Major quantitative trait locus on chromosome 2 for glucose tolerance in diabetic SMXA-5 mouse established from non-diabetic SM/J and A/J strains

Aims/hypothesis: The SMXA-5 mouse is one of the SMXA recombinant inbred substrains established from the non-diabetic SM/J and A/J strains, and is a model for polygenic type 2 diabetes, characterised by moderately impaired glucose tolerance and hyperinsulinaemia. These diabetic traits are worsened by feeding a high-fat diet. The aim of this study was to dissect the diabetogenic loci in the A/J regions of the SMXA-5 genome that contribute to diabetes-related traits. Materials and methods: We analysed the quantitative trait loci (QTL) for diabetes-related traits and obesity in (SM/JxSMXA-5)F-2 intercross mice fed a high-fat diet. To verify the function of the responsible locus that was mapped in the present study, we constructed a congenic strain and characterised its diabetes-related traits. Results: A major QTL for glucose tolerance, free-fed blood glucose concentration and BMI was mapped on chromosome 2. This locus existed near D2Mit15, with the highest logarithm of the odds score (12.6) for glucose concentration at 120 min in a glucose tolerance test, and was designated T2dm2sa. The diabetogenic allele of T2dm2sa originated in the A/J strain. SM.A-T2dm2sa, a congenic strain that introgressed the T2dm2sa region of A/J genome into SM/J, exhibited overt impaired glucose tolerance and hyperinsulinaemia. Conclusions/interpretation: The development of impaired glucose tolerance in SM.A-T2dm2sa mice confirmed the results of QTL analysis for diabetes-related traits in F-2 intercross mice. The present results suggest that there are latent diabetogenic loci in the genomes of non-diabetic A/J and SM/J mice, and that the coexistence of these loci, including T2dm2sa, causes impaired glucose tolerance in SMXA-5 and SM.A-T2dm2sa mice.