Cell chemical biologyJul 8, 2026

Interaction between GLP-1 and GIP receptors influences insulin-releasing signals

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 9, 2026

Abstract

Drugs targeting glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors show strong clinical effects in type 2 diabetes and obesity.

GLP-1 and semaglutide promote the formation of complexes between GLP-1R and GIPR, while exendin-4 does not.
Different agonists activate distinct signaling pathways in human pancreatic islets, indicating varied effects on receptor activity.
Semaglutide and exenatide exhibit different safety profiles as reported by the FDA.
When GLP-1R and GIPR are co-expressed, GLP-1R enhances GIPR signaling in a specific manner, while increased GIPR levels can reduce GLP-1R signaling.
Changes in GIPR expression are clinically linked to body fat and diabetes characteristics.

Simplified

Drugs targeting glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors (GLP-1R and GIPR) show strong clinical effects in type 2 diabetes and obesity. Both GIPR agonism and antagonism enhance GLP-1R agonist efficacy, indicating important incretin receptor crosstalk. We show that GLP-1 and semaglutide, but not exendin-4, promote heterodimerization between GLP-1R and GIPR through interactions between TM4 of GLP-1R and TM1/2 of GIPR. Phosphoproteomics and molecular dynamics reveal that dimerizing and non-dimerizing agonists differentially influence GLP-1R, activating divergent signaling pathways in human pancreatic islets. Moreover, semaglutide and exenatide display distinct patterns in their FDA-reported safety profiles. When co-expressed, GLP-1R enhances GIPR signaling in a β-arrestin-dependent manner, while increasing GIPR levels decreases GLP-1R signaling. Additionally, we show that changes in GIPR expression are clinically associated with adiposity and diabetic phenotypes. These findings highlight heterodimerization and receptor expression as key modulators of GLP-1R/GIPR signaling, offering mechanistic insights, and guiding drug design strategies that incorporate receptor crosstalk.

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Funding

Competing interests

Declaration of interests The authors declare that the study was conducted without any competing interests. T.M.: employed by InterAx Biotech A.G. L.S.G.: received one speaker honorarium from Novo Nordisk and is a co-founder and minority shareholder of Antag Therapeutics. V.M.L.: cofounder and CEO of HepaPredict A.B., cofounder and shareholder of Shanghai Hepo Biotechnology Ltd. J.J.H. and M.M.R. minority shareholders and cofounders of Antag Therapeutics and Bainan Biotech. J.J.H.: served on scientific advisory panels for and/or has received speaker honoraria from AlphaSights, Eli Lilly, Novo Nordisk, MSD/Merck, Shouti/Structure X, and Zealand Pharma.

PubMed

Interaction between GLP-1 and GIP receptors influences insulin-releasing signals

Abstract

Full Text

Funding

Competing interests

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