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

Miles Berger, David W. Scheel, Hector Macias, Takeshi Miyatsuka, Hail Kimc, Phuong Hoang, Greg M. Ku, Gerard Honig, Angela Liou, Yunshuo Tang, Jean B. Regard, Panid Sharifnia, Lisa Yu, Juehu Wang, Shaun R. Coughlin, Bruce R. Conklin, Evan S. Deneris, Laurence H. Tecott, Michael S. German

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


Gi-GPCRs, G protein-coupled receptors that signal via Ga 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.

Original languageEnglish
Pages (from-to)2888-2893
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number9
StatePublished - Mar 3 2015


  • Diabetes mellitus
  • G-protein coupled receptors
  • Islet
  • Perinatal
  • β cell mass


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