GLP-1R and GIPR heterodimerization and expression determine downstream signaling and metabolic phenotypes

ABSTRACT: Advancements in unimolecular drugs co-targeting the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) have demonstrated remarkable clinical efficacy in treating type 2 diabetes (T2D) and obesity. However, the paradoxical ability of both GIPR agonism and antagonism to complement GLP-1R agonism underscores the need to elucidate molecular mechanisms underlying incretin receptor pharmacology and crosstalk. Here, we show that GLP-1 promotes heterodimerization via interactions between TM4 of GLP-1R and TM1/2 of GIPR. Phosphoproteomics profiling and molecular dynamics simulations reveal that dimerizing and non-dimerizing GLP-1R agonists differentially engage with GLP-1R and elicit distinct regulation of downstream signaling networks in human islets. Co-expression of GLP-1R and GIPR amplifies GIPR-mediated signaling in a β-arrestin-dependent manner, while GLP-1R-mediated signaling is suppressed by GIPR expression. Additionally, upregulation or downregulation of GIPR expression was associated with adiposity and diabetic traits, respectively. Collectively, these findings uncover mechanisms underlying the interplay between GLP-1R and GIPR and highlight heterodimerization as an innovative strategy for incretin-based therapies and personalized treatment.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pancreatic Islet

SUBMITTER: Pierre Sabatier  

LAB HEAD: Jesper Olsen

PROVIDER: PXD063931 | Pride | 2026-05-13

REPOSITORIES: Pride