Oral Presentation The Annual Scientific Meeting of the Australian Diabetes Society and the Australian Diabetes Educators Association 2013

Loss of the pro-apoptotic molecule Bim improves beta-cell function and glucose homeostasis in mouse models of type 2 diabetes (#150)

Jibran A Wali 1 2 , Lorraine Elkerbout 2 , Cameron Kos 2 , Sofianos Andrikopoulos 1 , Ross Laybutt 3 , Thomas W Kay 2 , Helen E Thomas 1 2
  1. Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
  2. St Vincent's Institute, Melbourne, Victoria, Australia
  3. Garvan Institute, Sydney, NSW, Australia

Type-2 diabetes is caused by insulin resistance, together with apoptosis of beta-cells. High glucose concentrations induce Bcl2-regulated apoptosis of islet cells in vitro through the pro-apoptotic BH3-only proteins Bim and Puma and this is inhibited by the pro-survival protein Bcl2. We hypothesized that blocking beta-cell apoptosis in type 2 diabetes would improve glucose homeostasis, and tested this using Bim deficient mice and transgenic mice over-expressing Bcl2 in beta-cells. Mice were placed on a 45% high-fat-diet (HFD) for 18 weeks as a model of insulin resistance, and mice were bred with leptin receptor deficient db/db mice as a model of type 2 diabetes characterized by beta-cell apoptosis.

Bim deficient mice gained less weight on HFD and their absolute body weight was lower when compared with wild-type mice. Mice lacking Bim had non-fasting blood glucose similar to wild-type mice but their fasting blood glucose was significantly lower. In addition, Bim deficient mice had improved insulin tolerance, as well as improved glucose tolerance. These results suggested that apoptosis inhibition results in an overall improvement in glucose homeostasis.

Loss of Bim decreased fasting blood glucose and improved glucose tolerance in db/db mice, although Bim deficient db/db mice gained more weight than control db/db mice. A two-fold increase in islet area was noticed at 9 months of age in Bim deficient db/db mice compared to control db/db mice or Puma-deficient db/db mice, suggesting that these changes were Bim specific. TUNEL staining showed that Bim deficiency reduced islet cell apoptosis in db/db islets.

Our data shows that Bim deficiency improves glucose homeostasis and shifts the balance from beta-cell apoptosis towards increased islet size in mouse models of insulin resistance and diabetes.