unpopular opinion: most of what gets said here about pharmacology is guesswork
Posting this as a discussion rather than a claim: unpopular opinion: most of what gets said here about pharmacology is guesswork. Why mechanism talk keeps misleading people, including me. A mechanism tells you a direction. It does not tell you a magnitude, a timescale, or whether the pathway is operative at the…
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.
Speculation is welcome here if it is labelled. This one has been relabelled rather than removed.
preclinical is not clinical and rodents are not small people
This. Albumin binding and modification are why the half-life is what it is, and it is a design decision rather than an accident.
tolerance to the gastric effect develops, appetite effect largely persists
glucagon agonism sounds paradoxical until you read the energy expenditure work
This.
This is the concept everything else on this board is downstream of.
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.
a mechanism you can state is not a mechanism you have demonstrated