Basic Science| Volume 62, ISSUE 1, P70-78, January 2013

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GPR119 expression in normal human tissues and islet cell tumors: evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function



      GPR119 is reportedly involved in regulating glucose metabolism and food intake in rodents, but little is known about its expression and functional significance in humans. To begin to assess the potential clinical importance of GPR119, the distribution of GPR119 gene expression in humans was examined.


      Expression of GPR119 mRNA in fresh samples of normal human pancreas (n=19) and pancreatic islets (n=3) and in insulinomas (n=2) and glucagonomas (n=2), all collected at surgery, was compared with the mRNA expression of various receptors highly expressed and operative in human pancreatic islets.


      GPR119 mRNA was most abundant in the pancreas, followed by the duodenum, stomach, jejunum, ileum and colon. Pancreatic levels of GPR119 mRNA were similar to those of GPR40 mRNA and were higher than those of GLP1R and SUR1 mRNA, which are strongly expressed in human pancreatic islets. Moreover, levels of GPR119 mRNA in pancreatic islets were more than 10 times higher than in adjacent pancreatic tissue, as were levels of GPR40 mRNA. GPR119 mRNA was also abundant in two cases of insulinoma and two cases of glucagonoma, but was undetectable in a pancreatic acinar cell tumor. Similar results were obtained with mouse pancreatic islets, MIN6 insulinoma cells and alpha-TC glucagonoma cells.


      The results provide evidence of an islet-gastrointestinal distribution of GPR119, its expression in pancreatic beta and alpha cells, and its possible involvement in islet function. They also provide the basis for a better understanding of the potential clinical importance of GPR119.


      FFPE (formalin-fixed, paraffin-embedded), GLP1R (glucagon-like peptide 1 receptor), GPR119 (G protein-coupled receptor 119), GPR40 (G protein-coupled receptor 40), SUR1 (sulfonylurea receptor 1)


