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

Laboratory for Molecular Pharmacology (B.H., K.L.E., C.J., P.S.P., M.V.Ø., T.W.S.) and Institute of Biomedical Sciences (T.M.-P., J.J.H., P.T., C.Ø.), University of Copenhagen, DK-2200 Copenhagen, Denmark; Hagedorn Research Institute (J.H., A.M.E.S., O.D.M.) and Steno Diabetes Center (J.S., T.M.-P.), DK-2820 Gentofte, Denmark; Department of Experimental Medical Science (N.W., F.S.), Lund University, SE-22 184 Lund, Sweden; and Prosidion Ltd. (T.W.S.), Watlington Road, Oxford OX4 6LT, UK

Address all correspondence and requests for reprints to: Birgitte Holst, Laboratory for Molecular Pharmacology, University of Copenhagen, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. E-mail: holst{at}sund.ku.dk.

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 and HNF-4, 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 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.

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