Journal article

The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity

JA Wali, D Rondas, MD McKenzie, Y Zhao, L Elkerbout, S Fynch, EN Gurzov, S Akira, C Mathieu, TWH Kay, L Overbergh, A Strasser, HE Thomas



Apoptosis of pancreatic beta cells is a feature of type 2 diabetes and its prevention may have therapeutic benefit. High glucose concentrations induce apoptosis of islet cells, and this requires the proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins Bim and Puma. We studied the stress pathways induced by glucotoxicity in beta cells that result in apoptosis. High concentrations of glucose or ribose increased expression of the transcription factor CHOP (C/EBP homologous protein) but not endoplasmic reticulum (ER) chaperones, indicating activation of proapoptotic ER stress signaling. Inhibition of ER stress prevented ribose-induced upregulation of Chop and Puma mRNA, and partially protect..

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Awarded by Juvenile Diabetes Research Foundation (JDRF)

Awarded by NHMRC project grant

Funding Acknowledgements

We thank Drs. P Bouillet and D Gray (Walter and Eliza Hall Institute) for Bim/Puma-deficient mice, Dr J Miyazaki (Osaka University) for MIN6 cells, Drs. J Allison and E Carrington (St. Vincent's Institute) for intellectual input, Dr. T Loudovaris and Ms L Mariana (Australian Islet Transplant Consortium, St. Vincent's Institute) for human islets and S Thorburn, D Novembre-Cycon, R Branch and A Gomes for genotyping and animal husbandry. This study was supported by a National Health and Medical Research Council of Australia (NHMRC) and Juvenile Diabetes Research Foundation (JDRF) joint special program grant in type 1 diabetes (APP466658), an NHMRC project grant (APP1032610), a fellowship from the NHMRC (HET), a University of Melbourne Viola Edith Reid Bequest Scholarship (JAW) and postdoctoral fellowships from the JDRF (YZ, EG). This study was supported in part by the Victorian Government's Operational Infrastructure Support Program.