Abstract
We have previously identified significant quantitative trait loci (QTL) Dbm1 (diabetic modifier QTL 1) on chromosome 6, affecting plasma glucose and insulin concentrations and body weight on F(2) progeny of hypoinsulinemic diabetic Akita mice, with the heterozygous Ins2 gene Cys96Tyr mutation, and non-diabetic A/J mice. To discover diabetic modifier genes on Dbm1, we constructed congenic strain for Dbm1 using the Akita allele as donor in A/J allele genetic background, and compared diabetes-related phenotypes to control mice. The homozygote for Akita allele of Dbm1 was associated with lower plasma glucose concentrations in glucose tolerance test (GTT) in the hypoinsulinemic condition derived from the Ins2 mutation and lower plasma insulin concentrations and body weight in the normoinsulinemic condition without the Ins2 mutation than the homozygote for A/J allele, as we performed QTL analysis on F(2) intercross mice. The Akita allele also decreased the epididymal white adipose tissue (EWAT) weight. According to the analysis of sub-congenic strains, we narrowed down the responsible diabetic modifier region to 9 Mb. As fourteen candidate genes exist in this region, we analyzed genomic variants of these genes and gene expression in the muscle, liver, and EWAT and identified that Bhlhe40 gene expression in muscle is decreased in congenic mice. According to the in vitro functional analyses, Bhlhe40 was shown to negatively control fatty acid oxidation in cultured myocyte. Based on these, we conclude that Bhlhe40 is a possible candidate diabetic modifier gene responsible for Dbm1 locus affecting diabetes and/or obesity through negatively controlling fatty acid oxidation in muscle.
Highlights
Type 2 diabetes and obesity are complex diseases caused by both genetic and environmental factors
Lower plasma glucose concentrations and lower body weight were observed in female congenic mice compared to female control mice in hypoinsulinemic insulin 2 gene (Ins2)-Hetero condition (Supplementary Table S2), no significant association was detected for female mice in our previous Quantitative trait loci (QTL) analysis
These data suggest that Ak/Ak genotype of the diabetic modifier gene(s) located on the Dbm1 locus may reduce the severity of diabetes or obesity, or improve the glucose tolerance or insulin sensitivity compared to the Aj/Aj genotype
Summary
Type 2 diabetes and obesity are complex diseases caused by both genetic and environmental factors. The Akita mouse is a spontaneous model of type 2 diabetes established from the C57BL/6 strain (Yoshioka et al, 1997), and a heterozygous Cys96Tyr mutation of the insulin 2 gene (Ins2) on chromosome 7 has been identified as the etiology for the hypoinsulinemic hyperglycemic diabetes (Kayo and Koizumi, 1998; Wang et al, 1999), with severe and mild diabetes, respectively, in male and female mice (Yoshioka et al, 1997). The Dbm affects plasma insulin concentrations and body weight with LOD score of 4.52 and 6.32, respectively, in normoinsulinemic conditions without Ins mutation, both of which were detected only in male mice showing more severe diabetes than female mice (Takeshita et al, 2006). We proposed that latent modifier gene(s) on the Dbm affected diabetic or obesity-related traits through some factors related to insulin sensitivity or resistance
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