title: Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion.
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.
authors.affiliation: Departments of Psychiatry and Center for Neurobiology and Psychiatry, Diabetes Center, Hormone Research Institute, and.
authors.forename: Miles
authors.initials: M
authors.lastname: Berger
authors.affiliation: Diabetes Center, Hormone Research Institute, and.
authors.forename: David W
authors.initials: DW
authors.lastname: Scheel
authors.affiliation: Diabetes Center, Hormone Research Institute, and.
authors.forename: Hector
authors.initials: H
authors.lastname: Macias
authors.affiliation: Diabetes Center, Hormone Research Institute, and.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyatsuka
authors.affiliation: Diabetes Center, Hormone Research Institute, and.
authors.forename: Hail
authors.initials: H
authors.lastname: Kim
authors.affiliation: Departments of Psychiatry and Center for Neurobiology and Psychiatry, Diabetes Center, Hormone Research Institute, and.
authors.forename: Phuong
authors.initials: P
authors.lastname: Hoang
authors.affiliation: Diabetes Center, Hormone Research Institute, and Medicine.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Ku
authors.affiliation: Departments of Psychiatry and Center for Neurobiology and Psychiatry.
authors.forename: Gerard
authors.initials: G
authors.lastname: Honig
authors.affiliation: Departments of Psychiatry and Center for Neurobiology and Psychiatry.
authors.forename: Angela
authors.initials: A
authors.lastname: Liou
authors.affiliation: Departments of Psychiatry and Center for Neurobiology and Psychiatry.
authors.forename: Yunshuo
authors.initials: Y
authors.lastname: Tang
authors.affiliation: The Cardiovascular Research Institute, University of California, San Francisco, CA 94143;
authors.forename: Jean B
authors.initials: JB
authors.lastname: Regard
authors.affiliation: Department of Molecular Cell Biology, University of California, Berkeley, CA 94720;
authors.forename: Panid
authors.initials: P
authors.lastname: Sharifnia
authors.affiliation: Department of Molecular Cell Biology, University of California, Berkeley, CA 94720;
authors.forename: Lisa
authors.initials: L
authors.lastname: Yu
authors.affiliation: Diabetes Center, Hormone Research Institute, and.
authors.forename: Juehu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Medicine, The Cardiovascular Research Institute, University of California, San Francisco, CA 94143;
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Coughlin
authors.affiliation: Medicine, The Gladstone Institute for Cardiovascular Disease, San Francisco, CA 94143; and.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Conklin
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Evan S
authors.initials: ES
authors.lastname: Deneris
authors.affiliation: Departments of Psychiatry and Center for Neurobiology and Psychiatry.
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Tecott
authors.affiliation: Diabetes Center, Hormone Research Institute, and Medicine, mgerman@diabetes.ucsf.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: German
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C547769:Adra2a protein, mouse; D018341:Receptors, Adrenergic, alpha-2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D005947:Glucose
keywords: G-protein coupled receptors; diabetes mellitus; islet; perinatal; β cell mass