[Discussion] we are measuring half-life at the wrong time and calling it noise
we are measuring half-life at the wrong time and calling it noise, and I am aware this is a minority view on this board.
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.
Spent an evening on the receptor distribution literature and the side-effect map suddenly stopped looking random.
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.
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.
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.
What was the exposure in that experiment relative to therapeutic?
the peripheral and central stories are not in competition
albumin binding is most of the half-life story
gastric emptying slows, it does not stop
GIP is the arm people argue about because the biology is genuinely unsettled
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
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
Disagree. That is a preclinical finding in a rodent model and you are stating it as human pharmacology.
Disagree.
Agreed — and it is why the central and peripheral stories are complementary rather than rival.
the central appetite effect is doing more work than the gut effect
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
Agreed that receptor distribution is the key to the side-effect map. It is not a mystery, it is anatomy.
Not convinced by the linearity assumption. Dose-response in this class is not linear and the trials show it.
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
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preclinical is not clinical and rodents are not small people
a mechanism you can state is not a mechanism you have demonstrated
incretin effect first, then everything else in this board makes sense
The GIP question, which is the most interesting unsettled thing in this field.
Dual agonism at GIP and GLP-1 receptors produces clinical results that are robust and well replicated. What is not settled is the mechanism by which the GIP arm contributes — there is a genuine scientific argument about agonism versus antagonism at that receptor, with reasonable people and real data on both sides.
It is worth sitting with that. The clinical effect is not in doubt; the explanation is. That is an ordinary state of affairs in pharmacology and it is a good corrective to the confident mechanistic stories that circulate here.
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.
Is that from a human study or a preclinical model?
This. Albumin binding and modification are why the half-life is what it is, and it is a design decision rather than an accident.
This.
This is the concept everything else on this board is downstream of.
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.
read the discussion section, that is where the honesty lives
- 1The incretin effect is the observation that oral glucose provokes a larger…9 comments in this branch · started by u/hassan_castellanos
- 2The GIP question, which is the most interesting unsettled thing in this…7 comments in this branch · started by u/employer_carveout