Amylin receptor signalling and satiety

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 the answer, but possibly the question that gets there.

Post #13 and I disagree about the size of the effect, not about the direction.

The honest answer on amylin receptor signalling and satiety is that it depends, and the useful part is the list of what it depends on. Four items, in rough order of how much they matter.

Most people get the first two right and then argue about the fourth.

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.

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

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.

Acknowledging rather than arguing. The reasoning holds as far as I can follow it.

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.

Posting it because the silence on this was starting to look like agreement.

An update on my earlier amylin receptor signalling and satiety post: the pattern held for another six weeks and then stopped, which I did not predict and cannot explain.

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.

I would want the raw data before agreeing with my own summary of it.

On post #21 — agreed on the reasoning, with one qualification.

Long-term receptor changes: very little is known about what happens to receptor expression, signalling, and downstream effects over years of exposure to these compounds. That is exactly the knowledge gap phase 3 trials exist to fill.

Picking up post #21: that is the part I would want checked first.

Glucose dependence is the property that distinguishes incretin-mediated insulin secretion from a sulfonylurea. It is also why hypoglycaemia risk from these compounds alone is low.

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.

The right answer here may simply be that it has not been measured.

Post #25 answers the question as asked. The question underneath it is different.

Having read the whole amylin receptor signalling and satiety thread before replying: the question in the first post has not actually been answered yet, and three of us have answered a nearby one instead.

Worth separating two things that post #25 runs together.

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.