High-throughput screening for GPR119 modulators identifies a novel compound with anti-diabetic efficacy in db/db mice

PLoS One. 2013 May 21;8(5):e63861. doi: 10.1371/journal.pone.0063861. Print 2013.


G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic β 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Drug Evaluation, Preclinical
  • Glucagon-Like Peptide 1 / metabolism
  • HEK293 Cells
  • High-Throughput Screening Assays*
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / metabolism
  • Insulin Secretion
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxadiazoles / pharmacology
  • Oxadiazoles / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism


  • AR 231453
  • GPR119 protein, human
  • Gpr119 protein, mouse
  • Hypoglycemic Agents
  • Insulin
  • Oxadiazoles
  • Pyrimidines
  • Receptors, G-Protein-Coupled
  • Glucagon-Like Peptide 1

Grants and funding

This work was supported in part by grants from the Ministry of Health of China (2012ZX09304011 and 2013ZX09507002), Shanghai Science and Technology Development Fund (11DZ2292200) and Les Laboratories Servier (France). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.