why does nobody talk about appetite
Genuine question, and the title is the question: why does nobody talk about appetite.
Spent an evening on the receptor distribution literature and the side-effect map suddenly stopped looking random.
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.
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.
Corrections welcome, especially the pedantic ones. Pedantry is how this board earns its reputation.
best — the order this archive was captured in
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.
a mechanism you can state is not a mechanism you have demonstrated
half-life is why these are weekly and not daily
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.
Left up and flaired Explainer. This is the standard of post the board was created for.
dose response is not linear and nobody should assume it is
Push back: a receptor being expressed in a tissue does not tell you the agonist reaches it at therapeutic exposure.
receptor distribution is why the side effects are where they are
Is that from a human study or a preclinical model?
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Correcting my own comment: I attributed that to the GIP arm and the paper attributes it to the GLP-1 arm.
That study was in a rodent model. Worth stating, since the thread has been reading it as human data.
Correcting my own comment: I attributed that to the GIP arm and the paper attributes it to the GLP-1 arm.
Disagreeing with this specific inference — that is a preclinical result being read as human pharmacology.
gastric emptying slows, it does not stop
The half-life explanation was the thing that made weekly dosing intuitive for me rather than arbitrary.
Yes. The central component is the one that explains the reports on this site better than gastric emptying does.
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.
GIP receptor biology is genuinely unsettled — there is a live argument about agonism versus antagonism at the receptor — and the clinical results are
This is the concept everything else on this board is downstream of.
Right — mechanism gives you a direction. It never gives you an effect size and people use it as though it does.
I would not read that in vitro number across to a person. The conditions are nothing like physiological.
Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.
Started reading limitations sections first. It has changed how much weight I give to almost everything posted here.
GLP-1 receptor agonism acts both peripherally — insulin secretion in a glucose-dependent way, slowed gastric emptying — and centrally, on appetite regulation. The central component is the better explanation for sustained intake reduction.
Which receptor arm are you attributing that to?
Does the effect persist with continued dosing or does tolerance develop?
mechanism explains a direction, not a magnitude
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.
Are we talking about receptor affinity or clinical potency?
the peripheral and central stories are not in competition
- 1GIP receptor biology is genuinely unsettled — there is a live argument about…13 comments in this branch · started by u/yannick_barros
- 2Tolerance to the gastric effect develops with continued exposure while the…7 comments in this branch · started by u/emil_agyeman