GPR40-Mediated Gα12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets

Abstract

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 Gq and Gi2 pathways, and in contrast to fasiglifam Compound A also induced G12 coupling. Compound A and AM-1638 displayed similar activity at all pathways tested. The G/G-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 G12/G13-mediated signaling, which may contribute to GPR40 agonists therapeutic efficacy, is a specific property of GPR40 allosteric full agonists.

Gα12/13 signaling in metabolic diseases

“…Subsequently, GPR40 full agonists have been under development in preclinical settings. A GPR40 allosteric full agonist enhanced the glucose-stimulated insulin secretion in pancreatic β cells via the GPR40-mediated activation of Gα 12 103 . However, the overexpression of Gα 12 decreased insulin secretion through JNK 38 .…”

Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators

“…The pharmacology of the FFAR1 molecular receptor is complex and not fully understood. The receptor is reported to couple to all four heterotrimeric G protein families (Gq, Gi, Gs, and G12) as well as to β-arrestins [58,59]. It is tempting to speculate that the fully available repertoire is differentially covered by various ligands, resulting in a phenomenon known as signaling bias, where certain pathways are preferentially activated over others.…”

“…Hauge et al proposed that combined signaling via Gs and Gq accounts for this feature as the full allosteric agonists AM 1638 or AM 5262 were more efficacious in GLP-1 induction in mice compared to the partial allosteric agonists fasiglifam or AM 837, which only activate Gq [52]. Whether additional coupling partners of FFAR1 further modulate the biological activity is currently not known, but reports suggest differences between partial and full agonists at the FFA1 receptor also apply to their coupling efficiency to G12 proteins [59].…”

The role of protein kinase D (PKD) in intracellular nutrient sensing and regulation of adaptive responses to the obese environment

“…Treatments for T2DM, such as GPR40 agonists that target the PKD signalling pathway in the pancreas, are currently in clinical trials 101 . GPR40 is a G‐protein coupled receptor that binds FFA, and evidence from isolated mouse islets suggests that its activation potentiates GSIS through a PKD‐mediated pathway 97 .…”