does incretin actually matter or is it forum lore at this point
The title is the whole question — does incretin actually matter or is it forum lore at this point — but here is why I am asking.
Went looking for human data on a mechanism everybody here asserts. Found preclinical work and one small study. That was clarifying.
Tried to build a mental model from mechanism alone and produced a confident prediction that the trial data flatly contradicted.
The half-life explanation was the thing that made weekly dosing intuitive for me rather than arbitrary.
Would rather be corrected in public than confident in private.
best — the order this archive was captured in
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
Yes. The central component is the one that explains the reports on this site better than gastric emptying does.
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
glucagon agonism sounds paradoxical until you read the energy expenditure work
half-life is why these are weekly and not daily
Which receptor arm are you attributing that to?
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.
Small fix — it slows gastric emptying, it does not halt it, and the distinction matters for the mechanism you are proposing.
receptor distribution is why the side effects are where they are
What does the discussion section say about the limitation you are glossing?
dose response is not linear and nobody should assume it is
mechanism explains a direction, not a magnitude
Disagree. That is a preclinical finding in a rodent model and you are stating it as human pharmacology.
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That study was in a rodent model. Worth stating, since the thread has been reading it as human data.
Does the effect persist with continued dosing or does tolerance develop?
Does the effect persist with continued dosing or does tolerance develop?
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
Is that from a human study or a preclinical model?
Yes. The discussion section is where the authors say what they actually think, and almost nobody here reads it.
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.
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.
Correcting my own comment: I attributed that to the GIP arm and the paper attributes it to the GLP-1 arm.
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.
Agreed that receptor distribution is the key to the side-effect map. It is not a mystery, it is anatomy.
Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.
Is there any human data on that mechanism yet?
a mechanism you can state is not a mechanism you have demonstrated
Retitled to distinguish preclinical from clinical, which the original ran together.
Do you have the paper, or a summary of it?
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.
- 1Does the effect persist with continued dosing or does tolerance develop?13 comments in this branch · started by u/elodie_grimaldi
- 2Glucose-dependent insulin secretion is why hypoglycaemia risk is low as…8 comments in this branch · started by u/bastian_ekstrom