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The pro-apoptotic BH3-only protein Bid is dispensable for development of insulitis and diabetes in the non-obese diabetic mouse

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Abstract

Type 1 diabetes is caused by death of insulin-producing pancreatic beta cells. Beta-cell apoptosis induced by FasL may be important in type 1 diabetes in humans and in the non-obese diabetic (NOD) mouse model. Deficiency of the pro-apoptotic BH3-only molecule Bid protects beta cells from FasL-induced apoptosis in vitro. We aimed to test the requirement for Bid, and the significance of Bid-dependent FasL-induced beta-cell apoptosis in type 1 diabetes. We backcrossed Bid-deficient mice, produced by homologous recombination and thus without transgene overexpression, onto a NOD genetic background. Genome-wide single nucleotide polymorphism analysis demonstrated that diabetes-related genetic regions were NOD genotype. Transferred beta cell antigen-specific CD8+ T cells proliferated normally in the pancreatic lymph nodes of Bid-deficient mice. Moreover, Bid-deficient NOD mice developed type 1 diabetes and insulitis similarly to wild-type NOD mice. Our data indicate that beta-cell apoptosis in type 1 diabetes can proceed without Fas-induced killing mediated by the BH3-only protein Bid.

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Acknowledgments

We thank Jonathan Chee, Cameron Kos and Lorraine Elkerbout for technical assistance. This study was supported by a grants and fellowships from the National Health and Medical Research Council of Australia, the Juvenile Diabetes Research Foundation, the Leukemia and Lymphoma Society of America and the NIH. P.S. is supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada and is a Scientist of Alberta Innovates-Health Solutions.

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Authors and Affiliations

  1. St. Vincent’s Institute of Medical Research, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia

    Zia U. A. Mollah, Jibran Wali, Mark D. McKenzie, Balasubramanian Krishnamurthy, Kate L. Graham, Stacey Fynch, Joshua Szanyi, Thomas Brodnicki, Janette Allison, Thomas W. H. Kay & Helen E. Thomas

  2. Department of Medicine, The University of Melbourne, St. Vincent’s Hospital, Fitzroy, VIC, Australia

    Jibran Wali, Thomas Brodnicki, Thomas W. H. Kay & Helen E. Thomas

  3. Julia McFarlane Diabetes Research Center and Department of Microbiology and Infectious Disease, University of Calgary Faculty of Medicine, Calgary, AB, Canada

    Pere Santamaria

  4. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

    Mark D. McKenzie & Andreas Strasser

  5. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia

    Andreas Strasser

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  1. Zia U. A. Mollah
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  2. Jibran Wali
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  12. Thomas W. H. Kay
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Correspondence to Helen E. Thomas.

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Mollah, Z.U.A., Wali, J., McKenzie, M.D. et al. The pro-apoptotic BH3-only protein Bid is dispensable for development of insulitis and diabetes in the non-obese diabetic mouse. Apoptosis 16, 822–830 (2011). https://doi.org/10.1007/s10495-011-0615-z

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