期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 9, 页码 2888-2893出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1319378112
关键词
islet; beta cell mass; perinatal; G-protein coupled receptors; diabetes mellitus
资金
- Larry L. Hillblom Foundation [2007/1B]
- Nora Eccles Treadwell Foundation
- Juvenile Diabetes Research Foundation [16-2007-428, 3-2007-721, 3-2007-187, 10-2010-553]
- American Diabetes Association Grant [ADA-7-11-MN-22]
- National Institutes of Health [R01 DK021344, U01 DK089541, T32 GM07618, F31 MH075708, P30 DK63720]
- University of California, San Francisco Sandler Program in Basic Science
Gi-GPCRs, G protein-coupled receptors that signal via G alpha proteins of the i/o class (G alpha(i/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 alpha-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.
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