Identifying the genes for insulin resistance in Japanese population.

鉴定日本人群的胰岛素抵抗基因。

基本信息

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

项目摘要

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

1，我们通过分析基因敲除小鼠和培养的细胞研究了胰岛素信号传导的机理。PkClamda被用作PI3K在胰岛素作用中的下游效应子。 We showed that mice that lack PKClamda specifically in the liver (L-lambdaKO mice) exhibit increased insulin sensitivity as well as a reduced triglyceride content and reduced expression of the SREBP-1c gene in the liver Restoration of PKClamda expression in the liver of L-lambdaKO mice corrected the metabolic abnormalities of these animals.因此，肝pkclamda是肝脂质含量和全身胰岛素敏感性的确定的。我们表明，在Stat-3中患有肝脏特异性缺乏的小鼠表明胰岛素耐药性与葡萄糖基因的肝肝表达增加有关。这些小鼠中肝Stat-3表达的恢复纠正了糖原性基因的代谢异常和肝表达的改变。肝脏特异性表达始终如一的活性形式o…更多的F Stat-3显着降低了血糖，血浆胰岛素浓度和肝糖素基因在糖尿病小鼠中的表达。因此，肝Stat-3信号传导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标。此外，我们已经展示了PI3-激酶，PDK-1，SREBP-1和P27^<KIP1>的作用，用于胰岛素信号传导和葡萄糖代谢。2，我们进行了病例对照关联研究以识别2型2型糖尿病的易感基因。我们已经显示了用于解偶联蛋白1（UCP1）基因的112A> C多态性（RS10011540）与日本个体中的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，包括通过磁共振光谱测量的肝内脂质含量（IMCL）和肝脂质含量（HLC）。 -112C等位基因（风险等位基因）患者的胰岛素抵抗（HOMA -IR）和HLC的稳态模型评估明显更大。这些结果表明，由-112C等位基因引起的胰岛素抵抗会影响2型糖尿病的敏感性。较少的

项目成果

期刊论文数量（113）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nuclear Translocation of SHP and 'Visualization of Interaction withHNF-4 a in Living Cells

SHP 的核转位以及活细胞中与 HNF-4a 相互作用的可视化

DOI：
发表时间：
2002
期刊：
Biochem.Biophys.Res.Commum 292
影响因子：
0
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.
通讯作者：
Ogata M et al.

Tanaka, N: "Association of solute carrier family 12 (sodium/chloride) member 3 with diabetic nephropathy, identified by genome-wide analyses of single nucleotide polymorphisms."Diabetes. 52. 2848-2853 (2003)

Tanaka, N：“溶质载体家族 12（钠/氯）成员 3 与糖尿病肾病的关联，通过单核苷酸多态性的全基因组分析确定。”糖尿病。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

A Novel Splice Site Mutation in the Hepatocyte Nuclear Factor-lb Gene, IVS2nt+1G>A, Associated with Maturity-Onset Diabetes of the Young, Agenesis of the Left Kidney and Bicornuate Uterus

肝细胞核因子-lb基因中的一个新剪接位点突变，IVS2nt 1G>A，与年轻人的成年期糖尿病、左肾发育不全和双角子宫相关

DOI：
发表时间：
2001
期刊：
Diabetologia 44
影响因子：
0
作者：
Matsumoto M et al.;Ohba M;Kuroki T;Kasuga M;Nakae J et al.;Tsuchida A et al.;Iwasaki N et al.;Iwasaki N et al.
通讯作者：
Iwasaki N et al.

Mori, H.: "A polymorphism in the 5' untranslated region and a Met^<229>→Leu variant in exon 5 of the human UCP1 gene are associated with susceptibility to type 2 diabetes melltitus"Diabetologia. 44. 373-376 (2001)

Mori, H.：“人类 UCP1 基因外显子 5 中的 5 非翻译区多态性和 Met^<229>→Leu 变异与 2 型糖尿病易感性相关”Diabetologia。 2001）