Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion

Gi-GPCRs, G protein-coupled receptors that signal via G alpha proteins of the i/o class (G alpha(i/o)), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic beta cells, and variants in genes encoding several Gi-GPCRs-including the alpha-2a adrenergic receptor, ADRA2A-increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total beta-cell mass, and the role of Gi-GPCRs in establishing beta-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates beta-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic beta cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal beta cells decreased beta-cell proliferation, reduced adult beta-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal beta-cell proliferation, increased adult beta-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult beta cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of beta-cell replication. These studies link Gi-GPCR signaling to beta-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase beta-cell mass in patients with diabetes.