Novel candidate genes for early-onset insulin resistance in a mouse model for type 2 diabetes

Background and aims Individual susceptibility for metabolic diseases are strongly influenced by genetic determinants, many of them still underexplored. Crossbreeding approaches using mouse inbred strains have successfully identified novel risk loci (QTL, quantitative trait loci) for obesity and type 2 diabetes (T2D). In our project, obesity and diabetes-susceptible NZO mice were crossbred with the lean and diabetes-resistant 129 / P2 strain.

Methods Animals of the backcross population (n = 284-290) were phenotyped for metabolic traits and genotyped using a genome-wide high-density SNP panel. In silico calculation of phenotype-genotype associations was performed using R-QTL software. Generation and phenotyping of recombinant congenic strains (RCS) and further gene expression profiling by PCR was used to narrow down critical genomic regions.

Results Heterozygous allele carriers (NZO / 129P2) of the QTL Nbg4 (chromosome 4) exhibited substantially increased blood glucose and plasma insulin levels compared to homozygous (NZO / NZO) mice, independent of body weight. Metabolic phenotyping of RCS animals confirmed early-onset insulin resistance in homozygous carriers of the 129P2 Nbg4 allele. Expression profiling identified Alad (Delta-aminolevulinic acid dehydratase) and Hdhd3 (Haloacid dehalogenase-like hydrolase domain-containing protein 3) as two novel candidate genes in liver and white adipose tissue, both organs contributing to the observed effect.

Conclusion We identified two novel diabetes candidate genes on proximal Nbg4 linked to early-onset insulin resistance in homozygous 129P2 allele carriers. These genes, Alad and Hdhd3 may play a major role in modulating insulin sensitivity, presumably in liver and adipose tissue. Further in vitro experiments will help to determine the molecular function of these genes in detail.

Publication History

Article published online:
06 May 2021