GIP receptor agonism and the argument about direction — does this still hold?

GIP receptor agonism and the argument about direction — does this still hold? — that is the question, and I have not found it answered plainly anywhere I have looked.

A question about GIP receptor agonism that I think has a definite answer, unlike most of what I ask here.

I have the reasoning below and I am fairly confident about the direction. I am not confident about the size, and the size is what the decision turns on.

Answering the question the opening post raises rather than the one it answers.

Central versus peripheral action: GLP-1 agonism works through both central nervous system effects (appetite) and peripheral effects (gastric motility, insulin). The balance is not fully characterised.

Building on the opening post rather than restating it.

GIP receptor biology is genuinely contested. Both agonism and antagonism have been argued to produce weight reduction, and the fact that the field can hold both positions tells you how open it is.

Amylin signalling reaches satiety through a distinct receptor complex, which is the mechanistic basis for expecting an amylin analogue and an incretin agonist to add rather than overlap.

I am confident about the direction and much less about the magnitude.

Narrowing post #4, because the general version has more than one answer.

GLP-1 receptor signalling: the GLP-1 receptor is expressed on beta cells (insulin secretion), on neurons (appetite and gastric motility), and on myocardium (contractility). Different tissues respond to the same signal in different ways.

Everything in post #2 holds. The case it does not cover is the one I have.

Cross-reactivity and selectivity: the compounds are not perfectly selective for their target receptors. Semaglutide has some activity on other receptors; tirzepatide activates both GLP-1 and GIP with different affinities. The off-target effects are part of the overall pharmacology.

The part I am sure of is shorter than the part I have written.

Quietly grateful for the plain phrasing. Not every thread gets that.

Receptor occupancy required for a clinical effect is not the same as full occupancy, and dose-response curves flattening at the top is what you would expect from that.

The conclusion is tentative; the arithmetic underneath it is not.

Glucagon receptor agonism: glucagon receptor agonism increases energy expenditure and promotes hepatic fat oxidation. The mechanism is distinct from GLP-1 and GIP agonism and the clinical consequences are still being characterised.

I would rather say I do not know than round it up to an answer.

Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.

Not a conclusion. A place to stand while looking for one.

Building on post #9 rather than restating it.

Biased agonism — where different ligands at the same receptor favour different downstream pathways — is a plausible explanation for differences between compounds in this class and is not a demonstrated one for any specific pair.

Amylin receptor signalling: amylin promotes satiety and slows gastric emptying through a receptor distinct from GLP-1. The hypothesis behind combination therapy is two complementary satiety mechanisms.

Noting that the question and the thing people usually mean by it are different.