title: Activation of Nicotinic Acetylcholine Receptors Decreases Apoptosis in Human and Female Murine Pancreatic Islets.
abstract: Type 1 diabetes (T1DM) results from destruction of most insulin-secreting pancreatic β-cells. The persistence of β-cells decades after the onset of the disease indicates that the resistance of individual cells to the autoimmune insult is heterogeneous and might depend on the metabolic status of a cell at a given moment. The aim of this study is to investigate whether activation of nicotinic acetylcholine receptors (nACh-Rs) could increase β-cell resistance against the adverse environment prevailing at the onset of T1DM. Here, we show that nACh-R activation by nicotine and choline, 2 agonists of the receptor, decreases murine and human β-cell apoptosis induced by proinflammatory cytokines known to be present in the islet environment at the onset of T1DM. The protective mechanism activated by nicotine and choline involves attenuation of mitochondrial outer membrane permeabilization via modulation of endoplasmic reticulum stress, of the activity of B-cell lymphoma 2 family proteins and cytoplasmic calcium levels. Local inflammation and endoplasmic reticulum stress being key determinants of β-cell death in T1DM, we conclude that pharmacological activation of nACh-R could represent a valuable therapeutic option in the modulation of β-cell death in T1DM.
authors.affiliation: Service of Development and Growth (P.K., A.G., E.S., A.T., V.S.), Department of Pediatrics, University Hospital of Geneva and Diabetes Center, University of Geneva, 1211 Geneva, Switzerland; Cell Isolation and Transplantation Center (D.B.), Department of Surgery, University Hospital of Geneva and University of Geneva, 1205 Geneva, Switzerland; and Department of Cell Physiology and Metabolism (P.M.), Geneva University Medical Center, 1205 Geneva, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Klee
authors.affiliation: Service of Development and Growth (P.K., A.G., E.S., A.T., V.S.), Department of Pediatrics, University Hospital of Geneva and Diabetes Center, University of Geneva, 1211 Geneva, Switzerland; Cell Isolation and Transplantation Center (D.B.), Department of Surgery, University Hospital of Geneva and University of Geneva, 1205 Geneva, Switzerland; and Department of Cell Physiology and Metabolism (P.M.), Geneva University Medical Center, 1205 Geneva, Switzerland.
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.affiliation: Service of Development and Growth (P.K., A.G., E.S., A.T., V.S.), Department of Pediatrics, University Hospital of Geneva and Diabetes Center, University of Geneva, 1211 Geneva, Switzerland; Cell Isolation and Transplantation Center (D.B.), Department of Surgery, University Hospital of Geneva and University of Geneva, 1205 Geneva, Switzerland; and Department of Cell Physiology and Metabolism (P.M.), Geneva University Medical Center, 1205 Geneva, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Guérardel
authors.affiliation: Service of Development and Growth (P.K., A.G., E.S., A.T., V.S.), Department of Pediatrics, University Hospital of Geneva and Diabetes Center, University of Geneva, 1211 Geneva, Switzerland; Cell Isolation and Transplantation Center (D.B.), Department of Surgery, University Hospital of Geneva and University of Geneva, 1205 Geneva, Switzerland; and Department of Cell Physiology and Metabolism (P.M.), Geneva University Medical Center, 1205 Geneva, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Somm
authors.affiliation: Service of Development and Growth (P.K., A.G., E.S., A.T., V.S.), Department of Pediatrics, University Hospital of Geneva and Diabetes Center, University of Geneva, 1211 Geneva, Switzerland; Cell Isolation and Transplantation Center (D.B.), Department of Surgery, University Hospital of Geneva and University of Geneva, 1205 Geneva, Switzerland; and Department of Cell Physiology and Metabolism (P.M.), Geneva University Medical Center, 1205 Geneva, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Toulotte
authors.affiliation: Service of Development and Growth (P.K., A.G., E.S., A.T., V.S.), Department of Pediatrics, University Hospital of Geneva and Diabetes Center, University of Geneva, 1211 Geneva, Switzerland; Cell Isolation and Transplantation Center (D.B.), Department of Surgery, University Hospital of Geneva and University of Geneva, 1205 Geneva, Switzerland; and Department of Cell Physiology and Metabolism (P.M.), Geneva University Medical Center, 1205 Geneva, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maechler
authors.affiliation: Service of Development and Growth (P.K., A.G., E.S., A.T., V.S.), Department of Pediatrics, University Hospital of Geneva and Diabetes Center, University of Geneva, 1211 Geneva, Switzerland; Cell Isolation and Transplantation Center (D.B.), Department of Surgery, University Hospital of Geneva and University of Geneva, 1205 Geneva, Switzerland; and Department of Cell Physiology and Metabolism (P.M.), Geneva University Medical Center, 1205 Geneva, Switzerland.
authors.forename: Valérie M
authors.initials: VM
authors.lastname: Schwitzgebel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002794:Choline; D046508:Culture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005786:Gene Expression Regulation; D019254:Genes, bcl-2; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D051336:Mitochondrial Membranes / Q000378:metabolism; D009538:Nicotine; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism
chemical_list: D018722:Nicotinic Agonists; D009569:Nitric Oxide; D009538:Nicotine; D053148:Caspase 3; D002794:Choline; D002118:Calcium