[Discussion] appetite is doing more work than we give it credit for
Something I keep coming back to: appetite is doing more work than we give it credit for.
Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.
The GIP question, which is the most interesting unsettled thing in this field.
Dual agonism at GIP and GLP-1 receptors produces clinical results that are robust and well replicated. What is not settled is the mechanism by which the GIP arm contributes — there is a genuine scientific argument about agonism versus antagonism at that receptor, with reasonable people and real data on both sides.
It is worth sitting with that. The clinical effect is not in doubt; the explanation is. That is an ordinary state of affairs in pharmacology and it is a good corrective to the confident mechanistic stories that circulate here.
Why mechanism talk keeps misleading people, including me.
A mechanism tells you a direction. It does not tell you a magnitude, a timescale, or whether the pathway is operative at the exposures involved. "Receptor X is expressed in tissue Y" is a fact; "therefore effect Z in a person" is a hypothesis with several missing steps.
The corrective is boring and it works: ask whether the evidence is preclinical or human, ask what exposure was used, and read the limitations section before the abstract. Most of the confidently wrong posts on this board — several of them mine — skipped all three.
Ask me anything specific. Anything general I will probably get wrong.
best — the order this archive was captured in
Speculation is welcome here if it is labelled. This one has been relabelled rather than removed.
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
gastric emptying slows, it does not stop
Agreed that receptor distribution is the key to the side-effect map. It is not a mystery, it is anatomy.
This. Albumin binding and modification are why the half-life is what it is, and it is a design decision rather than an accident.
receptor distribution is why the side effects are where they are
Spent an evening on the receptor distribution literature and the side-effect map suddenly stopped looking random.
GIP receptor biology is genuinely unsettled — there is a live argument about agonism versus antagonism at the receptor — and the clinical results are robust regardless, which is an uncomfortable and interesting position.
Tolerance to the gastric effect develops with continued exposure while the appetite effect largely persists. That single fact explains most of the "it settles but it still works" pattern the side-effect board reports.
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GIP is the arm people argue about because the biology is genuinely unsettled
I would not read that in vitro number across to a person. The conditions are nothing like physiological.
I would not read that in vitro number across to a person.
This is the concept everything else on this board is downstream of.
Small fix — it slows gastric emptying, it does not halt it, and the distinction matters for the mechanism you are proposing.
Was completely wrong about the gastric emptying story in a thread here two years ago. Someone corrected me with a citation and I have not made that mistake since.
The half-life explanation was the thing that made weekly dosing intuitive for me rather than arbitrary.
The half-life explanation was the thing that made weekly dosing intuitive for me rather than arbitrary.
Disagreeing with this specific inference — that is a preclinical result being read as human pharmacology.
Tried to build a mental model from mechanism alone and produced a confident prediction that the trial data flatly contradicted.
Receptor expression in a tissue is necessary but not sufficient for an effect. You also need the agonist to reach it at relevant exposure, and that is where a lot of confident mechanism talk falls down.
- 1Tolerance to the gastric effect develops with continued exposure while the…11 comments in this branch · started by u/anders_kuusela
- 2Speculation is welcome here if it is labelled. This one has been relabelled…6 comments in this branch · started by u/gastric_emptying_g