The Incretin Receptor Literature at a Glance: GLP-1, GIP and Glucagon Receptor Pharmacology

Three related receptors, one signalling family

The glucagon-like peptide-1 receptor (GLP1R), glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon receptor (GCGR) are class B (secretin-like) G-protein-coupled receptors that share a common structural architecture: a large N-terminal extracellular domain that provides initial peptide-hormone binding affinity, coupled to a seven-transmembrane helical bundle that undergoes conformational change to activate intracellular Gαs signalling and downstream cyclic-AMP production. All three receptors are expressed, among other tissues, in the pancreas and are central to the physiological regulation of glucose homeostasis, which is why they have attracted a large and still-growing body of receptor pharmacology and structural biology work.

Because the three receptors are structurally related but pharmacologically distinct, a considerable amount of published research is devoted to characterising the selectivity profile of a given peptide across all three — that is, quantifying not just whether a compound activates GLP1R, but how much residual or intentional activity it also has at GIPR and GCGR, and what that combination is proposed to contribute mechanistically.

Single-receptor agonists: the GLP1R-selective class

Selective GLP-1 receptor agonists, exemplified in the published pharmacology literature by exenatide, liraglutide and semaglutide, are designed to maximise potency and selectivity at GLP1R while minimising off-target receptor activity. Our overview of [semaglutide](/research/semaglutide) summarises the receptor-binding, cAMP-signalling and β-arrestin-recruitment data reported for this class, along with the structural modifications — an albumin-binding fatty diacid chain and a DPP-4-resistant amino-acid substitution — that are documented to extend plasma exposure in pharmacokinetic studies.

Receptor-binding assays in this class are generally reported using radioligand-displacement or fluorescence-based competition formats in cell lines transfected with the human receptor, and the resulting binding-affinity and functional potency values are commonly expressed as inhibition constants or half-maximal effective concentrations. Cross-study comparison of these values requires care, since assay format, cell background and receptor expression level all influence the absolute potency figure reported, even when the rank order of compounds is consistent between studies.

Dual and triple agonists: engineered polypharmacology

A more recent line of peptide engineering has combined GLP1R activity with GIPR activity in a single molecule (dual agonism, exemplified by tirzepatide), and, further, has added GCGR activity to produce triple agonists (exemplified by retatrutide). The stated pharmacological rationale in the primary literature is that GIPR and GCGR engagement contribute additional, receptor-specific physiological effects — GIPR engagement affecting adipose tissue and additional insulinotropic signalling, and GCGR engagement affecting hepatic glucose output and energy expenditure — that are proposed to act in combination with GLP1R-mediated effects. Our overviews of [tirzepatide](/research/tirzepatide) and [retatrutide](/research/retatrutide) set out the receptor-selectivity data reported for each, including the relative potency at each of the three receptors as characterised in transfected cell-based assays.

A key methodological point that recurs across this literature is that 'balanced' or 'biased' multi-receptor agonism is a design target validated primarily by in-vitro potency ratios; whether a given ratio of GLP1R:GIPR:GCGR activity measured in a transfected cell line translates into a proportionate physiological contribution from each receptor in an intact animal or human is a separate empirical question, addressed by pharmacodynamic and, ultimately, controlled trial data rather than by the binding assay alone.

Structural biology: what cryo-EM has added

Since approximately 2017, cryo-electron microscopy (cryo-EM) has resolved multiple structures of class B GPCRs in complex with their peptide ligands and downstream G-protein, including GLP1R- and GCGR-peptide complexes. These structures show the peptide N-terminus inserting into the receptor's transmembrane helical bundle, a mode of engagement termed the 'two-domain binding model', in which the extracellular domain first captures the peptide's C-terminal region and the transmembrane core subsequently engages the N-terminal region to trigger activation. This structural picture has helped rationalise why relatively small sequence substitutions near a peptide's N-terminus can substantially alter functional potency even when overall binding affinity is preserved.

Structural data of this kind is a valuable complement to functional pharmacology because it grounds potency and selectivity measurements in an explicit physical model of receptor engagement, but it remains, like the cell-based assays described above, evidence generated in isolated or reconstituted systems rather than in an intact physiological context.

Where the comparative evidence is thinner

Head-to-head published comparisons across the full incretin-receptor agonist class, using matched assay conditions in a single study, are less common than the number of individual-compound publications might suggest; much of the field-wide 'comparative potency' picture is assembled by readers combining figures from separate papers that used different cell lines, expression systems and assay formats. This is a genuine limitation for anyone trying to rank compounds by receptor selectivity, and it is one reason our research entries for [ipamorelin](/research/ipamorelin) and other growth-hormone-secretagogue-pathway peptides are kept in a clearly separate mechanistic category rather than folded into the incretin-receptor discussion, since they act through a structurally unrelated receptor system (the growth-hormone secretagogue receptor) despite occasional overlap in the lay literature.

• GLP1R, GIPR and GCGR are structurally related class B GPCRs but have distinct downstream physiology.
• Selective, dual and triple agonists differ by design in their receptor-activity ratio, characterised mainly in transfected cell-based assays.
• Cryo-EM structures support a two-domain binding model but describe isolated receptor–ligand complexes, not intact-organism physiology.
• Cross-compound potency comparisons assembled from separate papers should be treated cautiously due to assay-format differences.