Dissection of the Mechanism of Diabetes by Genetically Engineered Animals

为了研究胰岛素抵抗的机制，我们采用基因靶向的方法制备了几种模型小鼠。到目前为止，我们已经获得了胰岛素受体底物(IRS)-1 (Tamemoto, et al.: Nature 372: 182-186,1994) PI3激酶p85调控亚基（Terauchi, et al.: Nature Genetics 21: 23 -235,1999）和PPARγ基因（Kubota, et al.: Mol.Cell 4: 567-609, 1999）缺陷小鼠。这些小鼠使我们能够解剖(1)胰岛素抵抗和胰岛素分泌功能障碍如何导致糖尿病的发展，(2)肝脏、骨骼肌、脂肪组织和胰腺β细胞等各个器官的缺陷如何导致糖尿病的发展。我们还能够找到补偿目标基因的途径。虽然IRS-1缺陷小鼠存在胰岛素抵抗，但它们仍保持正常的葡萄糖耐量，因为胰岛素抵抗可通过与β细胞增生相关的高胰岛素血症来补偿（Yamauchi等人：Mol.Cell.Biol）。16: 3074-3084, 1996)。通过将IRS-1-/-小鼠与胰岛素分泌功能障碍的h -葡萄糖激酶缺陷小鼠杂交，我们得出结论，胰岛素抵抗和胰岛素分泌功能障碍对于糖尿病的发展是必要的（Terauchi, et al.: J.Clin.Invest.）。99: 861 - 866, 1997)。我们还证明IRS-1-/-小鼠是“X综合征”的模型，因为它们在骨骼肌中表现出胰岛素抵抗、高甘油三酯血症、低高密度脂蛋白胆固醇、高血压和内皮功能障碍（Abe等：J. cline . invest）。101: 1784 - 1788, 1998)。我们还发现了一种新的胰岛素受体底物（IRS-2），它补偿IRS-1并介导IRS-1-/-小鼠的胰岛素作用（Tobe, et al.: j.b ol.chem）。270: 5698 - 5701, 1995)。目前，我们培养了IRS-2缺陷小鼠，并证明这些小鼠由于肝脏胰岛素抵抗和β细胞生长衰竭而发展为糖尿病（Kubota等人：糖尿病49:1880-1889,2000）。我们还报道了IRS-2-/-小鼠由于下丘脑瘦素抵抗而发生肥胖和脂肪肝（Tobe等：j.b oll . chem）。276-38337-38340, 2001)。少

In order to study the mechanism of insulin resistance, we generated several model mice by gene targeting. So far, we generated mice deficient in insulin receptor substrate (IRS)-1 (Tamemoto, et al.: Nature 372: 182-186,1994) PI3 kinase p85 regulatory subunit (Terauchi, et al.: Nature Genetics 21: 230-235,1999) and PPARγ gene (Kubota, et al.: Mol.Cell 4: 567-609, 1999). These mice enabled us to dissect (1)how insulin resistance and insulin secretory dysfunction lead to the development of diabetes, (2)how defects in each organ such us liver, skeletal muscle, adipose tissue and pancreatic β cells are responsible for the development of diabetes. We also were able to find pathways which compensate for the targeted gene. Although IRS-1 deficient mice were insulin resistant, they remaind normal glucose tolerance, because insulin resistance was compensated by hyperinsulinemia associated with β cell hyperplasia (Yamauchi, et al.: Mol.Cell.Biol. 16: 3074-3084, 1996). By crossing IRS-1-/-mice wit … More h glucokinase deficient mice with insulin secretory dysfunction, we came to the conclusion that both insulin resistance and insulin secretory dysfunction are necessary for the development of diabetes (Terauchi, et al.: J.Clin.Invest. 99: 861-866,1997).We also demonstrated that IRS-1-/-mice were a model for "Syndrome X" because they showed insulin resistance in skeletal muscle, hypertriglycerolemia, lower HDL Chol, hypertension and endothelial dysfunction (Abe, et al.: J. Clin.Invest. 101: 1784-1788,1998.). We also found a novel insulin receptor substrate, (IRS-2) which compensated IRS-1 and mediated insulin action in IRS-1-/-mice (Tobe, et al.: J.Biol.Chem. 270: 5698-5701,1995). Currently, we generated IRS-2 deficient mice and demonstrated that these mice developed diabetes due to insulin resistance in liver and β cell growth failure (Kubota, et al.: Diabetes 49: 1880-1889, 2000). We also reported that IRS-2-/-mice developed obesity and fatty liver due to leptin resistance in the hypothrlamus (Tobe, et al.: J.Biol.Chem. 276-38337-38340, 2001). Less