Replication confers ß cell immaturity.

ABSTRACT

Pancreatic ß cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in ß-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal ß cells that are functionally immature as defined by a lower set point for glucose-stimulated insulin secretion. Here we show that ß-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non-oncogenic levels of c-Myc. Adult ß cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal ß 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 ß cell reverts to a less functional one in response to proliferative cues.