title: The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity.
abstract: 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 protected islets from glucotoxicity. Loss of Bim or Puma partially protected islets from the canonical ER stressor thapsigargin. The antioxidant N-acetyl-cysteine also partially protected islets from glucotoxicity. Islets deficient in both Bim and Puma, but not Bim or Puma alone, were significantly protected from killing induced by the mitochondrial reactive oxygen species donor rotenone. Our data demonstrate that high concentrations of glucose induce ER and oxidative stress, which causes cell death mediated by Bim and Puma. We observed significantly higher Bim and Puma mRNA in islets of human donors with type 2 diabetes. This indicates that inhibition of Bim and Puma, or their inducers, may prevent beta-cell destruction in type 2 diabetes.
authors.affiliation: 1] St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia [2] Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Wali
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Rondas
authors.affiliation: 1] St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia [2] The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: McKenzie
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Elkerbout
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Fynch
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
authors.forename: E N
authors.initials: EN
authors.lastname: Gurzov
authors.affiliation: Department of Host Defense, Osaka University, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, Leuven, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Mathieu
authors.affiliation: 1] St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia [2] Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia.
authors.forename: T W H
authors.initials: TW
authors.lastname: Kay
authors.affiliation: Laboratory for Clinical and Experimental Endocrinology, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Overbergh
authors.affiliation: 1] The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.affiliation: 1] St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia [2] Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia.
authors.forename: H E
authors.initials: HE
authors.lastname: Thomas
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012266:Ribose / Q000378:metabolism; D046509:Tissue Culture Techniques; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C497250:Ddit3 protein, mouse; D008565:Membrane Proteins; D016877:Oxidants; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D051742:Transcription Factor CHOP; D012266:Ribose; D005947:Glucose