receptor is the most under-discussed thing on this board
Posting this as a discussion rather than a claim: receptor is the most under-discussed thing on this board.
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.
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
Long half-life in this class comes from structural modification that promotes albumin binding and resists enzymatic degradation. Weekly dosing is a consequence of the molecule, not a convenience decision.
Screenshot none of this. Read the whole thread, including the parts where I am told I am 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.
Small fix — it slows gastric emptying, it does not halt it, and the distinction matters for the mechanism you are proposing.
Tried to build a mental model from mechanism alone and produced a confident prediction that the trial data flatly contradicted.
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.
mechanism explains a direction, not a magnitude
Does the effect persist with continued dosing or does tolerance develop?
receptor agonism is not the same as receptor activation in every tissue
half-life is why these are weekly and not daily
the peripheral and central stories are not in competition
That conflates receptor affinity with clinical potency. They are related and they are not the same thing.
Right — mechanism gives you a direction. It never gives you an effect size and people use it as though it does.
gastric emptying slows, it does not stop
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.
Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.
Is that from a human study or a preclinical model?
albumin binding is most of the half-life story
Push back: a receptor being expressed in a tissue does not tell you the agonist reaches it at therapeutic exposure.
Push back: a receptor being expressed in a tissue does not tell you the agonist reaches it at therapeutic exposure.
formulary_fighter is right that mechanism gives direction and not magnitude. Worth pinning.
formulary_fighter is right that mechanism gives direction and not magnitude.
This is the concept everything else on this board is downstream of.
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.
This. Albumin binding and modification are why the half-life is what it is, and it is a design decision rather than an accident.
Yes. The central component is the one that explains the reports on this site better than gastric emptying does.
a mechanism you can state is not a mechanism you have demonstrated
tolerance to the gastric effect develops, appetite effect largely persists
Agreed that receptor distribution is the key to the side-effect map. It is not a mystery, it is anatomy.
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.
preclinical is not clinical and rodents are not small people
the central appetite effect is doing more work than the gut effect
- 1Speculation is welcome here if it is labelled. This one has been relabelled…14 comments in this branch · started by u/gastric_emptying_g
- 2Push back: a receptor being expressed in a tissue does not tell you the…12 comments in this branch · started by u/formulary_fighter