The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a class B1 G protein-coupled receptor (GPCR) that promotes glucose-dependent insulin secretion upon activation by GIP. Dual agonism of GIPR and glucagon-like peptide-1 receptor (GLP-1R) has emerged as a breakthrough therapeutic strategy for type 2 diabetes and obesity, improving glycaemic control and promoting weight loss. Although GIPR is widely expressed in the central nervous system, endogenous GIP expression in the brain is controversial, and peripherally-administered fluorescent GIPR/GLP-1R agonists predominantly localise to circumventricular organs, suggesting a lack of GIP-ligand for receptors shielded by the blood-brain barrier. Here, we considered the existence of alternative endogenous ligands for GIPR, potentially modulated by receptor activity-modifying proteins (RAMPs). Ligand activity was profiled at heterologously expressed human GIPR using cAMP accumulation, calcium mobilisation, and cAMP inhibition assays. Among the 42 ligands tested, glicentin was the only non-proGIP-derived peptide to elicit a cAMP response at GIPR (EC₅₀ = 877nM). No ligand-induced calcium mobilisation or cAMP inhibition was observed. Glicentin also activated human GLP-1R and glucagon receptor (GCGR), with receptor-specific antibody blockade reducing potency by 10-20-fold at all three receptors. Glicentin's activity was conserved at rodent GIPRs, albeit with reduced potency. Co-expression with RAMP2 or RAMP3 attenuated cAMP responses to GIPR-active ligands, including glicentin, but did not affect other ligands tested. These findings show that the GIPR is highly selective and identifies glicentin as a low-potency, cross-reactive agonist at GIPR, GLP-1R and GCGR, although its high EC₅₀ makes it unlikely to act as a physiological ligand under basal conditions.
