Author:
Berger Miles,Scheel David W.,Macias Hector,Miyatsuka Takeshi,Kim Hail,Hoang Phuong,Ku Greg M.,Honig Gerard,Liou Angela,Tang Yunshuo,Regard Jean B.,Sharifnia Panid,Yu Lisa,Wang Juehu,Coughlin Shaun R.,Conklin Bruce R.,Deneris Evan S.,Tecott Laurence H.,German Michael S.
Abstract
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.
Funder
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
HHS | NIH | National Institute of Mental Health
Larry L. Hillblom Foundation
Nora Eccles Treadwell Foundation
Juvenile Diabetes Research Foundation International
American Diabetes Association
Publisher
Proceedings of the National Academy of Sciences
Cited by
62 articles.
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