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G protein-coupled receptor 40 (GPR40)/free fatty acid 1 (FFA1) is a G protein-coupled receptor involved in free fatty acid-induced insulin secretion. To analyze the effect of our novel GPR40/FFA1-selective agonist, [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate (TAK-875), on insulin and glucagon secretion, we performed hormone secretion assays and measured intracellular Ca²⁺ concentration ([Ca²⁺](i)) in both human and rat islets. Insulin and glucagon secretion were measured in static and dynamic conditions by using groups of isolated rat and human pancreatic islets. [Ca²⁺](i) was recorded by using confocal microscopy. GPR40/FFA1 expression was measured by quantitative polymerase chain reaction. In both human and rat islets, TAK-875 enhanced glucose-induced insulin secretion in a glucose-dependent manner. The stimulatory effect of TAK-875 was similar to that produced by glucagon-like peptide-1 and correlated with the elevation of β-cell [Ca²⁺](i). TAK-875 was without effect on glucagon secretion at both 1 and 16 mM glucose in human islets. These data indicate that GPR40/FFA1 influences mainly insulin secretion in a glucose-dependent manner. The β-cell-specific action of TAK-875 in human islets may represent a therapeutically useful feature that allows plasma glucose control without compromising counter-regulation of glucagon secretion, thus minimizing the risk of hypoglycemia.

Original publication




Journal article


J Pharmacol Exp Ther

Publication Date





483 - 489


ATP-Binding Cassette Transporters, Animals, Benzofurans, Calcium Signaling, Drug Synergism, Gene Expression, Glucagon, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucagon-Secreting Cells, Glucose, Humans, In Vitro Techniques, Insulin, Insulin Secretion, Insulin-Secreting Cells, Islets of Langerhans, Potassium Channels, Inwardly Rectifying, Rats, Rats, Sprague-Dawley, Receptors, Drug, Receptors, G-Protein-Coupled, Receptors, Glucagon, Sulfones, Sulfonylurea Receptors