Topic summary

Receptor desensitisation as a tolerance hypothesis, and its weak evidence — the long version

Pharmacology › Receptor biology retatrutide amylin analogues semaglutide

This is a generated summary. It shows the 9 most-liked posts from a topic of 64, in their original order, with the accepted answer included where one exists. It is a reading aid and it will miss nuance — the full topic is the record.

a.eriksenTL25 Dec 2025#3

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.

20 likes 8mo

taper_tableTL3Regular10 Dec 2025 · edited#8

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 the reasoning and check the arithmetic; I do not always get it right.

29 likes 8mo

a.nwosuTL215 Dec 2025#14

vial_desk, post #4: Where I part company with post #2, and it is a narrow parting. 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. Go to post

Picking up post #13: that is the part I would want checked first.

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.

Happy to be corrected if someone holds better data than mine.

27 likes in reply to #4 7mo

e.nilsenTL219 Dec 2025#18

This is the sort of exchange that makes the archive worth searching.

20 likes 7mo

sterile_fileTL3Regular22 Dec 2025#23

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.

It took me longer than it should have to see that.

24 likes 7mo

n.brobergTL228 Dec 2025#31

I had written a reply contradicting post #28 and deleted it. Here is what survived.

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.

22 likes 7mo

f.piresTL25 Jan 2026#43

Post #40 is right about the mechanism and I think understates the practical bit.

The claim about Receptor desensitisation upthread is stronger than its source supports. I have read the source. The source says "associated with" and the post says "causes".

20 likes 7mo

r.weissTL27 Jan 2026#47

forest_plot, post #29: 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. Genuinely open to being wrong about this one. Go to post

Post #44 answers the question as asked. The question underneath it is different.

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.

27 likes in reply to #29 7mo

n.kirchnerTL214 Jan 2026#57

I read post #53 twice before replying, because I had assumed the opposite.

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.

A single observation, in a thread that deserves better than single observations.

25 likes 6mo

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Receptor desensitisation as a tolerance hypothesis, and its weak evidencePharmacology › Receptor biology · 57 replies

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