TY - JOUR
T1 - Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion
AU - Berger, Miles
AU - Scheel, David W.
AU - Macias, Hector
AU - Miyatsuka, Takeshi
AU - Kimc, Hail
AU - Hoang, Phuong
AU - Ku, Greg M.
AU - Honig, Gerard
AU - Liou, Angela
AU - Tang, Yunshuo
AU - Regard, Jean B.
AU - Sharifnia, Panid
AU - Yu, Lisa
AU - Wang, Juehu
AU - Coughlin, Shaun R.
AU - Conklin, Bruce R.
AU - Deneris, Evan S.
AU - Tecott, Laurence H.
AU - German, Michael S.
PY - 2015/3/3
Y1 - 2015/3/3
N2 - 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.
AB - 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.
KW - Diabetes mellitus
KW - G-protein coupled receptors
KW - Islet
KW - Perinatal
KW - β cell mass
UR - http://www.scopus.com/inward/record.url?scp=84924390208&partnerID=8YFLogxK
U2 - 10.1073/pnas.1319378112
DO - 10.1073/pnas.1319378112
M3 - Article
C2 - 25695968
AN - SCOPUS:84924390208
SN - 0027-8424
VL - 112
SP - 2888
EP - 2893
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -