TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats

J Pharmacol Exp Ther. 2011 Oct;339(1):228-37. doi: 10.1124/jpet.111.183772. Epub 2011 Jul 13.


G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic β cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. The insulinotropic action of TAK-875 (10 μM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired β cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity.

MeSH terms

  • Animals
  • Benzofurans / pharmacology*
  • Blood Glucose / metabolism
  • CHO Cells
  • Calcium / metabolism
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Survival / drug effects
  • Cricetinae
  • Cricetulus
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Fasting / physiology
  • Glucose / physiology*
  • Hyperglycemia / blood
  • Hyperglycemia / drug therapy*
  • Hypoglycemic Agents*
  • Insulin / metabolism*
  • Insulin Resistance / physiology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Male
  • Postprandial Period / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / agonists*
  • Signal Transduction / drug effects
  • Sulfones / pharmacology*


  • Benzofurans
  • Blood Glucose
  • G-protein-coupled receptor 40, rat
  • Hypoglycemic Agents
  • Insulin
  • Receptors, G-Protein-Coupled
  • Sulfones
  • TAK-875
  • Caspase 3
  • Caspase 7
  • Glucose
  • Calcium