6494 GLP-1/GIP/Glucagon Triagonist Improves Glycemic Control via Gαq Signaling Pathway and TRPM5 Activation

Abstract

Abstract Disclosure: N. Khajavi: None. P.C. Schreier: None. P. Beyerle: None. P.S. Reinach: None. A. Breit: None. I. Boekhoff: None. T.D. Müller: Grant Recipient; Self; Novo Nordisk. Speaker; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. T. Gudermann: None. Cutting-edge research on obesity and diabetes strives to pioneer innovative drug combinations targeting various dysfunctional metabolic regulatory pathways. The single-molecule triagonist has been developed to directly interact with the glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GcgR). It provides a breakthrough in the treatment of obesity and type 2 diabetes because of greater efficacy compared to conventional single-agonist therapy. While the triagonist is already undergoing phase two clinical trials, the downstream mechanism requires further study. Previously, we showed that triagonist elicits transient rises in intracellular Ca2+ concentration that augment glucose-induced rises in insulin secretion in murine (MIN6) and human (1.1B4) pancreatic β cell lines. Although Gαs signaling is known as the main mediator of both GLP-1 and GIP signaling, our research indicates that the superior effect of the triagonist on insulin secretion is not solely dependent on the activation of the classical Gαs pathway and the exchange factor activated by cAMP (EPAC) signaling. Instead, we report that the triagonist enhances glucose-induced rises in insulin secretion via Gαq signaling and its downstream effector, the TRPM5 channel. This involvement is evident, as blocking Gαq signaling with a specific blocker, YM254890, reduced triagonist-induced rises in insulin secretion in mouse pancreatic islets. Similarly, blocking TRPM5 with the TPPO blocker attenuated triagonist-induced increases in insulin secretion and Ca2+ signaling in mouse pancreatic islets. Strikingly, both blockers had no remarkable impact on GLP-1- and GIP-induced rises in insulin secretion. Our in vivo analysis demonstrates that the triagonist improves glucose tolerance in diet-induced obese wild-type mice, but this effect was absent in TRPM5 knockout mice. Notably, the triagonist augments glucose-induced insulin secretion in isolated islets of wild-type mice more than treatment with GLP1 and GIP mono-agonists. Furthermore, this enhanced response is absent in TRPM5 knockout islets. Recent studies propose that persistent membrane depolarization of β cells leads to a switch from Gαs to Gαq signaling, which is a major amplifying pathway of insulin secretion under diabetic conditions. Our study shows that the enhancing effect of the triagonist, acting as a biased agonist, on insulin secretion is dependent on TRPM5 activation through the Gαq signaling pathway. Presentation: 6/2/2024