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        • Stein D.T.
        • Stevenson B.E.
        • Chester M.W.
        • et al.
        The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation.
        J Clin Invest. 1997; 100: 398-403
        • Lam T.K.
        • Pocai A.
        • Gutierrez-Juarez R.
        • et al.
        Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis.
        Nat Med. 2005; 11: 320-327
        • Fu J.
        • Gaetani S.
        • Oveisi F.
        • et al.
        Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha.
        Nature. 2003; 425: 90-93
        • Itoh Y.
        • Kawamata Y.
        • Harada M.
        • et al.
        Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40.
        Nature. 2003; 422: 173-176
        • Brown A.J.
        • Goldsworthy S.M.
        • Barnes A.A.
        • et al.
        The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids.
        J Biol Chem. 2003; 278: 11312-11319
        • Hirasawa A.
        • Tsumaya K.
        • Awaji T.
        • et al.
        Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120.
        Nat Med. 2005; 11: 90-94
        • Ahren B.
        Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes.
        Nat Rev Drug Discov. 2009; 8: 369-385
        • Kebede M.A.
        • Alquier T.
        • Latour M.G.
        • et al.
        Lipid receptors and islet function: therapeutic implications?.
        Diabetes Obes Metab. 2009; 11: 10-20
        • Tomita T.
        • Masuzaki H.
        • Iwakura H.
        • et al.
        Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans: evidence for GPR40 expression in pancreatic beta cells and implications for insulin secretion.
        Diabetologia. 2006; 49: 962-968
        • Tomita T.
        • Masuzaki H.
        • Noguchi M.
        • et al.
        GPR40 gene expression in human pancreas and insulinoma.
        Biochem Biophys Res Commun. 2005; 338: 1788-1790
        • Overton H.A.
        • Babbs A.J.
        • Doel S.M.
        • et al.
        Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.
        Cell Metab. 2006; 3: 167-175
        • Lauffer L.M.
        • Iakoubov R.
        • Brubaker P.L.
        GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell.
        Diabetes. 2009; 58: 1058-1066
        • Hansen K.B.
        • Rosenkilde M.M.
        • Knop F.K.
        • et al.
        2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans.
        J Clin Endocrinol Metab. 2011; 96: E1409-E1417
        • Chu Z.L.
        • Carroll C.
        • Chen R.
        • et al.
        N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119.
        Mol Endocrinol. 2010; 24: 161-170
        • Soga T.
        • Ohishi T.
        • Matsui T.
        • et al.
        Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor.
        Biochem Biophys Res Commun. 2005; 326: 744-751
        • Kogure R.
        • Toyama K.
        • Hiyamuta S.
        • et al.
        5-Hydroxy-eicosapentaenoic acid is an endogenous GPR119 agonist and enhances glucose-dependent insulin secretion.
        Biochem Biophys Res Commun. 2011; 416: 58-63
        • Ning Y.
        • O'Neill K.
        • Lan H.
        • et al.
        Endogenous and synthetic agonists of GPR119 differ in signalling pathways and their effects on insulin secretion in MIN6c4 insulinoma cells.
        Br J Pharmacol. 2008; 155: 1056-1065
        • Chu Z.L.
        • Jones R.M.
        • He H.
        • et al.
        A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release.
        Endocrinology. 2007; 148: 2601-2609
        • Chu Z.L.
        • Carroll C.
        • Alfonso J.
        • et al.
        A role for intestinal endocrine cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release.
        Endocrinology. 2008; 149: 2038-2047
        • Lan H.
        • Lin H.V.
        • Wang C.F.
        • et al.
        Agonists at GPR119 mediate secretion of GLP-1 from mouse enteroendocrine cells through glucose-independent pathways.
        Br J Pharmacol. 2012; 165: 2799-2807
        • Semple G.
        • Fioravanti B.
        • Pereira G.
        • et al.
        Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119.
        J Med Chem. 2008; 51: 5172-5175
        • Lan H.
        • Vassileva G.
        • Corona A.
        • et al.
        GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis.
        J Endocrinol. 2009; 201: 219-230
        • Gao J.
        • Tian L.
        • Weng G.
        • et al.
        Stimulating beta-cell replication and improving islet graft function by AR231453, A gpr119 agonist.
        Transplant Proc. 2011; 43: 3217-3220
        • Flock G.
        • Holland D.
        • Seino Y.
        • et al.
        GPR119 regulates murine glucose homeostasis through incretin receptor-dependent and independent mechanisms.
        Endocrinology. 2011; 152: 374-383
        • Semple G.
        • Ren A.
        • Fioravanti B.
        • et al.
        Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control.
        Bioorg Med Chem Lett. 2011; 21: 3134-3141
        • Semple G.
        • Lehmann J.
        • Wong A.
        • et al.
        Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile.
        Bioorg Med Chem Lett. 2011; 22: 1750-1755
        • Yoshida S.
        • Ohishi T.
        • Matsui T.
        • et al.
        The role of small molecule GPR119 agonist, AS1535907, in glucose-stimulated insulin secretion and pancreatic beta-cell function.
        Diabetes Obes Metab. 2011; 13: 34-41
        • Cox H.M.
        • Tough I.R.
        • Woolston A.M.
        • et al.
        Peptide YY is critical for acylethanolamine receptor Gpr119-induced activation of gastrointestinal mucosal responses.
        Cell Metab. 2010; 11: 532-542
        • Katz L.B.
        • Gambale J.J.
        • Rothenberg P.L.
        • et al.
        Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential antidiabetes agent, in healthy male subjects.
        Clin Pharmacol Ther. 2011; 90: 685-692
        • Katz L.B.
        • Gambale J.J.
        • Rothenberg P.L.
        • et al.
        Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes.
        Diabetes Obes Metab. 2012; 14: 709-716; 10.1111/j.1463-1326.2012.01587.x
        • Vassilopoulos S.
        • Esk C.
        • Hoshino S.
        • et al.
        A role for the CHC22 clathrin heavy-chain isoform in human glucose metabolism.
        Science. 2009; 324: 1192-1196
        • Seino Y.
        • Nanjo K.
        • Tajima N.
        • et al.
        Report of the Committee on the Classification and diagnostic Criteria of Diabetes Mellitus.
        Diabetol Int. 2010; 1: 2-20
        • Iwakura H.
        • Hosoda K.
        • Son C.
        • et al.
        Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice.
        J Biol Chem. 2005; 280: 15247-15256
        • Miyazaki J.
        • Araki K.
        • Yamato E.
        • et al.
        Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms.
        Endocrinology. 1990; 127: 126-132
        • Ferrannini E.
        • Gastaldelli A.
        • Miyazaki Y.
        • et al.
        beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis.
        J Clin Endocrinol Metab. 2005; 90: 493-500
        • Matthews D.R.
        • Hosker J.P.
        • Rudenski A.S.
        • et al.
        Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
        Diabetologia. 1985; 28: 412-419
        • Briscoe C.P.
        • Tadayyon M.
        • Andrews J.L.
        • et al.
        The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids.
        J Biol Chem. 2003; 278: 11303-11311
        • Rajan A.S.
        • Aguilar-Bryan L.
        • Nelson D.A.
        • et al.
        Sulfonylurea receptors and ATP-sensitive K+ channels in clonal pancreatic alpha cells. Evidence for two high affinity sulfonylurea receptors.
        J Biol Chem. 1993; 268: 15221-15228
        • Gribble F.M.
        • Reimann F.
        Sulphonylurea action revisited: the post-cloning era.
        Diabetologia. 2003; 46: 875-891
        • Cooperberg B.A.
        • Cryer P.E.
        Beta-cell-mediated signaling predominates over direct alpha-cell signaling in the regulation of glucagon secretion in humans.
        Diabetes Care. 2009; 32: 2275-2280
        • Rodriguez de Fonseca F.
        • Navarro M.
        • Gomez R.
        • et al.
        An anorexic lipid mediator regulated by feeding.
        Nature. 2001; 414: 209-212
        • Dockray G.J.
        The versatility of the vagus.
        Physiol Behav. 2009; 97: 531-536
        • Engelstoft M.S.
        • Egerod K.L.
        • Holst B.
        • et al.
        A gut feeling for obesity: 7TM sensors on enteroendocrine cells.
        Cell Metab. 2008; 8: 447-449
        • Imagawa A.
        • Hanafusa T.
        • Uchigata Y.
        • et al.
        Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus.
        Diabetologia. 2005; 48: 294-300