Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory β-cell hyperplasia
Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory β-cell hyperplasia
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DOI：
10.2337/diabetes.49.11.1880
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发表时间：
2000-11-01
期刊：
影响因子：
7.7
通讯作者：
Kadowaki, T
中科院分区：
文献类型：
--
作者：
Kubota, N;Tobe, K;Kadowaki, T
为了研究胰岛素受体底物（IRS）-2在体内的作用，我们通过基因打靶产生IRS-2缺陷小鼠。虽然纯合子IRS-2缺陷小鼠（IRS-2（-/-）小鼠）的体重与野生型小鼠相似，但它们在10周时逐渐发展为2型糖尿病。IRS-2（-/-）小鼠表现出胰岛素抵抗和肝脏中胰岛素刺激信号通路的缺陷，但骨骼肌中没有。尽管存在胰岛素抵抗，但β细胞的量减少到野生型小鼠的83%，这与IRS-1缺陷小鼠（IRS-1（-/-）小鼠）中β细胞的量增加85%以补偿胰岛素抵抗形成鲜明对比。因此，IRS-2在β细胞群的调节中起着至关重要的作用。另一方面，与野生型小鼠相比，IRS-2（-/-）小鼠中相同数量的细胞响应于离体测量的葡萄糖的胰岛素分泌显著增加，但IRS-1（-/-）小鼠中减少。这些结果表明，IRS-1和IRS-S可能在β细胞质量和单个β细胞功能的调节中发挥不同的作用。
To investigate the role of insulin receptor substrate (IRS)-2 in vivo, we generated IRS-2-deficient mice by gene targeting. Although homozygous IRS-2-deficient mice (IRS-2(-/-) mice) had a body weight similar to wildtype mice, they progressively developed type 2 diabetes at 10 weeks. IRS-2(-/-) mice showed insulin resistance and a defect in the insulin-stimulated signaling pathway in liver but not in skeletal muscle. Despite insulin resistance, the amount of beta -cells was reduced to 83% of that in wild-type mice, which was in marked contrast to the 85% increase in the amount of beta -cells in IRS-1-deficient mice (IRS-1(-/-) mice) to compensate for insulin resistance. Thus, IRS-2 plays a crucial role in the regulation of beta -cell mass. On the other hand, insulin secretion by the same number of cells in response to glucose measured ex vivo was significantly increased in IRS-2(-/-) mice compared with wild-type mice but was decreased in IRS-1(-/-) mice. These results suggest that IRS-1 and IRS-S may play different roles in the regulation of beta -cell mass and the function of individual beta -cells.