Glucocorticoid-mediated induction of ZBTB16 affects insulin secretion in human islets and EndoC-H1 -cells

Glucocorticoid use is associated with steroid-induced diabetes mellitus and impaired pancreatic 0 -cell insulin secretion. Here, the glucocorticoid-mediated transcriptomic changes in human pancreatic islets and the human insulin -secreting EndoC-0H1 cells were investigated to uncover genes involved in 0 -cell steroid stress-response processes. Bioinformatics analysis revealed gluco-corticoids to exert their effects mainly on enhancer genomic regions in collabora-tion with auxiliary transcription factor families including AP-1, ETS/TEAD, and FOX. Remarkably, we identified the transcription factor ZBTB16 as a highly confi-dent direct glucocorticoid target. Glucocorticoid-mediated induction of ZBTB16 was time-and dose-dependent. Manipulation of ZBTB16 expression in EndoC-0H1 cells combined with dexamethasone treatment demonstrated its protective role against glucocorticoid-induced reduction of insulin secretion and mitochon-drial 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 0 -cell function. Our findings can pave the way for therapies against steroid-induced diabetes mellitus.