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Molecular Pathogenesis of diabetes in rodent models

啮齿动物模型糖尿病的分子发病机制

基本信息

批准号：
12480249
负责人：
IZUMI Tetsuro
金额：
$ 7.68万
依托单位：
Institute for Molecular and Cellular Regulation, Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12480249/
关键词：
diabetes rodent models quantitative trait locus insulin secretion pancreatic beta cells 肥満

项目摘要

We have investigated the molecular pathogenesis of diabetes using rodent disease models.(1) TSOD mouseWe previously performed genetic analysis of diabetes and obesity in TSOD mice and identified three quantitative trait loci (QTLs). Our final goal is to identify genetic alterations at each QTL. For this-purpose, we have generated several congenic strains. For example, 17 congenic strains were constructed for the QTL on chromosome 2 that influences the body weight and plasma insulin levels of TSOD mice. By comparing phenotypes between the congenic strains and parental TSOD mice, the QTL regions can be narrowed down. In case of the QTL on chromosome 2, we can successfully define it to a 12.8-Mb region that contains 49 candidate genes.(2) Akita mouseWe previously discovered that autosomal dominant diabetes in the Akita mouse is caused by mutation of, the insulin 2 gene, whose product replaces a cysteine residue that is engaged in the formation of an intramolecular disulfide bond. The heterozygous mice exhibit severe insulin deficiency despite coexpression of normal insulin molecules derived from three other wild-type alleles of the insulin 1 and 2 genes. We investigated the dominant-negative pathogenic mechanisms induced by the mutant proinsulin 2, and found that the trafficking of constitutively secreted alkaline phosphatase is significantly decreased in the islets of Akita mice. Morphologic analysis also revealed that secretory pathway organelle architecture is progressively devastated in the β-cells of Akita mice. These findings suggest that the organelle dysfunction due to the intracellular accumulation of misfolded proinsulin 2 is primarily responsible for the defect of coexisting wild-type insulin secretion in Akita β-cells.

我们使用啮齿动物疾病模型研究了糖尿病的分子发病机制。(1)TSOD小鼠我们先前在TSOD小鼠中进行了糖尿病和肥胖的遗传分析，并确定了三个数量性状位点（QTL）。我们的最终目标是确定每个QTL的遗传变异。为此，我们已经产生了几个同源菌株。例如，针对影响TSOD小鼠的体重和血浆胰岛素水平的2号染色体上的QTL构建了17个同源株。通过比较TSOD小鼠的表型，可以缩小TSOD小鼠的QTL区域。对于2号染色体上的QTL，我们可以成功地将其定位到包含49个候选基因的12.8-Mb区域。(2)秋田小鼠我们以前发现，秋田小鼠的常染色体显性糖尿病是由胰岛素2基因突变引起的，其产物取代了参与分子内二硫键形成的半胱氨酸残基。杂合子小鼠表现出严重的胰岛素缺乏症，尽管共表达来自胰岛素1和2基因的其他三个野生型等位基因的正常胰岛素分子。我们研究了突变胰岛素原2诱导的显性负性致病机制，发现组成性分泌的碱性磷酸酶在秋田小鼠胰岛中的运输显著减少。形态学分析还显示，分泌途径细胞器结构在秋田小鼠的β细胞中被逐渐破坏。这些结果表明，细胞器功能障碍，由于细胞内积累的错误折叠的胰岛素原2是主要负责的缺陷共存的野生型胰岛素分泌的秋田β细胞。