Circadian regulation of pancreatic islet function and the transcriptome by glucocorticoid signaling

Glucocorticoids exhibit a circadian secretory pattern and act through the glucocorticoid receptor (GR), a nuclear hormone receptor that promotes cell-type-specific gene expression. However, GR targets and the regulatory role of glucocorticoids in pancreatic β-cells remain incompletely understood. We used transcriptional, epigenetic, and physiological assays to delineate the role of glucocorticoid signaling in β-cells. The results indicate that GR targets in β-cells are enriched for transcriptional regulators associated with β-cell function and circadian rhythms. Genetic ablation of GR in mouse β-cells impairs β-cell function and GR target gene expression within islets. Additionally, expression of GR-dependent enhancer-associated genes in islets exhibits rhythmicity in vivo, which can be amplified or phase-shifted by timed glucocorticoid administration. Furthermore, reinforcement of glucocorticoid signaling in male mice subjected to circadian disruption improves β-cell function and the rhythmicity of genes involved in circadian regulation and insulin secretion. Our findings suggest that the circadian timing of glucocorticoid secretion exerts control over diurnal β-cell gene expression and function. Glucocorticoid (GC) signaling through the glucocorticoid receptor (GR) is an important regulator of metabolism, but its role in pancreatic β-cell function and circadian regulation remains poorly understood. Using transcriptional, epigenetic, and physiological approaches, the authors identify β-cell GR targets involved in insulin secretion, β-cell identity, and circadian rhythms, and show that timed GC signaling modulates rhythmic gene expression and β-cell function under circadian disruption.