Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

NODk compared to C57BL/10 Mice are more Prone to Islet Beta-Cell Failure Due to Greater Susceptibility to Endoplasmic Reticulum Stress. (#102)

Viviane Delghingaro-Augusto 1 , Luis A Socha 1 , Ainy Hussain 1 , Jeng Yie Y Chan 2 , Ross Laybutt 2 , Christopher J Nolan 1
  1. Endocrinology and Diabetes Research Unit, Australian National University, Garran, ACT, Australia
  2. Garvan Institute of Medical Research, Sydney, NSW, Australia
Intrinsic defects of islet beta-cells may be important in the pathophysiology of both non-immune and immune-mediated diabetes. We studied NOD and C57BL/10 inbred mice strains that share the autoimmune diabetes-resistant H2k major histocompatibility complex (NODk and B10k strains, respectively). Neither strain develops diabetes on chow diet. Male NODk mice stressed with either beta-cell transgenic (Tg) expression of hen egg lysozyme (HEL) protein or high fat (HF) diet develop non-immune diabetes, whereas male B10k do not (90 days old, fed blood glucose- NODk 5.1 ± 0.2 vs 23.5 ± 4.1 mmol/l, p<0.001, and B10k 7.1 ± 0.5 vs 8.6 ± 1.2 mmol/l, NonTg vs Tg, respectively; NODk 7.3 ± 0.3 vs 16.2 ± 2.9 mmol/l, p<0.001, and B10k 7.8 ± 0.5 vs 8.2 ±0.4 mmol/l, chow vs HF, respectively). The ratio of proinsulin/c-peptide at 90 days of age was dramatically and similarly increased in HEL Tg mice irrespective of whether the mouse background was NODk or B10k (NODk 0.08 ± 0.01 vs 1.83 ± 0.33, B10k 0.07 ± 0.01 vs 3.97 ± 0.82, nonTg vs Tg, respectively, p<0.001 for both); whereas HF diet had no effect to increase the proinsulin/insulin ratio (NODk 0.052 ± 0.011 vs 0.019 ± 0.003, B10k 0.067 ± 0.012 vs 0.045 ± 0.008, chow vs HF, respectively). NODk HEL Tg mice had increased islet mRNA expression of five endoplasmic reticulum (ER) stress markers (p58, BIP, CHOP, GPR94 and FKBP11) compared to one (p58) in B10k HEL Tg mice. The results show an enormous capacity for islet beta-cell compensation for severe defects in insulin processing without induction of ER stress and preservation of glycemia in B10k HEL Tg mice. The same insult does cause ER stress and diabetes in NODk mice. Diabetes development in HF fed NODk mice, however, is not associated with an abnormality of insulin processing.