GLP-1 and Semaglutide Induce GLP-1R/GIPR Heterodimerization, Diverging from Exendin-4 in Islet Signaling

Drugs targeting glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) have revolutionized treatment for type 2 diabetes and obesity. Despite their clinical success, a paradox exists where both GIPR agonism and antagonism can enhance GLP-1R agonist efficacy, suggesting complex incretin receptor crosstalk. The precise molecular mechanisms underlying this interaction, particularly how different agonists influence receptor dimerization and downstream signaling, have remained poorly understood. This knowledge gap limits the rational design of next-generation incretin-based therapeutics that could optimize efficacy and safety.

Researchers investigated the molecular mechanisms of GLP-1R and GIPR crosstalk, focusing on heterodimerization and signaling. They used phosphoproteomics and molecular dynamics simulations to analyze the effects of various agonists—GLP-1, semaglutide, and exendin-4—on GLP-1R/GIPR interactions in human pancreatic islets. The study specifically examined how these agonists promote receptor heterodimerization and subsequently influence divergent signaling pathways. Additionally, they compared the FDA-reported safety profiles of semaglutide and exenatide and assessed the clinical association between GIPR expression changes and adiposity and diabetic phenotypes.

The study revealed that GLP-1 and semaglutide, but notably not exendin-4, actively promote heterodimerization between GLP-1R and GIPR. This interaction occurs through specific binding between the TM4 domain of GLP-1R and the TM1/2 domains of GIPR. Phosphoproteomics and molecular dynamics analyses demonstrated that agonists capable of inducing this dimerization activate GLP-1R through distinct signaling pathways compared to non-dimerizing agonists. This differential pathway activation suggests a mechanism for varied clinical outcomes. Furthermore, when co-expressed, GLP-1R was found to enhance GIPR signaling in a β-arrestin-dependent manner. Conversely, increasing GIPR levels led to a decrease in GLP-1R signaling, highlighting a bidirectional regulatory loop. The researchers also observed that semaglutide and exenatide exhibit distinct patterns in their FDA-reported safety profiles, potentially linked to these mechanistic differences. Clinically, changes in GIPR expression were significantly associated with adiposity and diabetic phenotypes.

GLP-1 and semaglutide promote GLP-1R/GIPR heterodimerization via TM4 of GLP-1R and TM1/2 of GIPR, a mechanism absent with exendin-4.