作者: Chiori Yabuki , Hidetoshi Komatsu , Yoshiyuki Tsujihata , Risa Maeda , Ryo Ito
DOI: 10.1371/JOURNAL.PONE.0076280
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摘要: 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 pancreatic β cells. Although significantly improved glycemic control type 2 diabetes patients with minimum risk of hypoglycemia study, the precise mechanisms its potent pharmacological effects are not fully understood. Here we demonstrate that acts as ago-allosteric modulator partial agonistic activity for FFAR1. In both Ca2+ influx and assays using cell lines mouse islets, showed positive cooperativity ligand γ-linolenic (γ-LA). Augmentation glucose-induced fasiglifam, γ-LA, or their combination was completely abolished islets FFAR1-knockout mice. diabetic rats, insulinotropic effect suppressed reduction plasma (FFA) levels lipolysis inhibitor, suggesting release conjunction FFAs vivo. Point mutations differentially affected activities further indicating these agonists may bind to distinct binding sites. Our results strongly suggest is exerts acting cooperatively endogenous human well animals. These findings contribute our understanding attractive novel mechanism action.