期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：9
页码：2888-2893
DOI：10.1073/pnas.1319378112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThis paper shows that a class of receptors known to modulate insulin release by pancreatic {beta} cells also regulates the proliferation of these cells and restrains the perinatal {beta}-cell expansion that establishes adult {beta}-cell mass, suggesting that alterations in signaling by these receptors could contribute to the decreased {beta}-cell numbers seen in patients with type 2 diabetes. Further, inhibition of signaling through these receptors potentially could be used to generate more {beta} cells for people with diabetes. Gi-GPCRs, G protein-coupled receptors that signal via G proteins of the i/o class (Gi/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 {beta} cells, and variants in genes encoding several Gi-GPCRs--including the -2a adrenergic receptor, ADRA2A--increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total {beta}-cell mass, and the role of Gi-GPCRs in establishing {beta}-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates {beta}-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic {beta} cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal {beta} cells decreased {beta}-cell proliferation, reduced adult {beta}-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal {beta}-cell proliferation, increased adult {beta}-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult {beta} cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of {beta}-cell replication. These studies link Gi-GPCR signaling to {beta}-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase {beta}-cell mass in patients with diabetes.
