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

解析IRS家族蛋白在胰腺β细胞生长发育中的作用

• 批准号: 17390261
• 负责人: TOBE Kazuyuki
• 金额: $ 9.86万
• 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: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390261/
• 关键词: pancreatic β cell; β cell proliferation; IRS; IRS-2; High Fat Diet; insulin secretion; diabetes; 増殖

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.

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（IGF）受体酪氨酸激酶的两种主要底物。Irs 1 ^<-/->小鼠具有胰岛素抵抗骨骼肌，但不会发展成糖尿病，因为β细胞能够经历增生并分泌更多胰岛素以补偿胰岛素抵抗。相比之下，Irs 2 ^<-/->小鼠发展糖尿病，因为β-细胞未能响应于由于肥胖和肝脏中的胰岛素信号传导缺陷引起的胰岛素抵抗而经历增生。我们还通过将大鼠胰岛素II启动子（RIP）-Cre和irs 2/loxP小鼠杂交来开发β细胞和下丘脑中缺乏Irs 2的小鼠。来自任一实验室的条件性基因敲除小鼠通常显示高血糖症伴β细胞质量减少和肥胖。在我们命名为β HT-IRS 2小鼠的动物中，β细胞增殖显著降低。这些研究表明，IRS-2对成年动物β细胞群的调节至关重要。我们还显示在高脂肪饮食喂养的野生型小鼠的胰岛中显著诱导β细胞生长和Irs 2表达。由于我们观察到高脂饮食喂养的葡萄糖激酶（+/-）小鼠胰岛中Irs 2蛋白表达减少和β细胞生长减弱，我们得出结论，Gck和Irs 2是响应高脂饮食诱导的胰岛素抵抗而发生β细胞增生的关键要求。

项目成果

Overexpression of MCP-1 in adipose tissues causes macrophage recruitment and insulin resistance

脂肪组织中 MCP-1 的过度表达导致巨噬细胞募集和胰岛素抵抗

• 发表时间: 2006
• 期刊: J. Biol. Chem 281
• 作者: Kamei N;Tobe K;Suzuki R;Ohsugi M;Watanabe T;Kubota N;Ohtsuka-Kowatari N;Kumagai K;Sakamoto K;Kobayashi M;Yamauchi T;Ueki K;Oishi Y;Nishimura S;Manabe I;Hashimoto H;Ohnishi Y;Ogata H;Tokuyama K;Tsunoda M;Ide T;Murakami K;Nagai R;Kado
• 通讯作者: Kado

Adiponectin-dependent and -independent pathways in insulin-sensitizing and antidiabetic actions of thiazolidinediones

• DOI: 10.2337/db06-s005
• 发表时间: 2006-12-01
• 期刊: DIABETES
• 影响因子: 7.7
• 作者: Kubota, Naoto;Yamauchi, Toshimasa;Kadowaki, Takashi
• 通讯作者: Kadowaki, Takashi

Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin dependent and independent pathway.

吡格列酮通过脂联素依赖性和非依赖性途径改善胰岛素抵抗和糖尿病。

• 发表时间: 2006
• 期刊: J. Biol. Chem. 281(13)
• 作者: N.Kubota;T.Noda et al.(total 20;18th)
• 通讯作者: 18th)

Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis

• DOI: 10.1016/j.cmet.2006.02.010
• 发表时间: 2006-04-01
• 期刊: CELL METABOLISM
• 影响因子: 29
• 作者: Baumgartl, J;Baudler, S;Brüning, JC
• 通讯作者: Brüning, JC

Hepatocyte nuclear factor-4alpha P2 promoter haplotypes are associated with type 2 diabetes in the Japanese population.

肝细胞核因子 4α P2 启动子单倍型与日本人群的 2 型糖尿病相关。

• 发表时间: 2006
• 期刊: Diabetes 55・5
• 作者: Hara K;Horikoshi M;Yamauchi T;Yago H;Miyazaki O;Ebinuma H;Imai Y;Nagai R;Kadowaki T.;Hara K
• 通讯作者: Hara K