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G Protein-Coupled Receptor 39 Deficiency Is Associated with Pancreatic Islet Dysfunction

Holst, Birgitte; Egerod, Kristoffer L.; Jin, Chunyu; Petersen, Pia Steen; Ostergaard, Mette Viberg; Hald, Jacob; Sprinkel, A. M. Ejernaes; Storling, Joachim; Mandrup-Poulsen, Thomas and Holst, Jens J., et al. (2009) Keystone Meeting on Beta-Cell Function In Endocrinology 150. p.2577-2585
Abstract
G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn++ sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1 alpha and HNF-4 alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was... (More)
G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn++ sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1 alpha and HNF-4 alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was down-regulated on differentiation of the pluripotent pancreatic cell line AR42J cells toward the exocrine phenotype but was along with Pdx-1 strongly up-regulated on differentiation toward the endocrine phenotype. Immunohistochemistry demonstrated that GRP39 is localized selectively in the insulin-storing cells of the pancreatic islets as well as in the duct cells of the exocrine pancreas. Gpr39(-/-) mice displayed normal insulin sensitivity but moderately impaired glucose tolerance both during oral and iv glucose tolerance tests, and Gpr39(-/-) mice had decreased plasma insulin response to oral glucose. Islet architecture was normal in the Gpr39 null mice, but expression of Pdx-1 and Hnf-1 alpha was reduced. Isolated, perifused islets from Gpr39 null mice secreted less insulin in response to glucose stimulation than islets from wild-type littermates. It is concluded that GPR39 is involved in the control of endocrine pancreatic function, and it is suggested that this receptor could be a novel potential target for the treatment of diabetes. (Endocrinology 150: 2577-2585, 2009) (Less)
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Contribution to journal
publication status
published
subject
in
Endocrinology
volume
150
pages
2577 - 2585
publisher
Endocrine Society
conference name
Keystone Meeting on Beta-Cell Function
external identifiers
  • WOS:000266256700015
  • PMID:19213833
  • Scopus:66649087112
ISSN
0013-7227
DOI
10.1210/en.2008-1250
language
English
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yes
id
0329d13a-4c63-412e-8dc6-3d1582fb8369 (old id 1425670)
date added to LUP
2009-03-02 14:20:24
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2016-12-04 04:52:09
@misc{0329d13a-4c63-412e-8dc6-3d1582fb8369,
  abstract     = {G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn++ sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1 alpha and HNF-4 alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines. Gpr39(-/-) mice were studied in vivo, especially in respect of glucose tolerance and insulin sensitivity, and in vitro in respect of islet architecture, gene expression, and insulin secretion. Gpr39 was down-regulated on differentiation of the pluripotent pancreatic cell line AR42J cells toward the exocrine phenotype but was along with Pdx-1 strongly up-regulated on differentiation toward the endocrine phenotype. Immunohistochemistry demonstrated that GRP39 is localized selectively in the insulin-storing cells of the pancreatic islets as well as in the duct cells of the exocrine pancreas. Gpr39(-/-) mice displayed normal insulin sensitivity but moderately impaired glucose tolerance both during oral and iv glucose tolerance tests, and Gpr39(-/-) mice had decreased plasma insulin response to oral glucose. Islet architecture was normal in the Gpr39 null mice, but expression of Pdx-1 and Hnf-1 alpha was reduced. Isolated, perifused islets from Gpr39 null mice secreted less insulin in response to glucose stimulation than islets from wild-type littermates. It is concluded that GPR39 is involved in the control of endocrine pancreatic function, and it is suggested that this receptor could be a novel potential target for the treatment of diabetes. (Endocrinology 150: 2577-2585, 2009)},
  author       = {Holst, Birgitte and Egerod, Kristoffer L. and Jin, Chunyu and Petersen, Pia Steen and Ostergaard, Mette Viberg and Hald, Jacob and Sprinkel, A. M. Ejernaes and Storling, Joachim and Mandrup-Poulsen, Thomas and Holst, Jens J. and Thams, Peter and Orskov, Cathrine and Wierup, Nils and Sundler, Frank and Madsen, Ole D. and Schwartz, Thue W.},
  issn         = {0013-7227},
  language     = {eng},
  pages        = {2577--2585},
  publisher    = {ARRAY(0x9326e90)},
  series       = {Endocrinology},
  title        = {G Protein-Coupled Receptor 39 Deficiency Is Associated with Pancreatic Islet Dysfunction},
  url          = {http://dx.doi.org/10.1210/en.2008-1250},
  volume       = {150},
  year         = {2009},
}