GLP-1/GIP/GCG receptor triagonist (IUB447) enhances insulin secretion via GLP-1 receptor and Gαq signalling pathway in mice – Published online 09/09/2025

Pascale C. F. Schreier, Philipp Beyerle, Severin Boulassel, Andreas Beck, Aaron Novikoff, Peter S. Reinach, Ingrid Boekhoff, Andreas Breit, Arthur Neuberger, Timo D. Müller, Alberto Cebrian Serrano, Thomas Gudermann, Noushafarin Khajavi

Unimolecular triagonist peptides combining glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon activity represent a new frontier in the treatment of obesity and type 2 diabetes. In this issue, Schreier et al (https://doi.org/10.1007/s00125-025-06525-0) show that the triagonist IUB447 improves glycaemic management primarily through the GLP-1 receptor. Unlike classical incretin signalling, which depends on Gαs activation and cAMP accumulation, IUB447 engages a Gαq-dependent pathway that triggers protein kinase C activation and enhances calcium influx and insulin secretion. Central to this mechanism is the ion channel transient receptor potential melastatin 5 (TRPM5), whose pharmacological inhibition or genetic deletion abolishes the metabolic benefits of triagonist therapy. Structural modelling further suggests that additional stabilising interactions strengthen and prolong IUB447–GLP-1 receptor binding compared with native GLP-1, potentially explaining its superior efficacy. The authors conclude that these findings highlight the therapeutic potential of selectively targeting the GLP-1 receptor–TRPM5 signalling axis, paving the way for next-generation incretin-based therapies for type 2 diabetes.

All News