Fasiglifam is a Selective and Orally Active GPR40 Agonist

Fasiglifam (TAK-875) acts as a novel, orally available, selective GPR40 agonist.

TAK-875 (0.01-10 μM) produces a concentration-dependent increase in intracellular IP production in CHO-hGPR40, with EC50 of 0.072 μM. Fasiglifam (TAK-875) (0.1-10 μM) dose-dependently augments intracellular IP production in CHO cells. And it (3-30 μM) concentration-dependently augments [Ca2+]i. In the presence of 10 mM glucose, TAK-875 (0.001-10 μM) dose-dependently stimulats insulin secretion from INS-1 833/15 cells.

Fasiglifam (TAK-875) increases intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway.

TAK-875 (1-100 μM) significantly altered glucose-stimulated insulin secretion in these cells. Fasiglifam (TAK-875, 6.25-100 μM) did not show any effect on caspase 3/7 activity under the same conditions.

Fasiglifam (TAK-875) also enhanced intracellular IP production, thus, an increase in [Ca2+]i with TAK-875 may, at least in part, result from calcium release from the ER.

The compound (10 mg/kg, p.o.) increases plasma insulin levels in ZDF rats. Fasiglifam (TAK-875) (30 mg/kg, p.o.) improves fasting hyperglycemia without affecting fasting normoglycemia. Also, Fasiglifam (TAK-875) at 30 mg/kg, which is a 3- to 10-fold higher dose compared with the dose that improved glucose tolerance in diabetic rats, does not alter fasting glucose levels in SD rats with normal glucose homeostasis. Likewise, Fasiglifam (TAK-875) does not significantly alter insulin secretion in SD rats with normal fasting glucose levels. Moreover, Fasiglifam (TAK-875) directly acts on pancreatic β cells but augments insulin secretion only when blood glucose levels are elevated. Fasiglifam (TAK-875) might enhance insulin secretion and reduce blood glucose.


Tsujihata Y,et al. 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.

Yoshiyuki Tsujihata, et al. TAK-875, an Orally Available GPR40/FFA1 Agonist Enhances Glucose-Dependent Insulin Secretion and Improves Both Postprandial and Fasting Hyperglycemia in Type 2 Diabetic Rats.. JPET July 13, 2011