Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus.
Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus.
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DOI：
10.1172/jci21484
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发表时间：
2004-10
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影响因子：
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通讯作者：
N. Kubota;Y. Terauchi;K. Tobe;Wataru Yano;R. Suzuki;K. Ueki;Iseki Takamoto;H. Satoh;Toshiyuki Maki;Tetsuya Kubota;M. Moroi;Miki Okada-Iwabu;O. Ezaki;R. Nagai;Y. Ueta;T. Kadowaki;T. Noda
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作者：
N. Kubota;Y. Terauchi;K. Tobe;Wataru Yano;R. Suzuki;K. Ueki;Iseki Takamoto;H. Satoh;Toshiyuki Maki;Tetsuya Kubota;M. Moroi;Miki Okada-Iwabu;O. Ezaki;R. Nagai;Y. Ueta;T. Kadowaki;T. Noda
我们之前证明胰岛素受体底物2 (Irs2) KO小鼠发生糖尿病与肝脏胰岛素抵抗、代偿性β细胞增生缺乏和瘦素抵抗相关。为了更精确地确定Irs2在β细胞和下丘脑中的作用，我们产生了β细胞特异性Irs2 KO和下丘脑特异性Irs2敲低（betaHT-IRS2）小鼠。Irs2 mRNA在胰岛中的表达减少了约90%，在下丘脑弓状核中的表达也明显减少。相比之下，β - Irs2小鼠的肝脏、肌肉和脂肪组织中的Irs2表达与对照小鼠没有区别。β - irs2小鼠表现出肥胖和瘦素抵抗。在4周龄时，β - irs2小鼠表现出正常的胰岛素敏感性，但在8周和12周时，它们出现胰岛素抵抗并伴有进行性肥胖。尽管在8周的热量限制下它们的胰岛素敏感性正常，但β - irs2小鼠表现出葡萄糖耐受不良和葡萄糖诱导的胰岛素分泌受损。β - irs2小鼠的β细胞质量和β细胞增殖在第8周和12周显著减少，但在第10天没有。在高葡萄糖浓度下，β - irs2小鼠的胰岛素分泌显著增加，每个胰岛的细胞数量正常化。我们得出结论，在β细胞和下丘脑中，Irs2在调节β细胞质量和瘦素敏感性中起着至关重要的作用。
We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory beta cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in beta cells and the hypothalamus, we generated beta cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (betaHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of betaHT-IRS2 mice was indistinguishable from that of control mice. The betaHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the betaHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the betaHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. beta Cell mass and beta cell proliferation in the betaHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the betaHT-IRS2 mice. We conclude that, in beta cells and the hypothalamus, Irs2 is crucially involved in the regulation of beta cell mass and leptin sensitivity.