Dissection of the Mechanism of Diabetes by Genetically Engineered Animals

基因工程动物剖析糖尿病机制

• 批准号: 13470224
• 负责人: TOBE Kazuyuki
• 金额: $ 9.22万
• 依托单位: the University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470224/
• 关键词: insulin resistance; insulin receptor; SREBP-1; leptin resistance; fatty liver; IRS-2

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

为了研究胰岛素抵抗的发生机制，我们采用基因打靶的方法建立了胰岛素抵抗小鼠模型。到目前为止，我们产生了胰岛素受体底物（IRS）-1缺陷的小鼠（Tamemoto等人：Nature 372：182- 186，1994）PI 3激酶p85调节亚基（Terauchi等：Nature Genetics 21：230- 235，1999）和PPARγ基因（Kubota等人：Mol.Cell 4：567-609，1999）。这些小鼠使我们能够剖析（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）每个器官如肝脏，骨骼肌，脂肪组织和胰腺β细胞的缺陷如何导致糖尿病的发展。我们还能够找到补偿靶基因的途径。尽管IRS-1缺陷小鼠具有胰岛素抗性，但它们具有正常的葡萄糖耐量，因为胰岛素抗性通过与β细胞增生相关的高胰岛素血症得到补偿（Yamauchi等人：16：3074-3084，1996）。通过将IRS-1-/-小鼠与 ...更多信息 h具有胰岛素分泌功能障碍的葡萄糖激酶缺陷小鼠，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需的（Terauchi，et al.：J.Clin.Invest.九十九：861- 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抗性、高胆固醇血症、低HDL Chol、高血压和内皮功能障碍（Abe，等人：J. Clin.Invest. 101：1784- 1788，1998）。我们还发现了一种新的胰岛素受体底物（IRS-2），其补偿IRS-1并介导IRS-1-/-小鼠中的胰岛素作用（Tobe等人：270：5698- 5701，1995）。目前，我们产生了IRS-2缺陷小鼠，并证明这些小鼠由于肝脏中的胰岛素抵抗和β细胞生长失败而发展为糖尿病（Kubota等人：Diabetes 49：1880-1889，2000）。我们还报道了IRS-2-/-小鼠由于下丘脑中的瘦素抗性而发展肥胖和脂肪肝（Tobe等人：J.Biol.Chem. 276-38337-38340，2001）。少

项目成果

Chen, W.S., et al.: "Growth retardation and increased apoptosis in mice with homozygous disruption of the akt1 gene."Genes Dev.. 15. 2203-2208 (2001)

Chen, W.S. 等人：“AKT1 基因纯合破坏的小鼠中生长迟缓和细胞凋亡增加。”Genes Dev.. 15. 2203-2208 (2001)

Yamauchi, T., et al.: "Replenishment of the fat-derived hormone adiponectin reverses insulin resistance in lipoatrophic diabetes and type 2 diabetes."Nature Medicine. 7. 941-946 (2001)

Yamauchi, T. 等人：“补充脂肪源性激素脂联素可逆转脂肪萎缩性糖尿病和 2 型糖尿病的胰岛素抵抗。”《自然医学》。

Tobe, K., et al.: "Increased Expression of SREBP-1 gene in IRS-2(-/-) mice liver."J.Biol.Chem.. 276. 38337-38340 (2001)

Tobe, K., 等人：“IRS-2(-/-) 小鼠肝脏中 SREBP-1 基因的表达增加。”J.Biol.Chem.. 276. 38337-38340 (2001)

Yamauchi, T., et al.: "The central role of PPARγ in the regulation of insulin sensitivity"J.Clim.Invest.. 108. 1001-1013 (2001)

Yamauchi, T., et al.：“PPARγ 在胰岛素敏感性调节中的核心作用”J.Clim.Invest.. 108. 1001-1013 (2001)

Tsuji, Y., et al.: "Distinct subcellular localization and IRS family proteins associating PI3-kinase activity following insulin stimulation and its functional implications in primary mice adipocytes"Diabetes. 50. 1455-1463 (2001)

Tsuji, Y. 等人：“胰岛素刺激后与 PI3 激酶活性相关的独特亚细胞定位和 IRS 家族蛋白及其对原代小鼠脂肪细胞的功能影响”糖尿病。