Screening 42 candidate peptides against the glucose-dependent insulinotropic polypeptide receptor (GIPR), Cambridge researchers identified glicentin as the sole non-proGIP-derived peptide capable of eliciting a cAMP response at human GIPR, with an EC₅₀ of 877nM. Glicentin also activated GLP-1R and the glucagon receptor (GCGR), with receptor-specific antibody blockade reducing potency 10–20-fold across all three. Notably, co-expression with RAMP2 or RAMP3 attenuated cAMP signaling at GIPR for active ligands including glicentin, suggesting receptor-modifying proteins shape GIPR pharmacology in tissue-specific contexts.
The clinical weight of this finding is primarily mechanistic rather than immediately therapeutic. Dual GIPR/GLP-1R agonists like tirzepatide have reshaped metabolic medicine, yet a central puzzle has persisted: GIPR is broadly expressed in the brain, but endogenous GIP rarely crosses the blood-brain barrier. This work begins mapping whether alternative endogenous ligands might engage central GIPR. Glicentin — a proglucagon-derived peptide released from intestinal L-cells — is already present in circulation, but its 877nM EC₅₀ is orders of magnitude above likely physiological concentrations, making it a pharmacological curiosity rather than a confirmed endogenous agonist. The RAMP interaction data is arguably the most novel angle, hinting that receptor context could unmask or suppress glicentin activity in vivo. This is incremental but directionally important work, flagging glicentin for further investigation and reinforcing that GIPR's endogenous ligand landscape in the CNS remains genuinely unresolved.