[Meta] the incretin rule is doing its job and people should stop complaining
the incretin rule is doing its job and people should stop complaining. Nothing about this affects the ranking maths, before anyone asks.
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.
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.
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
Sceptical readings welcome. The confident ones are the ones I distrust.
best — the order this archive was captured in
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.
The incretin effect is the observation that oral glucose provokes a larger insulin response than intravenous glucose at matched glycaemia, and the difference is mediated by gut hormones. That is the foundation the whole class sits on.
That study was in a rodent model. Worth stating, since the thread has been reading it as human data.
Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.
Went looking for human data on a mechanism everybody here asserts. Found preclinical work and one small study. That was clarifying.
Cosigning on GIP. The genuinely interesting thing is that the biology is not settled and the clinical result is nonetheless robust.
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
I would not read that in vitro number across to a person. The conditions are nothing like physiological.
Small fix — it slows gastric emptying, it does not halt it, and the distinction matters for the mechanism you are proposing.
Correcting my own comment: I attributed that to the GIP arm and the paper attributes it to the GLP-1 arm.
Disagree. That is a preclinical finding in a rodent model and you are stating it as human pharmacology.
Retitled to distinguish preclinical from clinical, which the original ran together.
incretin effect first, then everything else in this board makes sense
Does the effect persist with continued dosing or does tolerance develop?
That conflates receptor affinity with clinical potency. They are related and they are not the same thing.
Push back: a receptor being expressed in a tissue does not tell you the agonist reaches it at therapeutic exposure.
Which receptor arm are you attributing that to?
Is there any human data on that mechanism yet?
receptor distribution is why the side effects are where they are
the peripheral and central stories are not in competition
glucagon agonism sounds paradoxical until you read the energy expenditure work
Is that from a human study or a preclinical model?
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.
Yes. The discussion section is where the authors say what they actually think, and almost nobody here reads it.
- 1Disagree. That is a preclinical finding in a rodent model and you are…15 comments in this branch · started by u/rafael_ostergaard