Glucocorticoid-mediated induction of ZBTB16 affects insulin secretion in human islets and EndoC-βH1 β-cells
Alexandros Karagiannopoulos,
Efraim Westholm,
Jones K. Ofori,
Elaine Cowan,
Jonathan L.S. Esguerra,
Lena Eliasson
Affiliations
Alexandros Karagiannopoulos
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden; Corresponding author
Efraim Westholm
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden
Jones K. Ofori
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden; Epigenetic and Diabetes, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden
Elaine Cowan
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden
Jonathan L.S. Esguerra
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden; Novo Nordisk A/S, Copenhagen, Denmark
Lena Eliasson
Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden; Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden; Corresponding author
Summary: Glucocorticoid use is associated with steroid-induced diabetes mellitus and impaired pancreatic β-cell insulin secretion. Here, the glucocorticoid-mediated transcriptomic changes in human pancreatic islets and the human insulin-secreting EndoC-βH1 cells were investigated to uncover genes involved in β-cell steroid stress-response processes. Bioinformatics analysis revealed glucocorticoids to exert their effects mainly on enhancer genomic regions in collaboration with auxiliary transcription factor families including AP-1, ETS/TEAD, and FOX. Remarkably, we identified the transcription factor ZBTB16 as a highly confident direct glucocorticoid target. Glucocorticoid-mediated induction of ZBTB16 was time- and dose-dependent. Manipulation of ZBTB16 expression in EndoC-βH1 cells combined with dexamethasone treatment demonstrated its protective role against glucocorticoid-induced reduction of insulin secretion and mitochondrial function impairment. In conclusion, we determine the molecular impact of glucocorticoids on human islets and insulin-secreting cells and investigate the effects of glucocorticoid targets on β-cell function. Our findings can pave the way for therapies against steroid-induced diabetes mellitus.