Combinations of Nondiabetic Parental Genomes Elicit Impaired Glucose Tolerance in Mouse SMXA Recombinant Inbred Strains

Abstract

Type 2 diabetes in humans is not a single gene disorder but a multifactorial disease caused 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, nonfasting blood glucose concentration, and blood glucose concentration during intraperitoneal glucose tolerance tests). For minimizing the variation of glucose tolerance in each strain, all mice were fed the high-carbohydrate diet and subjected to phenotypic and genetic analyses. The parental strains, SM/J and A/J, were nondiabetic, and the differences of the mean values of diabetes-related traits were small. In contrast, an impaired glucose tolerance was observed in (SM ؋ A)F1 mice, and marked differences in diabetes-related traits were observed in 19 SMXA RI strains. In particular, several SMXA RI strains showed markedly impaired glucose tolerance and hyperglycemia. Quantitative trait locus (QTL) analysis revealed a locus on chromosome (Chr) 10 contributing significant effect on nonfasting blood glucose concentration, as well as six diabetes-related loci on four chromosomes with suggestive evidence of linkage with diabetes-related phenotypes. The A/J-derived QTLs on Chr 2 and 18 and an SM/J-derived QTL on Chr 10 contributed to the impairment of glucose tolerance and/or the increase of blood glucose concentration. The present study indicates that QTLs derived from parental SM/J and A/J genomes, both of which are nondiabetic, interact in the RI genomes, leading to the development of hyperglycemia and diabetic phenotypes. Genetic dissection of this kind of diabetogenesis will increase our understanding of the complex gene-gene interaction and mode of inheritance in human type 2 diabetes.

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

“…We previously reported that QTL analysis of 19 SMXA RI strains fed a high-carbohydrate diet revealed several diabetogenic loci on four chromosomes (chromosomes 2, 6, 10 and 18), and the SMXA-5 mouse seems to possess these loci [19]. Except for the QTL on chromosome 2, the diabetogenic QTLs identified by using 19 SMXA RI strains were different from those identified in this study using (SM×SMXA-5)F 2 mice.…”

“…Each SMXA RI strain has a mosaic genome derived from the SM/J and A/J strains. Although the parental strains were non-diabetic when fed a high-carbohydrate diet, SMXA-5 mice showed impaired glucose tolerance and hyperglycaemia [18,19]. These results suggested that diabetogenic loci in the nondiabetic parental SM/J and A/J genomes coexist in the genomes of RI strains, leading to the development of diabetic phenotypes.…”

“…It is suggested that the gene commonly contributing to obesity may exist in the centromeric region of chromosome 12. However, there is no QTL for obesity on chromosome 12 in the studies using SMXA RI substrains or (SM×A)F 2 mice [19,48,49]. Therefore, this QTL may be a locus specifically activated under a high-fat diet.…”

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

“…10 was not confirmed in A.SM-T2dm1sa congenic mice, in contrast to the results obtained with A/J mice. Although the parental strains (SM/J and A/J strains) are non-diabetic, the SMXA-5 strain, i.e., an SMXA RI strain, develops impaired glucose tolerance and hyperinsulinemia (10,13). Thus, the combination of diabetogenic genes present in SM/J and A/J mice leads to the development of diabetic traits in SMXA-5 mice.…”

“…Mouse SMXA recombinant inbred (SMXA RI) strains have been established from the SM/J and A/J strains by Nishimura and collaborators ( 9 ). In a previous study, we performed quantitative trait locus (QTL) analysis of diabetes-related traits in 19 SMXA RI strains fed a high-carbohydrate diet ( 10 ). We mapped a significant QTL ( T2dm1sa ; Type 2 diabetes mellitus 1 in smxa ) on Chromosome (Chr.)…”