{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:04:10Z","timestamp":1791187450676,"version":"4.1.0"},"reference-count":46,"publisher":"The Endocrine Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,6,1]]},"abstract":"<jats:p>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 Gq and G12\/13 pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1\u03b1 and HNF-4\u03b1, 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(\u2212\/\u2212) 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(\u2212\/\u2212) mice displayed normal insulin sensitivity but moderately impaired glucose tolerance both during oral and iv glucose tolerance tests, and Gpr39(\u2212\/\u2212) 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\u03b1 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.<\/jats:p>","DOI":"10.1210\/en.2008-1250","type":"journal-article","created":{"date-parts":[[2009,2,13]],"date-time":"2009-02-13T01:45:47Z","timestamp":1234489547000},"page":"2577-2585","source":"Crossref","is-referenced-by-count":88,"title":["G Protein-Coupled Receptor 39 Deficiency Is Associated with Pancreatic Islet Dysfunction"],"prefix":"10.1210","volume":"150","author":[{"given":"Birgitte","family":"Holst","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Pharmacology (B.H., K.L.E., C.J., P.S.P., M.V.\u00d8., T.W.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristoffer L.","family":"Egerod","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Pharmacology (B.H., K.L.E., C.J., P.S.P., M.V.\u00d8., T.W.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Jin","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Pharmacology (B.H., K.L.E., C.J., P.S.P., M.V.\u00d8., T.W.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia Steen","family":"Petersen","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Pharmacology (B.H., K.L.E., C.J., P.S.P., M.V.\u00d8., T.W.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette Viberg","family":"\u00d8stergaard","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Pharmacology (B.H., K.L.E., C.J., P.S.P., M.V.\u00d8., T.W.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Hald","sequence":"first","affiliation":[{"name":"Hagedorn Research Institute (J.H., A.M.E.S., O.D.M.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. M. Ejernaes","family":"Sprinkel","sequence":"first","affiliation":[{"name":"Hagedorn Research Institute (J.H., A.M.E.S., O.D.M.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"St\u00f8rling","sequence":"first","affiliation":[{"name":"Steno Diabetes Center (J.S., T.M.-P.), DK-2820 Gentofte, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Mandrup-Poulsen","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences (T.M.-P., J.J.H., P.T., C.\u00d8.), University of Copenhagen, DK-2200 Copenhagen, Denmark"},{"name":"Steno Diabetes Center (J.S., T.M.-P.), DK-2820 Gentofte, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens J.","family":"Holst","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences (T.M.-P., J.J.H., P.T., C.\u00d8.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Thams","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences (T.M.-P., J.J.H., P.T., C.\u00d8.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathrine","family":"\u00d8rskov","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences (T.M.-P., J.J.H., P.T., C.\u00d8.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Wierup","sequence":"first","affiliation":[{"name":"Department of Experimental Medical Science (N.W., F.S.), Lund University, SE-22 184 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Sundler","sequence":"first","affiliation":[{"name":"Department of Experimental Medical Science (N.W., F.S.), Lund University, SE-22 184 Lund, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole D.","family":"Madsen","sequence":"first","affiliation":[{"name":"Hagedorn Research Institute (J.H., A.M.E.S., O.D.M.), University of Copenhagen, DK-2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thue W.","family":"Schwartz","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Pharmacology (B.H., K.L.E., C.J., P.S.P., M.V.\u00d8., T.W.S.), University of Copenhagen, DK-2200 Copenhagen, Denmark"},{"name":"Prosidion Ltd. (T.W.S.), Watlington Road, Oxford OX4 6LT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2009,2,12]]},"reference":[{"key":"2020071612500426900_R1","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1006\/geno.1997.5069","article-title":"Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors.","volume":"46","author":"McKee","year":"1997","journal-title":"Genomics"},{"key":"2020071612500426900_R2","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/35038090","article-title":"Ghrelin induces adiposity in rodents.","volume":"407","author":"Tscho\u0308p","year":"2000","journal-title":"Nature"},{"key":"2020071612500426900_R3","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1172\/JCI25811","article-title":"Ghrelin action in the brain controls adipocyte metabolism.","volume":"116","author":"Theander-Carrillo","year":"2006","journal-title":"J Clin Invest"},{"key":"2020071612500426900_R4","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.cmet.2006.04.004","article-title":"Ablation of ghrelin improves the diabetic but not obese phenotype of ob\/ob mice.","volume":"3","author":"Sun","year":"2006","journal-title":"Cell Metab"},{"key":"2020071612500426900_R5","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1210\/me.2007-0055","article-title":"GPR39 splice variants versus antisense gene LYPD1: expression and regulation in gastrointestinal tract, endocrine pancreas, liver, and white adipose tissue.","volume":"21","author":"Egerod","year":"2007","journal-title":"Mol Endocrinol"},{"key":"2020071612500426900_R6","doi-asserted-by":"crossref","first-page":"53806","DOI":"10.1074\/jbc.M407676200","article-title":"Common structural basis for constitutive activity of the ghrelin receptor family.","volume":"279","author":"Holst","year":"2004","journal-title":"J