Pharmacology research & perspectivesSep 30, 2022

Different effects of combined glucose-dependent insulin and glucagon-like peptide receptors on cell signaling in lab-grown cells

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Apr 6, 2026

Abstract

GLP-1R and GIPR form heteromers that influence cell signaling in distinct ways.

Real-time fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) experiments confirm the formation of GLP-1R and GIPR heteromers.
Stimulation with 1 μM GLP-1 increases both FRET and BRET ratios, indicating enhanced interaction.
Stimulation with 1 μM GIP decreases the BRET signal, suggesting a different interaction effect.
GIPR expression did not significantly affect the recruitment of certain signaling molecules to GLP-1R but inhibited GLP-1 stimulated recruitment.
The presence of GLP-1R enhanced GIP stimulated recruitment to GIPR, indicating a supportive role in signaling.

Simplified

The incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important regulators of many aspects of metabolism including insulin secretion. Their receptors (GIPR and GLP-1R) are closely related members of the secretin class of G-protein-coupled receptors. As both receptors are expressed on pancreatic β-cells there is at least the hypothetical possibility that they may form heteromers. In the present study, we investigated GIPR/GLP-1R and the impact of GIPR on GLP-1R-mediated signaling and vice versa in HEK-293 cells. Real-time fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) saturation experiments confirm that GLP-1R and GIPR form heteromers. Stimulation with 1 μM GLP-1 caused an increase in both FRET and BRET ratio, whereas stimulation with 1 μM GIP caused a decrease. The only other ligand tested to cause a significant change in BRET signal was the GLP-1 metabolite, GLP-1 (9-36). GIPR expression had no significant effect on mini-Grecruitment to GLP-1R but significantly inhibited GLP-1 stimulated mini-Gand arrestin recruitment. In contrast, the presence of GLP-1R improved GIP stimulated mini-Gand mini-Grecruitment to GIPR. These data support the hypothesis that GIPR and GLP-1R form heteromers with differential consequences on cell signaling. s q s q

Key numbers

1 μM GLP-1

Increase in BRET Ratio

Stimulation with GLP-1 resulted in a significant increase in BRET ratio.

1 μM GIP

Decrease in BRET Ratio

Stimulation with GIP resulted in a significant decrease in BRET ratio.

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Different effects of combined glucose-dependent insulin and glucagon-like peptide receptors on cell signaling in lab-grown cells

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