Identifying the genes for insulin resistance in Japanese population.

鉴定日本人群的胰岛素抵抗基因。

• 批准号: 13204058
• 负责人: KASUGA Masato
• 金额: $ 59.01万
• 依托单位: Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine,
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13204058/
• 关键词: PKCλ; STAT3; PI 3-kinase; PDK-1; SREBP-1; p27^<kip1>; UCP1; Munc 18c; SREBP1; CPT1A; 罹患同胞対; SLC12A3; アデノウイルスベクター; PI3-キナーゼ; IRS-2; AMPK; UCP-1遺伝子; AMPK遺伝子; 2型糖尿病; インスリン抵抗性

1, We have investigated the mechanism of insulin signaling by analyzing knockout mice and cultured cells.PKClambda is implicated as a downstream effector of PI3K in insulin action. We showed that mice that lack PKClambda specifically in the liver (L-lambdaKO mice) exhibit increased insulin sensitivity as well as a decreased triglyceride content and reduced expression of the SREBP-1c gene in the liver Restoration of PKClambda expression in the liver of L-lambdaKO mice corrected the metabolic abnormalities of these animals. Hepatic PKClambda is thus a determinant of hepatic lipid content and whole-body insulin sensitivity.We showed that mice with liver-specific deficiency in STAT-3 show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Liver-specific expression of a constitutively active form o … More f STAT-3 markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signalling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes.Moreover we have shown the roles of PI3-kinase, PDK-1, SREBP-1 and p27^<kip1> for insulin signaling and glucose metabolism.2, We have performed case-control association studies to identify susceptibility genes for type 2 diabetes mellitus. We have shown the-112A > C polymorphism (rs10011540) of the gene for uncoupling protein 1 (UCP1) is associated with type 2 diabetes mellitus in Japanese individuals. Furthermore, we investigated the effects of this polymorphism on clinical characteristics including intramyocellular lipid content (IMCL) and hepatic lipid content (HLC) measured by magnetic resonance spectroscopy. Homeostasis model assessment for insulin resistance (HOMA-IR) and HLC were significantly greater in patients with the -112C allele (risk allele). These results suggest insulin resistance caused by the -112C allele influences the susceptibility to type 2 diabetes. Less

我们通过分析敲除小鼠和培养细胞来研究胰岛素信号传导的机制。PKClambda作为PI3K的下游效应因子参与胰岛素作用。我们发现肝脏中特异性缺乏PKClambda的小鼠（L-lambdaKO小鼠）表现出胰岛素敏感性增加，甘油三酯含量降低，肝脏中SREBP-1c基因表达减少。L-lambdaKO小鼠肝脏中PKClambda表达的恢复纠正了这些动物的代谢异常。因此，肝脏pkclbda是肝脏脂质含量和全身胰岛素敏感性的决定因素。我们发现肝特异性STAT-3缺乏的小鼠表现出胰岛素抵抗，这与肝脏糖异生基因表达增加有关。这些小鼠肝脏STAT-3表达的恢复纠正了代谢异常和肝脏糖异生基因表达的改变。在糖尿病小鼠中，肝脏特异性表达一种组成活性形式的fstat3显著降低血糖、血浆胰岛素浓度和肝脏糖异生基因表达。因此，肝脏STAT-3信号对于正常的葡萄糖稳态至关重要，可能为糖尿病提供新的治疗靶点。此外，我们还发现了pi3激酶、PDK-1、SREBP-1和p27^<kip1>在胰岛素信号传导和葡萄糖代谢中的作用。我们进行了病例对照关联研究，以确定2型糖尿病的易感基因。我们已经证明解偶联蛋白1 （UCP1）基因的112a > C多态性（rs10011540）与日本个体的2型糖尿病有关。此外，我们研究了这种多态性对临床特征的影响，包括用磁共振波谱测量的细胞内脂质含量（IMCL）和肝脂质含量（HLC）。携带-112C等位基因（风险等位基因）的患者胰岛素抵抗（HOMA-IR）和hcc的稳态模型评估明显更高。这些结果表明，由-112C等位基因引起的胰岛素抵抗影响2型糖尿病的易感性。少

项目成果

Role of Kruppel-like factor 15 in PEPCK gene expression in the liver

• DOI: 10.1016/j.bbrc.2004.12.096
• 发表时间: 2005-02-18
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Teshigawara, K;Ogawa, W;Kasuga, M
• 通讯作者: Kasuga, M

PKCλ regulates glucose-induced insulin secretion throuth modulation of gene expression in pancrestic beta cells.

PKCλ 通过调节胰腺 β 细胞中的基因表达来调节葡萄糖诱导的胰岛素分泌。

• 发表时间: 2005
• 期刊: J.Clin.Invest. 115
• 作者: Hashimoto N

Inoue, H: "Role of STAT-3 in regulation of hepatic gluconeogenic genes and of carbohydrate metabolism in vivo."Nature Med. 10. 168-174 (2004)

Inoue, H：“STAT-3 在体内肝糖异生基因和碳水化合物代谢调节中的作用。”Nature Med。

Iwamoto, K: "Identification of a single nucleotide polymorphism showing no insulin-mediated suppression of the promoter activity in the human insulin receptor substrate 2 gene"Diabetologia. 45. 1182-1192 (2002)

Iwamoto, K：“单核苷酸多态性的鉴定，显示人胰岛素受体底物 2 基因中启动子活性没有胰岛素介导的抑制”Diabetologia。

Identification of three missense mutations in peroxisome proliferator-activated receptor a in Japanese subjects with MODY but no association with diabetes

鉴定日本 MODY 受试者中过氧化物酶体增殖物激活受体 a 的三个错义突变，但与糖尿病无关

• 发表时间: 2001
• 期刊: Hum Genet 46
• 作者: Iwasaki N et al.;Kasuga M et al.;Sakaue H et al.;Matsumoto M et al.;Iwasaki-N et al.;Sakaue H et al.;Matsumoto M et al.;Tamori Y et al.;Iwamoto K et al.;Miyake K et al.;Ogata M et al.;Sakaue H et al.;Matsumoto M et al.;Tamori Y et al.;Iwamoto K et al.;Miyake K et al.;Ogata M et al.;Mori H et al.;Matsumoto M et al.;Nakae J et al.;Tsuchida A et al.;Hara M et al.
• 通讯作者: Hara M et al.