋白的表达减少和β细胞生长减弱，我们得出结论，GCK和Irs2是高脂饮食诱导的胰岛素抵抗导致β细胞增殖的关键条件。

Insulin receptor substrate (IRS)^1-1 and IRS-2 are two major substrates for insulin receptor tyrosine kinase and insulin-like growth factor (IGF) receptor tyrosine kinase. Irs1^<-/-> mice have insulin-resistant skeletal muscles but do not develop diabetes because β-cells are able to undergo hyperplasia and secrete more insulin to compensate for the insulin resistance. In contrast, Irs2^<-/-> mice develop diabetes because β-cells failed to undergo hyperplasia in response to insulin resistance due to obesity and insulin signaling defects in the liver. We also developed mice lacking Irs2 in β-cells and the hypothalamus by crossing rat insulin II promoter (RIP)-Cre and irs2/loxP mice. The conditional knockout mice from either laboratory commonly show hyperglycemia with β-cell mass reduction and obesity. In our animals, which we designated βHT-IRS2 mice, β-cell proliferation is significantly decreased. These studies point to the conclusion that IRS-2 is crucial to the regulation of β-cell mass in adult animals. We also showed marked induction of β-cell growth and Irs2 expression in the islets of high fat diet-fed wild-type mice. Since we observed reduced expression of Irs2 protein and attenuated β-cell growth in the islets of high fat diet-fed glucokinase(+/-) mice, we conclude that Gck and Irs2 are critical requirements for β-cell hyperplasia to occur in response to high fat diet-induced insulin resistance.