the appetite question that gets asked weekly, answered properly
the appetite question that gets asked weekly, answered properly. Change my mind, genuinely — I have no stake in being right about this.
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.
Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.
The mental model, in four steps, that makes the rest of this site legible.
One: gut hormones amplify the insulin response to food. Two: agonists at those receptors act peripherally on insulin secretion and gastric emptying, and centrally on appetite. Three: structural modification gives them a long half-life, so exposure is smooth and weekly. Four: tolerance develops to some effects and not to others.
From those four, most of what the experience boards report falls out: why the side effects cluster early, why they settle at a stable dose, why appetite reduction persists, and why the scale and the appetite move on different clocks.
Please do not ask me what dose you should be on. I genuinely do not know and neither does anyone else here.
best — the order this archive was captured in
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.
Tried to build a mental model from mechanism alone and produced a confident prediction that the trial data flatly contradicted.
Yes. The central component is the one that explains the reports on this site better than gastric emptying does.
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.
Read the primary paper after arguing about the summary for a fortnight. The discussion section said almost the opposite of what the thread had concluded.
This. Albumin binding and modification are why the half-life is what it is, and it is a design decision rather than an accident.
Disagree. That is a preclinical finding in a rodent model and you are stating it as human pharmacology.
Same view. Tolerance developing to the gastric effect while the appetite effect persists explains most of what the side-effect board reports.
Went looking for human data on a mechanism everybody here asserts. Found preclinical work and one small study. That was clarifying.
Is there any human data on that mechanism yet?
Is that from a human study or a preclinical model?
Do you have the paper, or a summary of it?
The half-life explanation was the thing that made weekly dosing intuitive for me rather than arbitrary.
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.
gastric emptying slows, it does not stop
the central appetite effect is doing more work than the gut effect
preclinical is not clinical and rodents are not small people
preclinical is not clinical and rodents are not small people
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
- 1Went looking for human data on a mechanism everybody here asserts. Found…10 comments in this branch · started by u/rafael_ostergaard
- 2GIP receptor biology is genuinely unsettled — there is a live argument about…6 comments in this branch · started by u/zeynep_villalobos