Glucose-Dependent Insulinotropic Polypeptide (GIP)

Glucose-dependent insulinotropic polypeptide is a forty-two residue hormone from K-cells of the duodenum and proximal jejunum, and the first incretin identified, originally named gastric inhibitory polypeptide before its insulinotropic action became the defining one. Its receptor is a class B G protein-coupled receptor on beta cells, adipocytes, bone and parts of the central nervous system. Like GLP-1 it is a DPP-4 substrate, inactivated within minutes.

In people without diabetes GIP contributes the larger share of the incretin effect, and in type 2 diabetes its insulinotropic action is markedly blunted while the GLP-1 response is comparatively preserved, an asymmetry that made GIP look like a dead end for two decades. Tirzepatide reopened it: one molecule with agonist activity at both receptors, approved for type 2 diabetes in 2022 and obesity in 2023, which produced around twenty percent mean weight loss at seventy-two weeks in SURMOUNT-1 and outperformed semaglutide 1 mg on HbA1c in SURPASS-2.

The awkward part is that GIP receptor antagonism also produces weight loss in humans, with antibody-based antagonist programmes reporting substantial reductions. Both cannot be straightforwardly right, and the leading reconciliation is that sustained agonism desensitises and internalises the receptor, ending in a functionally antagonised state. You cannot, therefore, predict a GIP-directed compound's effect from the direction of its receptor activity.

The marketing shorthand that dual agonism is twice the drug does not survive this. The GIP contribution to tirzepatide's effect has not been isolated in humans, since no trial has given a matched GIP arm alone, so attributing the extra weight loss to GIP is inference, not measurement. Rodent data showing GIP promotes fat deposition is also quoted as established human harm, which it is not.