This Article Full Text Full Text (PDF) A correction has been published Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chu, Z.-L. Articles by Leonard, J. Search for Related Content PubMed PubMed Citation Articles by Chu, Z.-L. Articles by Leonard, J.

A Role for ß-Cell-Expressed G Protein-Coupled Receptor 119 in Glycemic Control by Enhancing Glucose-Dependent Insulin Release

Arena Pharmaceuticals (Z.-L.C., R.M.J., H.H., C.C., V.G., A.L., M.M., H.G., H.M., D.B., D.U., G.S., D.P.B., J.L.), San Diego, California 92121; and Johnson & Johnson Pharmaceutical Research and Development (Y.L., K.D.), Spring House, Pennsylvania 19477

Address all correspondence and requests for reprints to: James Leonard, Ph.D., Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121. E-mail: jleonard{at}arenapharm.com.

Pancreatic ß-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor have shown significant promise as antidiabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic ß-cell mass. These effects are mediated via stimulation of cAMP through ß-cell GLP-1 receptors. We report that the G_s-coupled receptor GPR119 is largely restricted to insulin-producing ß-cells of pancreatic islets. Additionally, we show here that GPR119 functions as a glucose-dependent insulinotropic receptor. Unlike receptors for GLP-1 and other peptides that mediate enhanced glucose-dependent insulin release, GPR119 was suitable for the development of potent, orally active, small-molecule agonists. The GPR119-specific agonist AR231453 significantly increased cAMP accumulation and insulin release in both HIT-T15 cells and rodent islets. In both cases, loss of GPR119 rendered AR231453 inactive. AR231453 also enhanced glucose-dependent insulin release in vivo and improved oral glucose tolerance in wild-type mice but not in GPR119-deficient mice. Diabetic KK/A^y mice were also highly responsive to AR231453. Orally active GPR119 agonists may offer significant promise as novel antihyperglycemic agents acting in a glucose-dependent fashion.

This article has been cited by other articles:

				B. Holst, K. L. Egerod, C. Jin, P. S. Petersen, M. V. Ostergaard, J. Hald, A. M. E. Sprinkel, J. Storling, T. Mandrup-Poulsen, J. J. Holst, et al. G Protein-Coupled Receptor 39 Deficiency Is Associated with Pancreatic Islet Dysfunction Endocrinology, June 1, 2009; 150(6): 2577 - 2585. [Abstract] [Full Text] [PDF]

				F. Tremblay, A.-M. T. Richard, S. Will, J. Syed, N. Stedman, M. Perreault, and R. E. Gimeno Disruption of G Protein-Coupled Receptor 39 Impairs Insulin Secretion in Vivo Endocrinology, June 1, 2009; 150(6): 2586 - 2595. [Abstract] [Full Text] [PDF]

				H. Lan, G. Vassileva, A. Corona, L. Liu, H. Baker, A. Golovko, S. J Abbondanzo, W. Hu, S. Yang, Y. Ning, et al. GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis J. Endocrinol., May 1, 2009; 201(2): 219 - 230. [Abstract] [Full Text] [PDF]

				L. M. Lauffer, R. Iakoubov, and P. L. Brubaker GPR119 Is Essential for Oleoylethanolamide-Induced Glucagon-Like Peptide-1 Secretion From the Intestinal Enteroendocrine L-Cell Diabetes, May 1, 2009; 58(5): 1058 - 1066. [Abstract] [Full Text] [PDF]

				S. Costanzi, S. Neumann, and M. C. Gershengorn Seven Transmembrane-spanning Receptors for Free Fatty Acids as Therapeutic Targets for Diabetes Mellitus: Pharmacological, Phylogenetic, and Drug Discovery Aspects J. Biol. Chem., June 13, 2008; 283(24): 16269 - 16273. [Full Text] [PDF]

				N. Sonoda, T. Imamura, T. Yoshizaki, J. L. Babendure, J.-C. Lu, and J. M. Olefsky {beta}-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic {beta} cells PNAS, May 6, 2008; 105(18): 6614 - 6619. [Abstract] [Full Text] [PDF]

				L. Lauffer, R. Iakoubov, and P. L. Brubaker GPR119: "Double-Dipping" for Better Glycemic Control Endocrinology, May 1, 2008; 149(5): 2035 - 2037. [Full Text] [PDF]

				Z.-L. Chu, C. Carroll, J. Alfonso, V. Gutierrez, H. He, A. Lucman, M. Pedraza, H. Mondala, H. Gao, D. Bagnol, 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, May 1, 2008; 149(5): 2038 - 2047. [Abstract] [Full Text] [PDF]