Moralejo D H, Wei S, Wei K, Weksler-Zangen S, Koike G, Jacob H J, Hirashima T, Kawano K, Sugiura K, Sasaki Y, Ogino T, Yamada T, Matsumoto K
Institute for Animal Experimentation, University of Tokushima School of Medicine, Kuramoto, Japan.
Proc Assoc Am Physicians. 1998 Nov-Dec;110(6):545-58.
Non-insulin-dependent diabetes mellitus (NIDDM) is a prototypical multifactorial disease. Genetic predisposition and obesity are major risk factors for NIDDM development and the interactions between these factors are likely to be important in the etiology of this disease. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is one of the best animal models of NIDDM, since the OLETF rat develops NIDDM with mild obesity that is very similar to human NIDDM. Therefore, the OLETF rat is a powerful model for investigating the interaction between genetic susceptibility to NIDDM and obesity. In this study, our goal was to clarify the relationship between an individual NIDDM susceptibility locus and obesity in the OLETF using a molecular genetics approach. We identified four novel quantitative trait loci (QTLs) that contribute to the susceptibility to NIDDM, none of which shows significant linkage with body weight. However, Nidd1/of on chromosome 7 and Nidd2/of on chromosome 14 have an interaction with body weight. In contrast, one locus was mapped to chromosome 10 for body weight, but not to fasting or postprandial glucose levels. These data illustrate that NIDDM and body weight are under separate genetic control in the OLETF yet interact to yield the final disease phenotype in the two Nidd/of loci. In addition, body weight could be used in place of body mass index as an indicator of obesity in our experimental system of genetic study. This study will facilitate the understanding of the complex interaction between genetic susceptibility to NIDDM and obesity.
非胰岛素依赖型糖尿病（NIDDM）是一种典型的多因素疾病。遗传易感性和肥胖是NIDDM发病的主要危险因素，这些因素之间的相互作用可能在该疾病的病因学中起重要作用。大冢长-艾维德斯岛肥胖（OLETF）大鼠是NIDDM的最佳动物模型之一，因为OLETF大鼠会发展出与人类NIDDM非常相似的轻度肥胖型NIDDM。因此，OLETF大鼠是研究NIDDM遗传易感性与肥胖之间相互作用的有力模型。在本研究中，我们的目标是使用分子遗传学方法阐明OLETF大鼠中单个NIDDM易感基因座与肥胖之间的关系。我们鉴定出四个导致NIDDM易感性的新的数量性状基因座（QTL），其中没有一个与体重有显著连锁关系。然而，7号染色体上的Nidd1/of和14号染色体上的Nidd2/of与体重存在相互作用。相比之下，一个基因座被定位到10号染色体上与体重相关，但与空腹或餐后血糖水平无关。这些数据表明，在OLETF大鼠中，NIDDM和体重受不同的遗传控制，但在两个Nidd/of基因座中相互作用产生最终的疾病表型。此外，在我们的基因研究实验系统中，体重可以替代体重指数作为肥胖的指标。这项研究将有助于理解NIDDM遗传易感性与肥胖之间的复杂相互作用。
