Circadian regulation of insulin secretion in transplanted human stem cell-derived pancreatic β-cells.

Cell replacement strategies utilizing stem cell-derived pancreatic β-cells (SCβ-cells) hold therapeutic potential for patients with diabetes. However, little is known about how endogenous (host) and exogenous (transplant) circadian systems interact to influence the engraftment and function of SCβ-cells. We report that differentiation of SCβ-cells in vitro is associated with the induction of key circadian clock genes known to regulate insulin secretion. Upon transplantation into severe combined immunodeficiency (SCID)-beige mice, SCβ-cells exhibit circadian rhythms in glucose-stimulated insulin secretion optimized to the host's active circadian phase. Furthermore, disrupting the host's circadian rhythms abolishes circadian regulation and the overall functional capacity of transplanted SCβ-cells. These observations suggest that the host's circadian system entrains SCβ-cell function to optimize the circadian control of insulin secretion.