title: Autophagy plays a protective role in endoplasmic reticulum stress-mediated pancreatic β cell death.
abstract: There is a growing evidence of the role of autophagy in pancreatic β cell homeostasis. During development of type 2 diabetes, β cells are required to supply the increased demand of insulin. In such a stage, β cells have to address high ER stress conditions that could lead to abnormal insulin secretion, and ultimately, β cell death and overt diabetes. In this study, we used insulin secretion-deficient β cells derived from fetal mice. These cells present an increased accumulation of polyubiquitinated protein aggregates and LC3B-positive puncta, when compared with insulinoma-derived β cell lines. We found that insulin secretion deficiency renders these cells hypersensitive to endoplasmic reticulum (ER) stress-mediated cell death. Chemical or shRNA-mediated inhibition of autophagy increased β cell death under ER stress. On the other hand, rapamycin treatment increased both autophagy and cell survival under ER stress. Insulin secretion-deficient β cells showed a marked reduction of the antiapoptotic protein BCL2, together with increased BAX expression and ERN1 hyperactivation upon ER stress induction. These results showed how insulin secretion deficiency in β cells may be contributing to ER stress-mediated cell death, and in this regard, we showed how the autophagic response plays a prosurvival role.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bartolome
authors.forename: Carlos
authors.initials: C
authors.lastname: Guillen
authors.forename: Manuel
authors.initials: M
authors.lastname: Benito
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D007328:Insulin; D046912:Multiprotein Complexes; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus