title: Prednisolone-induced beta cell dysfunction is associated with impaired endoplasmic reticulum homeostasis in INS-1E cells.
abstract: Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2α. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Margot M L
authors.initials: MM
authors.lastname: Linssen
authors.forename: Daniel H
authors.initials: DH
authors.lastname: van Raalte
authors.forename: Erik J M
authors.initials: EJ
authors.lastname: Toonen
authors.forename: Wynand
authors.initials: W
authors.lastname: Alkema
authors.forename: Gerard C
authors.initials: GC
authors.lastname: van der Zon
authors.forename: Wim H
authors.initials: WH
authors.lastname: Dokter
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.forename: Bruno
authors.initials: B
authors.lastname: Guigas
authors.forename: D Margriet
authors.initials: DM
authors.lastname: Ouwens
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011239:Prednisolone / Q000009:adverse effects / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000502:physiology; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D002154:Calpain; D015852:Eukaryotic Initiation Factor-2; D005947:Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D008565:Membrane Proteins; D015735:Mifepristone; D011239:Prednisolone; D017346:Protein Serine-Threonine Kinases; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D019892:eIF-2 Kinase; C497113:Atf6 protein, rat; C084010:pancreatic and duodenal homeobox 1 protein; C486557:Ern2 protein, rat; C415197:calpain 10