Novel GPR40 agonist AS2575959 exhibits glucose metabolism improvement and synergistic effect with sitagliptin on insulin and incretin secretion

Life Sci. 2014 Jan 17;94(2):115-21. doi: 10.1016/j.lfs.2013.11.010. Epub 2013 Nov 21.


Aims: GPR40 is a free fatty acid receptor that regulates glucose-dependent insulin secretion at pancreatic β-cells and glucagon-like peptide-1 (GLP-1), one of the major incretins, secretion at the endocrine cells of the gastrointestinal tract. We investigated the synergistic effect of AS2575959, a novel GPR40 agonist, in combination with sitagliptin, a major dipeptidyl peptidase-IV (DPP-IV) inhibitor, on glucose-dependent insulin secretion and GLP-1 secretion. In addition, we investigated the chronic effects of AS2575959 on whole-body glucose metabolism.

Main methods: We evaluated acute glucose metabolism on insulin and GLP-1 secretion using an oral glucose tolerance test (OGTT) as well as assessed the chronic glucose metabolism in diabetic ob/ob mice following the repeated administration of AS2575959.

Key findings: We discovered the novel GPR40 agonist sodium [(3S)-6-({4'-[(3S)-3,4-dihydroxybutoxy]-2,2',6'-trimethyl[1,1'-biphenyl]-3-yl}methoxy)-3H-spiro[1-benzofuran-2,1'-cyclopropan]-3-yl]acetate (AS2575959) and found that the compound influenced glucose-dependent insulin secretion both in vitro pancreas β-cell-derived cells and in vivo mice OGTT. Further, we observed a synergistic effect of AS2575959 and DPP-IV inhibitor on insulin secretion and plasma GLP-1 level. In addition, we discovered the improvement in glucose metabolism on repeated administration of AS2575959.

Significance: To our knowledge, this study is the first to demonstrate the synergistic effect of a GPR40 agonist and DPP-IV inhibitor on the glucose-dependent insulin secretion and GLP-1 concentration increase. These findings suggest that GPR40 agonists may represent a promising therapeutic strategy for the treatment of type 2 diabetes mellitus, particularly when used in combination with DPP-IV inhibitors.

Keywords: Diabetes; GPR40; Insulin secretion; OGTT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / pharmacology*
  • Animals
  • Blood Glucose / analysis
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Drug Synergism
  • Glucagon-Like Peptide 1 / blood
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Glycated Hemoglobin / analysis
  • Hypoglycemic Agents / pharmacology*
  • Incretins / metabolism*
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Secretion
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Obese
  • Pyrazines / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Sitagliptin Phosphate
  • Spiro Compounds / pharmacology*
  • Triazoles / pharmacology*


  • (6-((4'-(3,4-dihydroxybutoxy)-2,2',6'-trimethyl(1,1'-biphenyl)-3-yl)methoxy)-3H-spiro(1-benzofuran-2,1'-cyclopropan)-3-yl)acetic acid
  • Acetates
  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Ffar1 protein, mouse
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Incretins
  • Insulin
  • Pyrazines
  • Receptors, G-Protein-Coupled
  • Spiro Compounds
  • Triazoles
  • Glucagon-Like Peptide 1
  • Glucose
  • Sitagliptin Phosphate