Replication confers β cell immaturity

Pancreatic beta cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in beta-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal beta cells that are functionally immature as defined by a lower set point for glucose-stimulated insulin secretion. Here we show that beta-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non-oncogenic levels of c-Myc. Adult beta cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal beta that proliferate readily. We directly demonstrate that priming insulin-producing cells to enter the cell cycle promotes a functionally immature phenotype. We suggest that there exists a balance between mature functionality and the ability to expand, as the phenotypic state of the beta cell reverts to a less functional one in response to proliferative cues.