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Schreier, P.C.F.* ; Beyerle, P.* ; Boulassel, S.* ; Beck, A.* ; Novikoff, A. ; Reinach, P.S.* ; Boekhoff, I.* ; Breit, A.* ; Neuberger, A.* ; Müller, T.D. ; Cebrian Serrano, A. ; Gudermann, T.* ; Khajavi, N.*

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

Diabetologia, DOI: 10.1007/s00125-025-06525-0 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Glp-1 Receptor ; Gαq Signalling ; Insulin Secretion ; Pancreatic Islet ; Trpm5 ; Triagonist; Cryo-em Structure; Peptide-1 Receptor; Pancreatic-islets; Glycemic Control; Weight-loss; Beta-cell; Glucagon; Agonist; Trpm5; Gip
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Zeitschrift Diabetologia
Verlag Springer
Verlagsort Berlin ; Heidelberg [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
POF Topic(s) 30201 - Metabolic Health
90000 - German Center for Diabetes Research
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502200-001
G-501900-221
Förderungen WiFoMed (Verein zur Foerderung von Wissenschaft und Forschung an der Medizinischen Fakultaet der Ludwig-Maximilians-Universitaet Muenchen e.V.)
Deutsche Forschungsge-meinschaft (German Research Foundation, DFG)
German Research Foundation (DFG)
German Center for Diabetes Research (DZD)
European Union (ERC CoG) TRUSTED
Deutsche Forschungsgemeinschaft (DFG)
Forschungsausschuss der Universitaet des Saar-landes
Elite Network of Bavaria
Bavarian State Ministry of Science
Arts (Elitenetzwerk Bayern, Bayerisches Staatsministerium fur Wissenschaft und Kunst)
Projekt DEAL
DOI 10.1007/s00125-025-06525-0
WOS ID 001566739100001
Scopus ID 105015384614
PubMed ID 40924112
Erfassungsdatum 2025-10-17
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