Biol Chem"},{"key":"2020071612500426900_R7","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1126\/science.1117255","article-title":"Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin\u2019s effects on food intake.","volume":"310","author":"Zhang","year":"2005","journal-title":"Science"},{"key":"2020071612500426900_R8","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1210\/en.2006-0933","article-title":"GPR39 signaling is stimulated by zinc ions but not by obestatin.","volume":"148","author":"Holst","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612500426900_R9","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.bbrc.2006.09.141","article-title":"Obestatin does not activate orphan G protein-coupled receptor GPR39.","volume":"351","author":"Lauwers","year":"2006","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612500426900_R10","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1126\/science.1135047","article-title":"Comment on \u201cObestatin, a peptide encoded by the ghrelin gene, opposes ghrelin\u2019s effects on food intake.\u201d","volume":"315","author":"Chartrel","year":"2007","journal-title":"Science"},{"key":"2020071612500426900_R11","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1210\/en.2006-0915","article-title":"Effects of obestatin on energy balance and growth hormone secretion in rodents.","volume":"148","author":"Nogueiras","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612500426900_R12","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1080\/10799890701506147","article-title":"Isolation of Zn2+ as an endogenous agonist of GPR39 from fetal bovine serum.","volume":"27","author":"Yasuda","year":"2007","journal-title":"J Recept Signal Transduct Res"},{"key":"2020071612500426900_R13","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.2337\/diabetes.54.6.1808","article-title":"\u03b2-Cell secretory products activate \u03b1-cell ATP-dependent potassium channels to inhibit glucagon release.","volume":"54","author":"Franklin","year":"2005","journal-title":"Diabetes"},{"key":"2020071612500426900_R14","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ncb951","article-title":"Islet \u03b2-cell secretion determines glucagon release from neighbouring \u03b1-cells.","volume":"5","author":"Ishihara","year":"2003","journal-title":"Nat Cell Biol"},{"key":"2020071612500426900_R15","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1053\/j.gastro.2006.07.009","article-title":"Altered gastrointestinal and metabolic function in the GPR39-obestatin receptor-knockout mouse.","volume":"131","author":"Moechars","year":"2006","journal-title":"Gastroenterology"},{"key":"2020071612500426900_R16","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1210\/en.2006-1275","article-title":"Normal food intake and body weight in mice lacking the G protein-coupled receptor GPR39.","volume":"148","author":"Tremblay","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612500426900_R17","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1126\/science.1089769","article-title":"Control of pancreas and liver gene expression by HNF transcription factors.","volume":"303","author":"Odom","year":"2004","journal-title":"Science"},{"key":"2020071612500426900_R18","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1080\/ann.34.3.207.217","article-title":"Different genes, different diabetes: lessons from maturity-onset diabetes of the young.","volume":"34","author":"Stride","year":"2002","journal-title":"Ann Med"},{"key":"2020071612500426900_R19","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1369\/jhc.5A6827.2006","article-title":"Generation and characterization of monoclonal antibodies against the transcription factor Nkx6.1.","volume":"54","author":"Pedersen","year":"2006","journal-title":"J Histochem Cytochem"},{"key":"2020071612500426900_R20","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1177\/002215540405200301","article-title":"Ghrelin is expressed in a novel endocrine cell type in developing rat islets and inhibits insulin secretion from INS-1 (832\/13) cells.","volume":"52","author":"Wierup","year":"2004","journal-title":"J Histochem Cytochem"},{"key":"2020071612500426900_R21","first-page":"254","volume-title":"Methods in diabetes research.","author":"Brunstedt"},{"key":"2020071612500426900_R22","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.2337\/diabetes.48.12.2324","article-title":"\u03b2-Cell maturation leads to in vitro sensitivity to cytotoxins.","volume":"48","author":"Nielsen","year":"1999","journal-title":"Diabetes"},{"key":"2020071612500426900_R23","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1007\/s001250051683","article-title":"Differential mechanisms of glucose and palmitate in augmentation of insulin secretion in mouse pancreatic islets.","volume":"44","author":"Thams","year":"2001","journal-title":"Diabetologia"},{"key":"2020071612500426900_R24","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1210\/endo.138.1.4827","article-title":"Short-term insulin treatment prevents the diabetogenic action of streptozotocin in rats.","volume":"138","author":"Thulesen","year":"1997","journal-title":"Endocrinology"},{"key":"2020071612500426900_R25","doi-asserted-by":"crossref","first-page":"76","DOI":"10.2337\/diabetes.52.1.76","article-title":"All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal\/epithelial interactions in embryonic pancreas.","volume":"52","author":"Tulachan","year":"2003","journal-title":"Diabetes"},{"key":"2020071612500426900_R26","doi-asserted-by":"crossref","first-page":"646","DOI":"10.2337\/diabetes.47.4.646","article-title":"Mouse pancreatic \u03b2-cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-1 receptor gene.","volume":"47","author":"Flamez","year":"1998","journal-title":"Diabetes"},{"key":"2020071612500426900_R27","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1038\/nm1196-1254","article-title":"Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene.","volume":"2","author":"Scrocchi","year":"1996","journal-title":"Nat