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Genetic Analysis of Obese Diabetes in the TSOD Mouse

TSOD 小鼠肥胖糖尿病的遗传分析

基本信息

批准号：
08458273
负责人：
IZUMI Tetsuro
金额：
$ 4.35万
依托单位：
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：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

The molecular pathogenesis of diabetes remains poorly understood because of the genetic complexity of the disease. One possibly effective approach to elucidate the pathogenesis is to study an animal model with a similar phenotype. The TSOD (Tsumura, Suzuki, Obese Diabetes) mouse, a newly developed animal model, exhibits both diabetes and obesity with marked hyperinsulinemia and hypertrophy of the pancreatic islets, and might represent a common form of obese type 2 diabetes in humans. Phenotypic characterization revealed that the TSOD mouse had both insulin resistance and impaired glucose-stimulated insulin secretion. A comprehensive genetic dissection of diabetes and obesity has been performed using Fl and F2 progeny between the TSOD and control BALB/cA strains. A genome-wide screen for loci linked to glucose homeostasis and body weight allowed us to map three quantitative trait loci (QTLs) involved in this disorder. The major genetic determinant of blood glucose levels was identified on chromosome 11. Furthermore, two independent QTLs involved in controlling body weight were found on chromosomes 1 and 2. The QTh on chromosome 2 also affected insulin levels significantly. Each QTL has distinct effects on different traits and a different mode of inheritance. Our study indicates that hyperglycemia and obesity are clearly controlled by distinct combinations of genetic loci in this mouse model and provides insights into the genetic basis of common forms of human type 2 diabetes with obesity.

由于糖尿病的遗传复杂性，其分子发病机制仍然知之甚少。一种可能有效的方法来阐明发病机制是研究具有相似表型的动物模型。TSOD（Tsumura，Suzuki，Obese Diabetes）小鼠是一种新开发的动物模型，其表现出糖尿病和肥胖，具有显著的高胰岛素血症和胰岛肥大，并且可能代表人类肥胖2型糖尿病的常见形式。表型表征显示TSOD小鼠具有胰岛素抵抗和葡萄糖刺激的胰岛素分泌受损。已经使用TSOD和对照BALB/cA品系之间的F1和F2子代进行了糖尿病和肥胖症的全面遗传解剖。一个基因组范围内的屏幕与葡萄糖稳态和体重的基因座，使我们能够映射三个数量性状基因座（QTL）参与这种疾病。在11号染色体上确定了血糖水平的主要遗传决定因素。此外，在第1和第2染色体上发现了两个独立的控制体重的QTL。2号染色体上的QTh也显著影响胰岛素水平。每个QTL对不同的性状有不同的影响，具有不同的遗传模式。我们的研究表明，高血糖症和肥胖症在这种小鼠模型中明显受到遗传基因座的不同组合的控制，并提供了对人类2型糖尿病伴肥胖症常见形式的遗传基础的见解。