incretin: what the trials say vs what this community says
incretin: what the trials say vs what this community says. Making the case below, and I expect to lose some of it in the comments.
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.
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.
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.
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.
Do you have the paper, or a summary of it?
Which receptor arm are you attributing that to?
mechanism explains a direction, not a magnitude
Same view. Tolerance developing to the gastric effect while the appetite effect persists explains most of what the side-effect board reports.
Agreed that receptor distribution is the key to the side-effect map. It is not a mystery, it is anatomy.
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.
Receptor expression in a tissue is necessary but not sufficient for an effect.
Agreed — and it is why the central and peripheral stories are complementary rather than rival.
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
incretin effect first, then everything else in this board makes sense
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.
receptor agonism is not the same as receptor activation in every tissue
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
ingrid_correia is right that mechanism gives direction and not magnitude. Worth pinning.
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.
What does the discussion section say about the limitation you are glossing?
gastric emptying slows, it does not stop
Started reading limitations sections first. It has changed how much weight I give to almost everything posted here.
glucagon agonism sounds paradoxical until you read the energy expenditure work
Is that from a human study or a preclinical model?
receptor distribution is why the side effects are where they are
tolerance to the gastric effect develops, appetite effect largely persists
That conflates receptor affinity with clinical potency. They are related and they are not the same thing.
That conflates receptor affinity with clinical potency.
This is the concept everything else on this board is downstream of.
read the discussion section, that is where the honesty lives
Agreed — the incretin effect is the load-bearing concept and everything downstream reads differently once you have it.
- 1Receptor expression in a tissue is necessary but not sufficient for an…7 comments in this branch · started by u/sig_figs_sam
- 2Speculation is welcome here if it is labelled. This one has been relabelled…6 comments in this branch · started by u/gastric_emptying_g