title: Respective effects of oxygen and energy substrate deprivation on beta cell viability.
abstract: Deficit in oxygen and energetic substrates delivery is a key factor in islet loss during islet transplantation. Permeability transition pore (PTP) is a mitochondrial channel involved in cell death. We have studied the respective effects of oxygen and energy substrate deprivation on beta cell viability as well as the involvement of oxidative stress and PTP opening. Energy substrate deprivation for 1h followed by incubation in normal conditions led to a cyclosporin A (CsA)-sensitive-PTP-opening in INS-1 cells and human islets. Such a procedure dramatically decreased INS-1 cells viability except when transient removal of energy substrates was performed in anoxia, in the presence of antioxidant N-acetylcysteine (NAC) or when CsA or metformin inhibited PTP opening. Superoxide production increased during removal of energy substrates and increased again when normal energy substrates were restored. NAC, anoxia or metformin prevented the two phases of oxidative stress while CsA prevented the second one only. Hypoxia or anoxia alone did not induce oxidative stress, PTP opening or cell death. In conclusion, energy substrate deprivation leads to an oxidative stress followed by PTP opening, triggering beta cell death. Pharmacological prevention of PTP opening during islet transplantation may be a suitable option to improve islet survival and graft success.
authors: University of Grenoble Alpes, LBFA, Grenoble F-38000, France; U1055, INSERM, Grenoble F-38000, France; Department of Endocrinology, Grenoble University Hospital, Grenoble F-38043, France. Electronic address: slablanche@chu-grenoble.fr.
authors: Sandrine
authors: S
authors: Lablanche
authors: University of Grenoble Alpes, LBFA, Grenoble F-38000, France; U1055, INSERM, Grenoble F-38000, France.
authors: Cécile
authors: C
authors: Cottet-Rousselle
authors: CarMeN Laboratory, U1060, INSERM, Lyon F-69373, France.
authors: Laurent
authors: L
authors: Argaud
authors: University of Grenoble Alpes, LBFA, Grenoble F-38000, France; U1055, INSERM, Grenoble F-38000, France.
authors: Camille
authors: C
authors: Laporte
authors: University of Grenoble Alpes, LBFA, Grenoble F-38000, France; U1055, INSERM, Grenoble F-38000, France.
authors: Frédéric
authors: F
authors: Lamarche
authors: Cellular Therapy Unit, EFS Rhône-Alpes, Grenoble University Hospital, Grenoble, France.
authors: Marie-Jeanne
authors: MJ
authors: Richard
authors: Cell Isolation and Transplant Center, University of Geneva, Level R, 1 rue Michel Servet, Geneva 4, CH-1211, Switzerland.
authors: Thierry
authors: T
authors: Berney
authors: University of Grenoble Alpes, LBFA, Grenoble F-38000, France; U1055, INSERM, Grenoble F-38000, France; Department of Endocrinology, Grenoble University Hospital, Grenoble F-38043, France.
authors: Pierre-Yves
authors: PY
authors: Benhamou
authors: University of Grenoble Alpes, LBFA, Grenoble F-38000, France; U1055, INSERM, Grenoble F-38000, France; Department of Endocrinology, Grenoble University Hospital, Grenoble F-38043, France.
authors: Eric
authors: E
authors: Fontaine
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000860:Hypoxia; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D007004:Hypoglycemic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D008687:Metformin; D010100:Oxygen; D000111:Acetylcysteine
keywords: Apoptosis; Beta cell; Ischemia–reperfusion injury; Permeability transition