Identification of quantitative trait loci for non-insulin-dependent diabetes mellitus that interact with body weight in the Otsuka Long-Evans Tokushima Fatty rat

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.