Quantitative Trait Loci for Impaired Glucose Tolerance in Nondiabetic SM/J and A/J Mice

The SMXA-5 recombinant inbred strain, which was established from nondiabetic parental SM/J and A/J mice, develops diabetic phenotypes such as impaired glucose tolerance. The combination of diabetogenic genes in the SM/J and A/J genomes impairs glucose tolerance in SMXA-5 mice. Using (SM/J x SMXA-5)F2 mice fed a high-fat diet, we previously detected a diabetogenic locus, T2dm2sa, on chromosome (Chr) 2. The A/J allele at this locus is diabetogenic. The SM.A-T2dm2sa congenic mouse, in which the Chr 2 region of A/J including T2dm2sa was introgressed into SM/J, showed obviously impaired glucose tolerance. These results indicate that SM.A-T2dm2sa mice develop diabetogenic traits due to T2dm2sa with the A/J allele and unknown diabetogenic loci with the SM/J allele. The aim of this study was to dissect these unknown loci, using quantitative trait locus (QTL) analysis in the (A/J x SM.A-T2dm2sa) F2 intercross fed a high-fat diet. The results revealed a highly significant QTL, T2dm4sa, for glucose tolerance on Chr 6 and a significant QTL, T2dm5sa, for glucose tolerance on Chr 11. These loci with the SM/J allele were diabetogenic. The diabetogenic effect of T2dm4sa or T2dm5sa was verified by the impairment of glucose tolerance in the A/J-6(SM) or A/J-11(SM) consomic strain, in which Chr 6 or Chr 11 of SM/J is introgressed into A/J, respectively. These results demonstrate that diabetogenic loci exist in the genomes of nondiabetic A/J and SM/J mice and suggest that T2dm2sa with the A/J allele and T2dm4sa and/or T2dm5sa with the SM/J allele elicit impaired glucose tolerance in SM.A-T2dm2sa mice.