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Aims/hypothesis <p>Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) have been shown to improve glycaemic management in both mice and humans. Yet the identity of the downstream signalling events mediated by these peptides remain to be elucidated. Here, we aimed to assess the mechanisms by which a validated peptide triagonist for GLP-1/GIP/GCG receptors (IUB447) stimulates insulin secretion in murine pancreatic islets.</p> Methods <p>Islets were isolated from wild-type (WT), <i>Gipr</i>-knockout (<i>Gipr</i><sup>−/−</sup>), <i>Gcgr</i>-knockout (<i>Gcgr</i><sup>−/−</sup>), <i>Glp-1r</i> (also known as <i>Glp1r</i>)/<i>Gipr</i> double-knockout and <i>Trpm5</i>-knockout (<i>Trpm5</i><sup>−/−</sup>) mice, followed by assessment of beta cell function and insulin secretion in response to mono- and multi-agonist administration. Metabolic phenotypes of WT and <i>Trpm5</i><sup>−/−</sup> mice under chow and high-fat diets were investigated following triagonist application.</p> Results <p>The triagonist promoted glucose-stimulated insulin secretion (GSIS) to a greater degree than co-administration of conventional mono-agonists in WT mouse islets. The triagonist-induced increase in GSIS was unchanged in the absence of either <i>Gipr</i> or <i>Gcgr</i>. However, the triagonist failed to enhance insulin secretion in islets lacking both <i>Glp-1r</i> and <i>Gipr</i> and upon treatment with the GLP-1 receptor-specific antagonist exendin-3 (9–39). Similarly, the specific blocking of Gαq signalling with YM254890 or transient receptor potential melastatin 5 (TRPM5) with triphenylphosphine oxide (TPPO) suppressed the triagonist-induced enhancement of GSIS. In vivo assessment of high-fat-fed <i>Trpm5</i><sup>−/−</sup> mice demonstrated the absence of triagonist-induced therapeutic effects on glycaemic management.</p> Conclusions/interpretation <p>Triagonist-induced augmentation of GSIS is primarily mediated through its interaction with the GLP-1 receptor and subsequent activation of the Gαq–TRPM5 signalling pathway. Given that Gαq is a key player in the amplification of GSIS, particularly under diabetic conditions, these findings highlight a GLP-1 receptor-centric pharmacological profile that underlies the potent effects of this multi-receptor agonist.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月9日

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  • 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

摘要

Aims/hypothesis

Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) have been shown to improve glycaemic management in both mice and humans. Yet the identity of the downstream signalling events mediated by these peptides remain to be elucidated. Here, we aimed to assess the mechanisms by which a validated peptide triagonist for GLP-1/GIP/GCG receptors (IUB447) stimulates insulin secretion in murine pancreatic islets.

Methods

Islets were isolated from wild-type (WT), Gipr-knockout (Gipr−/−), Gcgr-knockout (Gcgr−/−), Glp-1r (also known as Glp1r)/Gipr double-knockout and Trpm5-knockout (Trpm5−/−) mice, followed by assessment of beta cell function and insulin secretion in response to mono- and multi-agonist administration. Metabolic phenotypes of WT and Trpm5−/− mice under chow and high-fat diets were investigated following triagonist application.

Results

The triagonist promoted glucose-stimulated insulin secretion (GSIS) to a greater degree than co-administration of conventional mono-agonists in WT mouse islets. The triagonist-induced increase in GSIS was unchanged in the absence of either Gipr or Gcgr. However, the triagonist failed to enhance insulin secretion in islets lacking both Glp-1r and Gipr and upon treatment with the GLP-1 receptor-specific antagonist exendin-3 (9–39). Similarly, the specific blocking of Gαq signalling with YM254890 or transient receptor potential melastatin 5 (TRPM5) with triphenylphosphine oxide (TPPO) suppressed the triagonist-induced enhancement of GSIS. In vivo assessment of high-fat-fed Trpm5−/− mice demonstrated the absence of triagonist-induced therapeutic effects on glycaemic management.

Conclusions/interpretation

Triagonist-induced augmentation of GSIS is primarily mediated through its interaction with the GLP-1 receptor and subsequent activation of the Gαq–TRPM5 signalling pathway. Given that Gαq is a key player in the amplification of GSIS, particularly under diabetic conditions, these findings highlight a GLP-1 receptor-centric pharmacological profile that underlies the potent effects of this multi-receptor agonist.

Graphical Abstract