Genetic analysis of diabetes in SMXA recombinant inbred strain of mice.

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Type 2 diabetes in humans is not a single gene disorder, but rather it is brought about by the interaction of multiple genes and environmental factors. Recombinant inbred (RI) strains are a powerful tool for analyzing not only single genetic traits, but also multifactorial genetic traits. By using the SMXA RI mice, we genetically dissected diabetes-related traits (BMI, non-fasting blood glucose concentration, and blood glucose concentration during IPGTT). In this study, all mice were fed the high-carbohydrate diet, because feeding this diet minimizes the variation of glucose tolerance in each strain. The parental strains, SM/J and A/J, were non-diabetic, and the differences of the mean values on diabetes-related traits were small. On the other hand, "notable differences" in the mean values of some diabetes-related traits were observed in 19 SMXA RI strains. Several SMXA RI strains showed distinct impaired glucose tolerance and hyperglycemia. QTL analysis revealed six diabetes-related loci on four chromosomes which exceeding the threshold for suggestive level. Especially, a locus on Chr 10 concerning non-fasting blood glucose concentration, was over significant threshold. The A/J-derived genome at two loci on Chr 2 and 18, oppositely the SM/J-derived genome at one locus on Chr 10, contributed to the impairment of glucose tolerance and/or the increase of blood glucose concentration. The present study indicate that the I combinations between silent SM/J and A/J allele can appear to elicit hyperglycemia and impaired glucose tolerance. Genetic dissection of this kind of diabetogenesis may contribute to understand the complex mode of inheritance in human type 2 diabetes.