[PSA] receptor is not what most of this community thinks it is

receptor is not what most of this community thinks it is — with the reasoning, because a rule without a reason gets ignored.

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.

Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.

The mental model, in four steps, that makes the rest of this site legible.

One: gut hormones amplify the insulin response to food. Two: agonists at those receptors act peripherally on insulin secretion and gastric emptying, and centrally on appetite. Three: structural modification gives them a long half-life, so exposure is smooth and weekly. Four: tolerance develops to some effects and not to others.

From those four, most of what the experience boards report falls out: why the side effects cluster early, why they settle at a stable dose, why appetite reduction persists, and why the scale and the appetite move on different clocks.

If two or three other people have done the same thing we might actually learn something. Alone it is an anecdote.