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

doi:10.1016/j.isci.2023.106555

Glucocorticoid-mediated induction of ZBTB16 affects insulin secretion in human islets and EndoC-βH1 β-cells

iScience. 2023 Apr 1;26(5):106555. doi: 10.1016/j.isci.2023.106555. eCollection 2023 May 19.

Authors

Alexandros Karagiannopoulos^{1

2}, Efraim Westholm^{1

2}, Jones K Ofori^{1

2

3}, Elaine Cowan^{1

2}, Jonathan L S Esguerra^{1

2

4}, Lena Eliasson^{1

2}

Affiliations

¹ Islet Cell Exocytosis, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden.
² Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
³ Epigenetic and Diabetes, Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden.
⁴ Novo Nordisk A/S, Copenhagen, Denmark.

Abstract

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.

Keywords: Bioinformatics; Endocrine system physiology; Human metabolism; Molecular mechanism of gene regulation.