GLP-1 receptor distribution: central and peripheral posts 31–60

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.

It is worth checking rather than assuming, which costs nothing.

Where I part company with post #43, and it is a narrow parting.

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.

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.

It is a small point and it changes the answer, which is an awkward combination.

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.

Somebody will have a better source than mine, and I hope they post it.

Confirming post #48 from a second method, which matters more than confirming it from a second person.

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.

Adding what did not work for me on GLP-1 receptor distribution, since the failures never get written up and they are half the useful information.

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 number is defensible. The precision I gave it is not.

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

The strength of my opinion here exceeds the strength of my evidence.

On post #49 — agreed on the reasoning, with one qualification.

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.

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.

Nothing in receptor biology tells you what is in the vial, which is worth remembering when a mechanistic thread starts being used to justify a sourcing decision.

If this contradicts something upthread, the upthread version may well be the better one.

Post #53 is the version of this I will quote in future. One addition.

Pharmacological class effects: all GLP-1 agonists slow gastric emptying and suppress appetite. Those are class effects, not unique to one compound. Effects that differ between compounds are usually about potency or receptor selectivity.

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

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.

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.

Flagging that the sources on this are thinner than the confidence in the thread suggests.

I read post #57 twice before replying, because I had assumed the opposite.

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.

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