Autor:innen:
H. Aga (Potsdam-Rehbrücke, DE)
N. Hallahan (Potsdam-Rehbrücke, DE)
W. Jonas (Potsdam-Rehbrücke, DE)
P. Gottmann (Potsdam-Rehbrücke, DE)
M. Jähnert (Potsdam-Rehbrücke, DE)
A. Schürmann (Potsdam-Rehbrücke, DE)
H. Vogel (Potsdam-Rehbrücke, DE)
Background
Type 2 diabetes is a complex metabolic disease regulated by genetics and environmental factors and considered to be today´s most severe health threats. The New Zealand Obese (NZO) mouse is an obese model of human T2D. DBA mice are lean, carry diabetes genes and develop hyperglycemia on obese background. Analysis of a NZOxDBA backcross population revealed one major susceptibility locus of diabetes (Nidd/DBA), whereby the DBA allele enhanced hyperglycemia and β-cell loss. The aim of this study was to elaborate the phenotype of the locus and to identify the genetic variant(s).
Methods
Recombinant congenic strains were generated via repeated backcross to NZO and were phenotypically characterized in respect to whole-body glucose homeostasis experiments. Haplotype mapping and RNAseq of pancreatic islets from congenic mice were performed to reduce the critical fragment size and to define candidate genes, respectively.
Results
Recombinant congenic mice carrying 6.3 Mbp of DBA alleles developed hyperglycemia at week 12 of age, whereas NZO allele carrier exhibited hyperglycemia only at week 20. In DBA allele carriers no abnormal metabolic phenotype could be observed at 6 weeks of age, while at 12 weeks of age they displayed an impaired glucose clearance, elevated fasting glucose levels and beta-cell loss. By combinating transcriptomics and haplotyping, four putative candidate genes were identified.
Conclusion
Generation of congenic mice in combination with haplotyping narrowed the diabetes locus Nidd/DBA to 6.3 Mbp comprising four putative candidate genes, which might be causal for beta-cell loss.