[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…
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.