Identification of novel genes mediating β-cell failure

Background:

Obesity is a complex metabolic disease that results in insulin resistance and with presence of diabetes genes in pancreatic β-cell failure. Analysis of a NZOxDBA backcross population identified one major QTL (Nidd/DBA) on chromosome 4, whereby the DBA allele enhanced hyperglycemia and ß-cell loss. The aim of this study was to identify new diabetes genes mediating β-cell loss and hyperglycemia within this locus.

Methods:

Recombinant congenic mice, carrying different fragments of the Nidd/DBA locus were generated via repeated backcross to NZO. The phenotypic characterization comprised the weekly measurements of blood glucose, body weight and body composition and oral glucose tolerance tests (oGTT) at 12 weeks of age. Haplotype mapping and RNAseq of pancreatic islets from congenic mice were performed to reduce the critical fragment size and to define candidate genes.

Results:

Recombinant congenic mice carrying 72.6 Mbp and 5.6 Mbp of Nidd/DBA locus developed hyperglycemia at week 12 of age, whereas homozygous NZO mice exhibited hyperglycemia only at a very late stage. OGTTs at week 12 showed enhanced insulin levels in homozygous DBA mice compared to Nidd/DBANN. Haplotype mapping of the critical region (5.6 Mbp) revealed 51 genes. Based on RNAseq data of pancreatic islets from mice carrying 5.6 Mbp, 3 genes (Spata6, Ttc39a and OsbpI9) are differently expressed between the homozygous groups.

Conclusion:

By generating congenic mice and using haplotyping, the diabetes QTL Nidd/DBA was narrowed down to 5.6 Mbp, comprising 3 differently expressed islet genes, which might be causal for the locus effect.