DEC1 regulates human β cell functional maturation and circadian rhythm.

Stem cell-derived islet (SC-islet) organoids offer hope for cell replacement therapy in diabetes, but their immature function remains a challenge. Mature islet function requires the β cell circadian clock, yet how the clock regulates maturation is unclear. Here, we show that a circadian transcription factor specific to maturing SC-β cells, DEC1, regulates insulin responsiveness to glucose. SC-islet organoids form normally from DEC1-ablated human pluripotent stem cells, but their insulin release capacity and glucose threshold fail to increase during in vitro culture and upon transplant. This deficit reflects the downregulation of maturity-linked effectors of glucose utilization and insulin exocytosis, blunting glycolytic and oxidative metabolism, and is rescued by increasing metabolic flux. Moreover, DEC1 is needed to boost SC-islet maturity by synchronizing circadian glucose-responsive insulin secretion rhythms and clock machinery. Thus, DEC1 links circadian rhythms to human β cell maturation, highlighting the essential role of circadian control in generating fully functional SC-islet organoids.