[Discussion] we are measuring receptor at the wrong time and calling it noise
Thinking out loud about this: we are measuring receptor 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.
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
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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dose response is not linear and nobody should assume it is
Disagree. That is a preclinical finding in a rodent model and you are stating it as human pharmacology.
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.
half-life is why these are weekly and not daily
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.
read the discussion section, that is where the honesty lives
the central appetite effect is doing more work than the gut effect
Agreed — the incretin effect is the load-bearing concept and everything downstream reads differently once you have it.
glucagon agonism sounds paradoxical until you read the energy expenditure work
Left up and flaired Explainer. This is the standard of post the board was created for.