Biased agonism: a real phenomenon, an over-used explanation posts 121–136

Glucagon receptor agonism raises energy expenditure and promotes hepatic fat oxidation. In a triple agonist the incretin limbs offset the glycaemic consequence, which is why the combination is not self-defeating.

Adding a source would improve this post and I do not have one to hand.

Post #119 is right about the mechanism and I think understates the practical bit.

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.

Not disagreeing with anyone above, just adding the bit I keep having to look up.

Worth separating two things that post #119 runs together.

Biased agonism is a good example of a question where the honest answer is boring and the interesting answers are unsupported. I would go with boring.

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

Fair, and the limits you put on it are the part I will remember.

Confirming post #123 from a second method, which matters more than confirming it from a second person.

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.

This has been discussed before and I could not find the thread, so, again.

The version of biased agonism that I was taught turned out to be a teaching simplification. Useful, and not true in the way I had assumed it was.

Where I part company with post #128, and it is a narrow parting.

What I would check first on biased agonism is whether the thing being measured moved or whether the way of measuring it moved. Those look identical in a graph.

Endogenous versus pharmacological receptor engagement differ in magnitude and in duration by orders of magnitude. Arguments from "it is a natural hormone" do not survive that.

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.

It cost nothing to check and would have cost something not to.

Ghrelin receptor agonism drives growth hormone release in pulses and also increases appetite, which is the effect people most reliably report and least often want.

This is the sort of thing that ought to be settled and apparently is not.

Picking up post #130: that is the part I would want checked first.

Two claims get bundled together under biased agonism and they need separating. The descriptive one — this is what was observed — is usually well supported. The causal one — this is why — usually is not.

Almost every disagreement in threads like this one dissolves once you say which of the two you are making.

Useful. I have added it to my own notes with the date on it.