Med"},{"key":"2020071612500426900_R28","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/ng1097-138","article-title":"Early-onset type-II diabetes mellitus (MODY4) linked to IPF1.","volume":"17","author":"Stoffers","year":"1997","journal-title":"Nat Genet"},{"key":"2020071612500426900_R29","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/384455a0","article-title":"Mutations in the hepatocyte nuclear factor-1\u03b1 gene in maturity-onset diabetes of the young (MODY3).","volume":"384","author":"Yamagata","year":"1996","journal-title":"Nature"},{"key":"2020071612500426900_R30","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1172\/JCI200522365","article-title":"The MODY1 gene HNF-4\u03b1 regulates selected genes involved in insulin secretion.","volume":"115","author":"Gupta","year":"2005","journal-title":"J Clin Invest"},{"key":"2020071612500426900_R31","doi-asserted-by":"crossref","first-page":"3564","DOI":"10.1172\/JCI26002","article-title":"Mice lacking ghrelin receptors resist the development of diet-induced obesity.","volume":"115","author":"Zigman","year":"2005","journal-title":"J Clin Invest"},{"key":"2020071612500426900_R32","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.cmet.2005.03.007","article-title":"The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse.","volume":"1","author":"Steneberg","year":"2005","journal-title":"Cell Metab"},{"key":"2020071612500426900_R33","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1210\/en.2006-1608","article-title":"A role for \u03b2-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release.","volume":"148","author":"Chu","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612500426900_R34","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1371\/journal.pmed.0040118","article-title":"Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene","volume":"4","author":"Pearson","year":"2007","journal-title":"PLoS Med"},{"key":"2020071612500426900_R35","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1210\/en.2004-1576","article-title":"Minireview: transcriptional regulation in pancreatic development.","volume":"146","author":"Habener","year":"2005","journal-title":"Endocrinology"},{"key":"2020071612500426900_R36","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1172\/JCI200316537","article-title":"Increased islet apoptosis in Pdx1+\/\u2212 mice.","volume":"111","author":"Johnson","year":"2003","journal-title":"J Clin Invest"},{"key":"2020071612500426900_R37","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nature05097","article-title":"Calcineurin\/NFAT signalling regulates pancreatic \u03b2-cell growth and function.","volume":"443","author":"Heit","year":"2006","journal-title":"Nature"},{"key":"2020071612500426900_R38","doi-asserted-by":"crossref","first-page":"7074","DOI":"10.1074\/jbc.M704323200","article-title":"The constitutively active orphan G-protein coupled receptor GPR39 protects from cell death by increasing secretion of pigment-epithelial derived growth factor PEDF.","volume":"283","author":"Dittmer","year":"2008","journal-title":"J Biol Chem"},{"key":"2020071612500426900_R39","doi-asserted-by":"crossref","first-page":"4199","DOI":"10.1242\/jcs.03164","article-title":"In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion.","volume":"119","author":"Chimienti","year":"2006","journal-title":"J Cell Sci"},{"key":"2020071612500426900_R40","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/nature05616","article-title":"A genome-wide association study identifies novel risk loci for type 2 diabetes.","volume":"445","author":"Sladek","year":"2007","journal-title":"Nature"},{"key":"2020071612500426900_R41","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1023\/A:1012905406548","article-title":"Functions of zinc in signaling, proliferation and differentiation of mammalian cells.","volume":"14","author":"Beyersmann","year":"2001","journal-title":"Biometals"},{"key":"2020071612500426900_R42","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1007\/s001250050009","article-title":"Zinc sulphate induces metallothionein in pancreatic islets of mice and protects against diabetes induced by multiple low doses of streptozotocin.","volume":"43","author":"Ohly","year":"2000","journal-title":"Diabetologia"},{"key":"2020071612500426900_R43","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1177\/153537020422901113","article-title":"Prevention of spontaneous and experimentally induced diabetes in mice with zinc sulfate-enriched drinking water is associated with activation and reduction of NF-\u03baB and AP-1 in islets, respectively.","volume":"229","author":"Schott-Ohly","year":"2004","journal-title":"Exp Biol Med (Maywood)"},{"key":"2020071612500426900_R44","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/mgme.1997.2672","article-title":"The role of dietary zinc in modifying the onset and severity of spontaneous diabetes in the BB Wistar rat.","volume":"63","author":"Tobia","year":"1998","journal-title":"Mol Genet Metab"},{"key":"2020071612500426900_R45","first-page":"65","author":"Schwartz","year":"2002"},{"key":"2020071612500426900_R46","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.1210\/en.2008-1251","article-title":"Disruption of G protein-coupled receptor 39 impairs insulin secretion in vivo.","volume":"150","author":"Tremblay","year":"2009","journal-title":"Endocrinology"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/150\/6\/2577\/9003702\/endo2577.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/150\/6\/2577\/9003702\/endo2577.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T22:03:36Z","timestamp":1594937016000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/150\/6\/2577\/2456069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2,12]]},"references-count":46,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2009,6,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2008-1250","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,2,12]]}}}