title: Delayed apoptosis allows islet β-cells to implement an autophagic mechanism to promote cell survival.
abstract: Increased β-cell death coupled with the inability to replicate existing β-cells drives the decline in β-cell mass observed in the progression of both major forms of diabetes. Understanding endogenous mechanisms of islet cell survival could have considerable value for the development of novel strategies to limit β-cell loss and thereby promote β-cell recovery. Insulinoma cells have provided useful insight into β-cell death pathways but observations made in cell lines sometimes fail to translate to primary islets. Here, we report dramatic differences in the temporal regulation and engagement of the apoptotic program in primary rodent islets relative to the INS-1 derived 832/13 cell line. As expected, 832/13 cells rapidly induced cell stress markers in response to ER stress or DNA damage and were fully committed to apoptosis, resulting in >80% cell death within 24 h. In contrast, primary rat islets were largely refractory to cell death in response to ER stress and DNA damage, despite rapid induction of stress markers, such as XBP-1(s), CHOP, and PUMA. Gene expression profiling revealed a general suppression of pro-apoptotic machinery, such as Apaf-1 and caspase 3, and sustained levels of pro-survival factors, such as cIAP-1, cIAP-2, and XIAP, in rat islets. Furthermore, we observed sustained induction of autophagy following chronic ER stress and found that inhibition of autophagy rendered islet β-cells highly vulnerable to ER stress-induced cell death. We propose that islet β-cells dampen the apoptotic response to delay the onset of cell death, providing a temporal window in which autophagy can be activated to limit cellular damage and promote survival.
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Hayes
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, United States of America.|Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Brett S
authors.initials: BS
authors.lastname: Peterson
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, United States of America.|Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Haldeman
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, United States of America.|Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Medicine, Division of Endocrinology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, United States of America.|Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Medicine, Division of Endocrinology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Hohmeier
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina, United States of America.|Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Samuel B
authors.identifier: http://orcid.org/0000-0003-1152-2691
authors.initials: SB
authors.lastname: Stephens
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D001343:Autophagy / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D005947:Glucose / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007340:Insulinoma / Q000473:pathology; D007515:Islets of Langerhans / Q000166:cytology* / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000473:pathology; D051381:Rats
chemical_list: C506594:Apaf1 protein, rat; D053477:Apoptotic Protease-Activating Factor 1; D051034:Inhibitor of Apoptosis Proteins; D007328:Insulin; C494837:Xiap protein, rat; D053148:Caspase 3; D005947:Glucose