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

Published

Journal Article

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

Full Text

Duke Authors

Cited Authors

  • Berger, M; Scheel, DW; Macias, H; Miyatsuka, T; Kim, H; Hoang, P; Ku, GM; Honig, G; Liou, A; Tang, Y; Regard, JB; Sharifnia, P; Yu, L; Wang, J; Coughlin, SR; Conklin, BR; Deneris, ES; Tecott, LH; German, MS

Published Date

  • March 3, 2015

Published In

Volume / Issue

  • 112 / 9

Start / End Page

  • 2888 - 2893

PubMed ID

  • 25695968

Pubmed Central ID

  • 25695968

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1319378112

Language

  • eng

Conference Location

  • United States