[Discussion] we are measuring appetite at the wrong time and calling it noise
Thinking out loud about this: we are measuring appetite at the wrong time and calling it noise.
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.
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.
If two or three other people have done the same thing we might actually learn something. Alone it is an anecdote.
best — the order this archive was captured in
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.
Tolerance to the gastric effect develops with continued exposure while the appetite effect largely persists.
Disagreeing with this specific inference — that is a preclinical result being read as human pharmacology.
Asked for a citation rather than removing. On this board a claim without one is an invitation, not an offence.
That study was in a rodent model. Worth stating, since the thread has been reading it as human data.
Asked for a citation rather than removing.
This is the concept everything else on this board is downstream of.
I would not read that in vitro number across to a person. The conditions are nothing like physiological.
This. Albumin binding and modification are why the half-life is what it is, and it is a design decision rather than an accident.
incretin effect first, then everything else in this board makes sense
albumin binding is most of the half-life story
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.
Disagree. That is a preclinical finding in a rodent model and you are stating it as human pharmacology.
Disagree.
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
the peripheral and central stories are not in competition
Careful — you have a plausible mechanism and no evidence that it is the operative one in the case you are describing.
receptor distribution is why the side effects are where they are
GIP is the arm people argue about because the biology is genuinely unsettled
Are we talking about receptor affinity or clinical potency?
glucagon agonism sounds paradoxical until you read the energy expenditure work
GIP is the arm people argue about because the biology is genuinely unsettled
Agreed — and it is why the central and peripheral stories are complementary rather than rival.
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
tolerance to the gastric effect develops, appetite effect largely persists
Careful — you have a plausible mechanism and no evidence that it is the operative one in the case you are describing.
split_dose_sceptic is right that mechanism gives direction and not magnitude. Worth pinning.
mechanism explains a direction, not a magnitude
receptor agonism is not the same as receptor activation in every tissue
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.
Correcting my own comment: I attributed that to the GIP arm and the paper attributes it to the GLP-1 arm.
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.
Push back: a receptor being expressed in a tissue does not tell you the agonist reaches it at therapeutic exposure.
preclinical is not clinical and rodents are not small people
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