TY - JOUR T1 - GPR40-mediated Gα12 activation by allosteric full agonists highly efficacious at potentiating glucose-stimulated insulin secretion in human islets JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.117.111369 SP - mol.117.111369 AU - Marie-Laure Rives AU - Brian Rady AU - Nadia Swanson AU - Shuyuan Zhao AU - Jenson Qi AU - Eric Arnoult AU - Ivona Bakaj AU - Arturo Mancini AU - Billy Breton AU - Paul S. Lee AU - Mark R Player AU - Alessandro Pocai Y1 - 2018/01/01 UR - http://molpharm.aspetjournals.org/content/early/2018/03/23/mol.117.111369.abstract N2 - GPR40 is a clinically validated molecular target for the treatment of diabetes. Many GPR40 agonists have been identified to date, with the partial agonist fasiglifam (TAK-875) reaching phase III clinical trials before its development was terminated due to off-target liver toxicity. Since then, attention has shifted toward the development of full agonists that exhibit superior efficacy in preclinical models. Full agonists bind to a distinct binding site, suggesting conformational plasticity and a potential for biased agonism. Indeed, it has been suggested that alternative pharmacology may be required for meaningful efficacy. In this study, we described the discovery and characterization of Compound A, a newly identified GPR40 allosteric full agonist highly efficacious in human islets at potentiating glucose-stimulated insulin secretion. We compared Compound A-induced GPR40 activity to that induced by both fasiglifam and AM-1638, another allosteric full agonist previously reported to be highly efficacious in preclinical models, at a panel of G proteins. Compound A was a full agonist at both the Gαq and Gαi2 pathways and in contrast to fasiglifam, Compound A also induced Gα12 coupling. Compound A and AM-1638 displayed similar activity at all pathways tested. The Gα12/Gα13-mediated signaling pathway has been linked to protein kinase D activation as well as actin remodeling, well known to contribute to the release of insulin vesicles. Our data suggest that the pharmacology of GPR40 is complex and that Gα12/Gα13-mediated signaling, which may contribute to GPR40 agonists therapeutic efficacy, is a specific property of GPR40 allosteric full agonists. ER -