Tirzepatide

Recognised among the best reviewed peptides UK for dual incretin research, tirzepatide is a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, representing a novel pharmacological class of unimolecular multi-agonists. Structurally, tirzepatide is a 39-amino acid peptide based on the GIP backbone with a C-20 fatty di-acid chain conjugated to lysine at position 20, enabling albumin binding and extending the half-life to approximately 5 days. The peptide retains GIP receptor affinity while incorporating modifications that confer GLP-1 receptor agonism, allowing simultaneous activation of both major incretin pathways. At the GIP receptor (GIPR), tirzepatide activates Galphas-coupled signalling in pancreatic beta-cells, potentiating glucose-dependent insulin secretion through cAMP/PKA pathways — complementing the GLP-1 receptor-mediated insulinotropic effect. The dual agonism produces supra-additive insulin secretion compared to selective GLP-1 agonism alone, as GIP and GLP-1 receptors activate partially distinct intracellular signalling cascades (GIP favouring PKA, GLP-1 favouring EPAC2). Beyond the pancreas, GIP receptor activation in adipose tissue modulates lipid metabolism and insulin sensitivity, while central GLP-1 receptor activation contributes to appetite suppression. The integrated dual-receptor signalling footprint produces broader metabolic pathway modulation than any single-receptor agonist.