Identification of novel susceptibility genes for type 2 diabetes in a mouse model for the metabolic syndrome

Background and aims

Despite the relative success from Genome-wide association studies (GWAs), the vast majority of genetic determinants associated with type 2 diabetes (T2D) in humans remain uncharacterized. For the identification of novel risk genes for obesity and T2D, a novel crossbreeding approach of obese, diabetes-prone NZO with lean and diabetes-resistant 129P2 mice was conducted.

Methods:

Animals of the backcross populations were fed a high-fat-diet (45 kcal% fat) and phenotyped for various metabolic traits. Moreover, all animals were genotyped using a genome-wide high-density SNP panel. Subsequent QTL-analysis by in silico calculation of phenotype-genotype associations was performed using R-QTL software. The generation of recombinant congenic strains (RCS) in combination with gene expression profiling was used to narrow down the identified QTL region and to detect potential candidate genes.

Results:

Linkage analysis revealed three overlapping QTL for metabolic traits on chromosome 4. Heterozygous (NZO/129P2) mice exhibited higher blood glucose (BG) levels, liver weight, and plasma insulin but no changes in body weight (BW) compared to homozygous (NZO/NZO) allele carriers. Metabolic phenotyping of RCS validated the phenotype. Expression analysis in the parental strains revealed three potential candidate genes in adipose and liver tissue.

Conclusion:

We identified a novel susceptibility locus on mouse chromosome 4 associated with elevated BG levels derived from the lean 129P2 mouse strain independent from BW development. Future functional investigations of the identified candidate in appropriate in vitro and in vivo models will help to determine a potential impact of the identified candidate genes on obesity and T2D progression.