title: G protein-coupled receptor 39 deficiency is associated with pancreatic islet dysfunction.
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)-1alpha and HNF-4alpha, 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-1alpha 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.
authors.affiliation: Laboratory for Molecular Pharmacology, University of Copenhagen, Copenhagen, Denmark. holst@sund.ku.dk
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.forename: Kristoffer L
authors.initials: KL
authors.lastname: Egerod
authors.forename: Chunyu
authors.initials: C
authors.lastname: Jin
authors.forename: Pia Steen
authors.initials: PS
authors.lastname: Petersen
authors.forename: Mette Viberg
authors.initials: MV
authors.lastname: Østergaard
authors.forename: Jacob
authors.initials: J
authors.lastname: Hald
authors.forename: A M Ejernaes
authors.initials: AM
authors.lastname: Sprinkel
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Peter
authors.initials: P
authors.lastname: Thams
authors.forename: Cathrine
authors.initials: C
authors.lastname: Orskov
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.forename: Frank
authors.initials: F
authors.lastname: Sundler
authors.forename: Ole D
authors.initials: OD
authors.lastname: Madsen
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: C512928:GPR39 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; D018398:Homeodomain Proteins; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose; D015032:Zinc