%0 Journal Article
%T High-Throughput Screening for GPR119 Modulators Identifies a Novel Compound with Anti-Diabetic Efficacy in db/db Mice
%A Meng Zhang
%A Yang Feng
%A Jia Wang
%A Jianwei Zhao
%A Ting Li
%A Min He
%A Dehua Yang
%A Olivier Nosjean
%A Jean Boutin
%A Pierre Renard
%A Ming-Wei Wang
%J PLOS ONE
%D 2013
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0063861
%X G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic ¦Â cells and enteroendocrine cells. It is involved in glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) release, thereby representing a promising target for the treatment of type 2 diabetes. Although a number of GPR119 agonists were developed, no positive allosteric modulator (PAM) to this receptor has been reported. Here we describe a high-throughput assay for screening GPR119 PAMs and agonists simultaneously. Following screening of a small molecule compound library containing 312,000 synthetic and natural product-derived samples, one potent GPR119 agonist with novel chemical structure, MW1219, was identified. Exposure of MIN6 and GLUTag cells to MW1219 enhanced glucose-stimulated insulin secretion and GLP-1 release; once-daily oral dosing of MW1219 for 6 weeks in diabetic db/db mice reduced hemoglobin A1c (HbA1c) and improved plasma glucose, insulin and GLP-1 levels; it also increased glucose tolerance. The results demonstrate that MW1219 is capable of effectively controlling blood glucose level and may have the potential to be developed as a new class of anti-diabetic agents.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0063861