Amylin receptor signalling and satiety — what changed since posts 61–79

Following this. I have the same question and no better information than the first post.

Reporting rather than recommending, on Amylin receptor signalling and satiety. What happened is above. Whether it should have is a different question and not one I am qualified to answer.

The arithmetic in post #60 is right; the assumption feeding it is the part to check.

Signalling through cyclic AMP is the canonical pathway and is not the only one. Beta-arrestin recruitment differs between ligands and its clinical significance here is unestablished.

Answering the question post #62 raises rather than the one it answers.

GIP receptor signalling: the glucose-dependent insulinotropic peptide receptor (GIP) is involved in glucose-stimulated insulin secretion. GIP agonism is thought to contribute to tirzepatide's effect but the mechanism is not fully settled.

Small point, but it is the one that usually catches people.

Confirming post #64 from a second method, which matters more than confirming it from a second person.

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.

It is worth stating the boring hypothesis before the interesting one.

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.

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

Post #66 describes the usual case. This is about the unusual one.

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.

Receptor desensitisation and internalisation are real phenomena in vitro and their clinical relevance to these compounds is not established. That distinction gets lost in discussions about tolerance.

Coming back to post #66, because the follow-up matters more than the original answer.

The area postrema sits outside the blood-brain barrier and is where a great deal of the nausea signalling in this class originates. That is why the effect is central and not gastric irritation.

GLP-1 receptor agonism produces its metabolic effects through more than one route: central satiety signalling, delayed gastric emptying, and glucose-dependent insulin secretion. Attributing everything to one of them is where most simplified accounts go wrong.

Take it as a starting point and not as a specification.

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.

For what it is worth, the same held on the two occasions I checked.

Post #69 describes the usual case. This is about the unusual one.

Where I have landed on Amylin receptor signalling and satiety, having got it wrong once in public: the direction is clear, the magnitude is not, and anyone quoting a precise magnitude has borrowed it from somewhere that did not measure it.

In vitro potency and clinical potency are related by a long chain of assumptions. A compound more potent at the receptor is not necessarily more effective at a tolerable dose.

The claim is narrower than it sounds, and deliberately so.