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Research for molecular mechanism of diabetes development in obese type 2 diabetes model db/db mice

肥胖2型糖尿病模型db/db小鼠糖尿病发生的分子机制研究

基本信息

批准号：
18591008
负责人：
KAKU Kohei
金额：
$ 2.28万
依托单位：
Kawasaki Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591008/
关键词：
db gene impaired β-cell function LCM method diet therapy pioglitazone oxidative stress β-cell mass β-cell restoration db遺伝子ホモ接合体マウス db遺伝子ヘテロ接合体マウス膵β細胞機能膵ラ氏島遺伝子発現肥満2型糖尿病モデル

项目摘要

The aim of this study is to clarify a molecular mechanism of diabetes development and cell dysfunction in obese db/db mice with spontaneous onset of diabetes. We carried out the morphological and biochemical analyses of pancreatic islets. In addition, The islet-selective gene expression profiling was done by using laser capture microdissection (LCM) method. In the first step, db gene homozygous db/db, db gene heterozygous db/m, and wild type m/m mice were used to compared their diabetic phenotypes and gene expressio profiles in the pancreatic islets. The db/db mice developed diabetes, but the other mice not. ERK1 and cyclinE genes related with cell proliferation were down-regulated, and CAD gene was up-regulated in db/db mice. The genes associated with oxidative stress were up-regulated, and anti-apoptotic bcl-2 gene was down-regulated in diabetic db/db mice. On the other hand, the bcl-2 gene was up-regulated in db/m mice, and insulin gene expression and insulin content were significan … More tly increased in db/m mice, suggesting the compensatory mechanism against diabetes development in db gene heterozygous (db/m) mice.In the next step, we tried to see the effects of diet restriction and/or anti-diabetic agent, pioglitazone on the pancreatic b cell function deranged in the diabetic db/db mice. The intervention with diet was effective to reduce the body weight, and blood glucose/insulin levels. ERK1 gene expression in the islet was increased, and apoptotic gene expressions were decreased. Anti-oxidative stress-related gene expression was up-regulated. Thus we concluded that deit treatment was effective to amekiorate the deranged pancreatic β cell function. Pioglitazone was also effective to improve glucolipotoxicity in db/db mice. The treatment with pioglitazone increased b cell proliferation-related gene expression, and decreased apoptosis-related gene expression. In addition, pioglitazone ddecreased oxidative stress-related gene expressions, and increased anti-oxidative stress-related gene expressions. Pioglitazone affected the gene expression even in non-diabetic db/m or m/m mice. These results strongly suggested that pioglitazone ameliorates the β-cell function via two mechanisms, a direct action as a PPARγ agonist and an indirect effect through improving glucolipotoxicity. Less

本研究的目的是阐明自发性糖尿病的肥胖db/db小鼠中糖尿病发展和细胞功能障碍的分子机制。我们对胰岛进行了形态学和生化分析。采用激光捕获显微切割（LCM）技术进行胰岛选择性基因表达谱分析。第一步，用db基因纯合db/db、db基因杂合db/m和野生型m/m小鼠比较它们的糖尿病表型和胰岛基因表达谱。db/db小鼠患上了糖尿病，但其他小鼠没有。db/db小鼠与细胞增殖相关的ERK 1和cyclinE基因表达下调，CAD基因表达上调。糖尿病db/db小鼠氧化应激相关基因表达上调，抗凋亡基因bcl-2表达下调。另一方面，db/m小鼠bcl-2基因表达上调，胰岛素基因表达和胰岛素含量显著高于正常对照组。 ...更多信息本实验进一步观察了饮食限制和/或抗糖尿病药物吡格列酮对糖尿病db/db小鼠胰岛B细胞功能紊乱的影响。饮食干预能有效降低体重和血糖/胰岛素水平。胰岛细胞ERK 1基因表达增加，凋亡基因表达减少。抗氧化应激相关基因表达上调。因此，我们认为，deit治疗是有效的，以纠正紊乱的胰腺β细胞功能。吡格列酮也可有效改善db/db小鼠的糖脂毒性。吡格列酮治疗增加了B细胞增殖相关基因的表达，降低了骨化相关基因的表达。此外，吡格列酮降低氧化应激相关基因的表达，增加抗氧化应激相关基因的表达。甚至在非糖尿病db/m或m/m小鼠中，吡格列酮也影响基因表达。这些结果强烈表明，吡格列酮通过两种机制改善β细胞功能，一种是作为PPARγ激动剂的直接作用，另一种是通过改善糖脂毒性的间接作用。少