title: A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric modulator of FFAR1.
abstract: Selective free fatty acid receptor 1 (FFAR1)/GPR40 agonist fasiglifam (TAK-875), an antidiabetic drug under phase 3 development, potentiates insulin secretion in a glucose-dependent manner by activating FFAR1 expressed in pancreatic β cells. Although fasiglifam significantly improved glycemic control in type 2 diabetes patients with a minimum risk of hypoglycemia in a phase 2 study, the precise mechanisms of its potent pharmacological effects are not fully understood. Here we demonstrate that fasiglifam acts as an ago-allosteric modulator with a partial agonistic activity for FFAR1. In both Ca(2+) influx and insulin secretion assays using cell lines and mouse islets, fasiglifam showed positive cooperativity with the FFAR1 ligand γ-linolenic acid (γ-LA). Augmentation of glucose-induced insulin secretion by fasiglifam, γ-LA, or their combination was completely abolished in pancreatic islets of FFAR1-knockout mice. In diabetic rats, the insulinotropic effect of fasiglifam was suppressed by pharmacological reduction of plasma free fatty acid (FFA) levels using a lipolysis inhibitor, suggesting that fasiglifam potentiates insulin release in conjunction with plasma FFAs in vivo. Point mutations of FFAR1 differentially affected Ca(2+) influx activities of fasiglifam and γ-LA, further indicating that these agonists may bind to distinct binding sites. Our results strongly suggest that fasiglifam is an ago-allosteric modulator of FFAR1 that exerts its effects by acting cooperatively with endogenous plasma FFAs in human patients as well as diabetic animals. These findings contribute to our understanding of fasiglifam as an attractive antidiabetic drug with a novel mechanism of action.
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Chiori
authors.initials: C
authors.lastname: Yabuki
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Komatsu
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsujihata
authors.forename: Risa
authors.initials: R
authors.lastname: Maeda
authors.forename: Ryo
authors.initials: R
authors.lastname: Ito
authors.forename: Kae
authors.initials: K
authors.lastname: Matsuda-Nagasumi
authors.forename: Kensuke
authors.initials: K
authors.lastname: Sakuma
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Miyawaki
authors.forename: Naoya
authors.initials: N
authors.lastname: Kikuchi
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Yugo
authors.initials: Y
authors.lastname: Habata
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mori
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D006224:Cricetinae; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D054333:Drug Partial Agonism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D009154:Mutation; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D017965:gamma-Linolenic Acid / Q000378:metabolism
chemical_list: D001572:Benzofurans; C473034:FFAR1 protein, human; D005230:Fatty Acids, Nonesterified; C473036:Ffar1 protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875; D017965:gamma-Linolenic Acid