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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/Ay 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.
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