[Discussion] we are measuring mechanism at the wrong time and calling it noise
we are measuring mechanism at the wrong time and calling it noise, and I am aware this is a minority view on this board.
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
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.
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.
Please do not ask me what dose you should be on. I genuinely do not know and neither does anyone else here.
best — the order this archive was captured in
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.
Cosigning on GIP. The genuinely interesting thing is that the biology is not settled and the clinical result is nonetheless robust.
Same view. Tolerance developing to the gastric effect while the appetite effect persists explains most of what 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.
Spent an evening on the receptor distribution literature and the side-effect map suddenly stopped looking random.
GIP is the arm people argue about because the biology is genuinely unsettled
receptor distribution is why the side effects are where they are
GIP is the arm people argue about because the biology is genuinely unsettled
aa_analysis_andy is right that mechanism gives direction and not magnitude. Worth pinning.
What was the exposure in that experiment relative to therapeutic?
Disagree. That is a preclinical finding in a rodent model and you are stating it as human pharmacology.
Careful — you have a plausible mechanism and no evidence that it is the operative one in the case you are describing.
the central appetite effect is doing more work than the gut effect
mechanism explains a direction, not a magnitude
read the discussion section, that is where the honesty lives
a mechanism you can state is not a mechanism you have demonstrated
Do you have the paper, or a summary of it?
a mechanism you can state is not a mechanism you have demonstrated
This is the concept everything else on this board is downstream of.
Not convinced by the linearity assumption. Dose-response in this class is not linear and the trials show it.
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.
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.
incretin effect first, then everything else in this board makes sense
gastric emptying slows, it does not stop
albumin binding is most of the half-life story
That conflates receptor affinity with clinical potency. They are related and they are not the same thing.
What does the discussion section say about the limitation you are glossing?
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
the peripheral and central stories are not in competition
- 1What was the exposure in that experiment relative to therapeutic?10 comments in this branch · started by u/second_week_sceptic
- 2The incretin effect is the observation that oral glucose provokes a larger…8 comments in this branch · started by u/employer_carveout