Neuropeptide Y expression marks partially differentiated β cells in mice and humans

beta Cells are formed in embryonic life by differentiation of endocrine progenitors and expand by replication during neonatal life, followed by transition into functional maturity. In this study, we addressed the potential contribution of neuropeptide Y (NPY) in pancreatic beta cell development and maturation. We show that NPY expression is restricted from the progenitor populations during pancreatic development and marks functionally immature beta cells in fetal and neonatal mice and humans. NPY expression is epigenetically downregulated in beta cells upon maturation. Neonatal beta cells that express NPY are more replicative, and knockdown of NPY expression in neonatal mouse islets reduces replication and enhances insulin secretion in response to high glucose. These data show that NPY expression likely promotes replication and contributes to impaired glucose responsiveness in neonatal beta cells. We show that NPY expression reemerges in beta cells in mice fed with high-fat diet as well as in diabetes in mice and humans, establishing a potential new mechanism to explain impaired beta cell maturity in diabetes. Together, these studies highlight the contribution of NPY in the regulation of beta cell differentiation and have potential applications for beta cell supplementation for diabetes therapy.