High fat fed NOD.B10 <em>foz/foz</em> mice have a type 2 diabetes phenotype without evidence of islet beta-cell dysfunction in vitro — ASN Events

High fat fed NOD.B10 foz/foz mice have a type 2 diabetes phenotype without evidence of islet beta-cell dysfunction in vitro (#95)

Viviane Delghingaro-Augusto 1 , Tenzin D Dagpo 1 , Sumaira Z Hasnain 2 , Jane E Dahlstrom 3 , John Prins 2 , Michael A McGuckin 2 , Geoffrey Farrell 1 , Christopher J Nolan 1
  1. Australian National University, Garran, ACT, Australia
  2. Mater Research Institute, University of Queensland, Woolloongabba, QLD, Australia
  3. Anatomical Pathology, ACT PATHOLOGY,, The Canberra Hospital, Garran, ACT, Australia

High fat (HF) fed NOD.B10 and Balb/c foz/foz mice develop obesity by 12 weeks of age, but only those of the NOD.B10 strain develop a hyperinsulinaemic type 2 diabetes (T2D) phenotype. The study aims were to determine the islet contribution to this T2D phenotype.

In chow and HF-fed NOD.B10 and Balb/c wild-type and foz/foz mice at 12 weeks of age, islet beta-cell mass, islet gene expression by Open Array, and in vitro glucose-stimulated insulin secretion (GSIS) were assessed. To determine the functional quality of the insulin from isolated islets of these mice groups, the ability of the secreted insulin to stimulate glucose uptake into differentiated 3T3 adipocytes was assessed at insulin concentrations of 0.125 to 2 ng/mL.

Islets of HF-fed NOD.B10 foz/foz mice compared to their Balb/c counterpart showed no evidence of pancreatic islet insulin degranulation, reduced insulin stained β-cell mass (1.2 ± 0.2 vs 1.1 ± 0.2 mg/pancreas, respectively) or defective GSIS. On analysis of islet gene expression, islet dedifferentiation was not evident in HF-fed NOD.B10 foz/foz compared to Balb/c mice, however, expression of apoptotic (Chop and Atf3) and inflammatory markers (TNFα, CxCl2, IL23) were generally increased in islets of NOD.B10 mice.

In conclusion, the hyperinsulinemic T2D phenotype of the HF fed foz/foz mice is not associated with reduced islet β-cell mass, islet dedifferentiation or abnormal insulin secretion in vitro. The expression of islet inflammatory genes is increased in NOD.B10 mice, irrespective of diet or genotype. The significance of the inflammatory genes to the T2D phenotype requires further investigation.

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