[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…
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