Poster Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Introduction: NOD^k compared to NOD (non-obese diabetic) mice carry a low risk H2^k MHC haplotype for autoimmunity, making it type 1 diabetes resistant. Two NOD^k sub-strains differ in their susceptibility to type 2 diabetes (T2D) with high fat (HF) feeding: O-NOD^k - the original sub-strain is T2D prone; RF-NOD^k - a refreshed sub-strain derived from backcrossing O-NOD^k on to the NOD/Lt background is T2D resistant.

Objective: To determine the genetic basis for the diabetes susceptibility of the O-NOD^k compared to the diabetes resistant RF-NOD^k mice.

Methods:, DNA was extracted from livers of two mice of each sub-strain (fed-blood glucose after 8-12 weeks of HF diet: O-NOD^k 11.7 & 19.0 mmol/l; RF-NOD^k 6.7 & 7.0 mmol/l) and whole genome sequencing (WGS) was conducted and compared to each other and to a reference NOD genome database. Variant bases were studied to shortlist candidate genes based on their polyphen predictions for damaging effects and the current literature relating to diabetes.

Results: From the polyphen analysis of exomal DNA, there was a total of 16 probably damaging, 35 benign and 5 unknown polyphens, of which 6 genes were selected for further analysis: Fibroblast growth factor receptor-4 (FGFR4), FGFR4 deficiency affects insulin secretion; Probable cation-transporting ATPase-13A3 (ATP13A3), affects calcium transport; Potassium voltage-gated channel subfamily-H member-7 (KCNH7), affects insulin secretion; LIM-domain only protein-7(LMO7), cell adhesion/signalling and expressed in islet β-cells; Vacuolar protein sorting-13 homolog-C (VPS13C), regulates mitochondrial function and expressed in b-cells; Disintegrin and mellatoprotease domain-9 (Adam9), tumorigenesis and expressed in islet β-cells.

Conclusion: From the whole genome analysis, we have 6 candidate genes to explain the genetic divergence and predisposition to diabetes within the NOD^k sub-strains. Following the development of PCR assays, the one or more candidate genes associating with the diabetes prone phenotype will be determined from backcrosses of O-NOD^k and RF-NOD^k mice.