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

Abstract

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/J×SMXA-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.

Diabetes quantitative trait locus research: from physiology to genetics and back

“…1). Overall, results from physiological investigations in fat-fed congenic mice are consistent with data obtained in mice of the SMXA-5 RI strain and the SMXA-5×SM/J intercross [2]. They show that when the genetic background is fixed for SM/J genotypes, the A/J haplotype at the QTL is associated with hyperglycaemia, hyperinsulinaemia, glucose intolerance and obesity.…”

“…Quantitative values of the traits were used to test for evidence of genetic linkage. A total of nine regions of linkage ranging from suggestive to highly significant were identified, demonstrating complex and probably polygenic control of these phenotypes in the cross [2]. The strongest statistical evidence of linkage was found between a locus in chromosome 2 and variations in BMI, glycaemia, insulinaemia and glucose tolerance.…”

“…A striking result from the study of Kobayashi et al is the consistent linkage of almost all phenotypes quantified in the cross to chromosome 2 loci, such that A/J alleles in the region contribute significantly to glucose intolerance, hyperinsulinaemia and high BMI [2]. The involvement of a single gene in all these variables (which could reflect a phenomenon termed pleiotropy, where one gene controls several variables) is a reasonable hypothesis.…”

“…Genetic studies require the production of hybrid animals, generally F 2 or backcross cohorts or recombinant inbred (RI) strains, which are used to follow the cosegregation of genotypes and disease-related phenotypes. In this issue of Diabetologia, Kobayashi and colleagues have addressed the genetic basis of spontaneous and high-fatdiet-induced diabetes and obesity in mice of the RI strain SMXA-5 [2].…”

Confirmation of Diabetes-Related Quantitative Trait Loci Derived from SM/J and A/J Mice by Using Congenic Strains Fed a High-Carbohydrate or High-Fat Diet

“…We had already confirmed and reported the diabetogenic effects of the QTL on Chr. 2 using SM.A-T2dm2sa congenic mice fed a high-fat diet ( 11 ). Therefore, in this study we used two congenic strains established for investigating QTLs on Chr.…”