Bim is a pro-apoptotic BH3-only protein in the Bcl-2 family that is required for cell death in response to a number of stimuli. A role for Bim in beta cell death has been described in response to stimuli that induce ER and oxidative stress. We tested whether deficiency of Bim protected islets from immune and non-immune stimuli in type 1 and type 2 diabetes. Mice lacking Bim on a C57BL/6 background had normal glucose tolerance, and their islets secreted insulin normally in response to glucose, indicating no gross abnormalities in beta cell function due to loss of Bim. Bim-deficient islets were not protected from toxic effects of pro-inflammatory cytokines (IL-1b, IFNg and TNFa), Fas ligand or recombinant perforin and granzyme B in vitro. They were also not protected from cytotoxicity induced by CD8+ or CD4+ T cells in vitro or in vivo, and adoptive transfer of splenocytes from diabetic NOD mice into NOD mice lacking Bim resulted in diabetes that was indistinguishable from wild-type recipients. Similarly, transplantation of Bim-deficient islets into diabetic NOD mice did not reverse diabetes and resulted in immune-mediated destruction of grafted islets. Surprisingly, Bim-deficient NOD mice were protected from diabetes, and this was due to enhanced production of self-reactive regulatory T cells because of disabled thymic negative selection. In contrast, Bim-deficiency protected islets against the toxic effects of the ER stress-inducing drugs thapsigargin or tunicamycin, and also from glucose toxicity induced by high concentrations of the reducing sugars glucose or ribose. Bim-deficient mice fed a high fat diet had lower fasting blood glucose and improved glucose tolerance compared to wild-type mice. Our data indicate that Bim is not involved in beta cell death in response to immune stimuli in type 1 diabetes. However, absence of Bim is protective in models of ER stress and type 2 diabetes, and its blockade may be an effective therapy for this disease.
Funding support: National Health and Medical Research Council of Australia, Juvenile Diabetes Research Foundation and Diabetes Australia Research Trust.