Genetic Analysis of Obese Diabetes in the TSOD Mouse

由于糖尿病的遗传复杂性，其分子发病机制仍然知之甚少。研究表型相似的动物模型可能是阐明发病机制的一种有效途径。TSOD(铃木，铃木，肥胖糖尿病)小鼠是一种新开发的动物模型，表现为糖尿病和肥胖，并伴有明显的高胰岛素血症和胰岛肥大，可能代表人类肥胖2型糖尿病的一种常见形式。表型特征显示，TSOD小鼠既有胰岛素抵抗，又有葡萄糖刺激的胰岛素分泌受损。利用TSOD和对照BALB/CA株之间的F1和F2后代，对糖尿病和肥胖症进行了全面的遗传解剖。全基因组筛选与葡萄糖动态平衡和体重相关的基因座，使我们能够定位与这种疾病有关的三个数量性状基因座(QTL)。在11号染色体上发现了控制血糖水平的主要遗传决定因素。此外，在1号和2号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对不同的性状和不同的遗传方式有不同的影响。我们的研究表明，在这个小鼠模型中，高血糖和肥胖明显受不同的遗传位点组合控制，并为人类常见的2型糖尿病合并肥胖的遗传基础提供了见解。

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.