GIP agonism AND GIP antagonism both seem to work. how?

mechanism_firstSenior Analyst

This is the thing in metabolic pharmacology I find hardest to square.

Tirzepatide includes GIP receptor agonism and works. There's separately credible work suggesting GIP receptor antagonism plus GLP-1 agonism also produces benefit.

Both directions can't be straightforwardly right under a simple receptor model. Resolutions I've seen argued:

1. Sustained agonism desensitizes the receptor, so chronic agonism is functionally closer to antagonism. The two converge. 2. Tissue specific effects. Central vs peripheral GIP signaling doing different things. 3. The benefit attributed to GIP in tirzepatide is actually from something else about the molecule.

I don't think any of these is established. 1 is the most cited and plausible but not obviously demonstrated. Mix of preclinical mechanism work and human trial outcomes, with the reconciliation being inference in every case.

Genuinely open question. Anyone seen a convincing resolution?

9 replies10 upvotesGLP-1 & Metabolic

Peptides discussed

9 replies

  • incretin_readerSenior Analyst

    Option 1 is where I'd bet, but "most cited" isn't "demonstrated". It's attractive partly because it dissolves the paradox neatly, and neat dissolutions deserve extra scrutiny.

    7 upvotes

  • MetabolicLurkerSenior Analyst

    this one hurts my brain

    4 upvotes

  • n_of_whatSenior Analyst

    Option 3 is underrated. Attributing an outcome to one receptor interaction in a molecule that does several things is hard to justify without a comparator lacking only that property.

    6 upvotes

    • mechanism_firstSenior Analyst

      Good point, and it's the same attribution problem as the blend thread one level down.

      4 upvotes

  • quick_qSenior Analyst

    eli5?

    3 upvotes

  • same_tbhSenior Analyst

    option 3 is the spicy one

    3 upvotes

  • cardiolipin_fanSenior Analyst

    Tissue specific explanations are often right and also the hardest to test. Bit of an epistemic trap.

    4 upvotes

  • quick_qSenior Analyst

    has anyone actually tested the antagonist version in people?

    3 upvotes

    • TripleAgonistWatchSenior Analyst

      There's been work in that direction, still early. Preclinical plus early clinical, nothing approved.

      5 upvotes

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