title: Protection of Human Pancreatic Islets from Lipotoxicity by Modulation of the Translocon.
abstract: Type 2 diabetes is characterized by peripheral insulin resistance and pancreatic beta cell dysfunction. Elevated free fatty acids (FFAs) may impair beta cell function and mass (lipotoxicity). Altered calcium homeostasis may be involved in defective insulin release. The endoplasmic reticulum (ER) is the major intracellular calcium store. Lipotoxicity induces ER stress and in parallel an ER calcium depletion through unknown ER calcium leak channels. The main purposes of this study is first to identify one of these channels and secondly, to check the opportunity to restore beta cells function (i.e., insulin secretion) after pharmacological inhibition of ER calcium store depletion. We investigated the functionality of translocon, an ER calcium leak channel and its involvement on FFAs-induced alterations in MIN6B1 cells and in human pancreatic islets. We evidenced that translocon acts as a functional ER calcium leak channel in human beta cells using anisomycin and puromycin (antibiotics), respectively blocker and opener of this channel. Puromycin induced a significant ER calcium release, inhibited by anisomycin pretreatment. Palmitate treatment was used as FFA model to induce a mild lipotoxic effect: ER calcium content was reduced, ER stress but not apoptosis were induced and glucose induced insulin secretion was decreased in our beta cells. Interestingly, translocon inhibition by chronic anisomycin treatment prevented dysfunctions induced by palmitate, avoiding reticular calcium depletion, ER stress and restoring insulin secretion. Our results provide for the first time compelling evidence that translocon actively participates to the palmitate-induced ER calcium leak and insulin secretion decrease in beta cells. Its inhibition reduces these lipotoxic effects. Taken together, our data indicate that TLC may be a new potential target for the treatment of type 2 diabetes.
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Charles Mérieux Lyon-Sud, F-69003 Lyon, France.
authors: R
authors: R
authors: Cassel
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Rockefeller, F-69003 Lyon, France.
authors: S
authors: S
authors: Ducreux
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Rockefeller, F-69003 Lyon, France.
authors: M R
authors: MR
authors: Alam
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Charles Mérieux Lyon-Sud, F-69003 Lyon, France.
authors: F
authors: F
authors: Dingreville
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Charles Mérieux Lyon-Sud, F-69003 Lyon, France.
authors: C
authors: C
authors: Berlé
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Charles Mérieux Lyon-Sud, F-69003 Lyon, France.
authors: K
authors: K
authors: Burda-Jacob
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Charles Mérieux Lyon-Sud, F-69003 Lyon, France.
authors: M A
authors: MA
authors: Chauvin
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Charles Mérieux Lyon-Sud, F-69003 Lyon, France.
authors: K
authors: K
authors: Chikh
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Rockefeller, F-69003 Lyon, France.
authors: L
authors: L
authors: Païta
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Rockefeller, F-69003 Lyon, France.
authors: R
authors: R
authors: Al-Mawla
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Rockefeller, F-69003 Lyon, France.
authors: C
authors: C
authors: Crola Da Silva
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Charles Mérieux Lyon-Sud, F-69003 Lyon, France.
authors: J
authors: J
authors: Rieusset
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Charles Mérieux Lyon-Sud, F-69003 Lyon, France.|Hospices Civils de Lyon, Hôpital Lyon-Sud, Service d'Endocrinologie, Diabétologie et Nutrition, F-69310 Pierre Bénite, France.
authors: C
authors: C
authors: Thivolet
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Rockefeller, F-69003 Lyon, France.
authors: F
authors: F
authors: Van Coppenolle
authors: Inserm UMR-U1060 CarMeN Laboratory, University Lyon 1, INRA U1235, INSA-Lyon, Facultés de médecine Charles Mérieux Lyon-Sud, F-69003 Lyon, France.
authors: A M
authors: AM
authors: Madec
mesh_terms: D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D017930:Genes, Reporter; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D051379:Mice; D010168:Palmitates / Q000633:toxicity*; D000069284:Protein Translocation Systems / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects; D011691:Puromycin / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007328:Insulin; D010168:Palmitates; D000069284:Protein Translocation Systems; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D011691:Puromycin; D000841:Anisomycin; D020169:Caspases; D002118:Calcium