Revisiting: GLP-1 receptor distribution: central and peripheral — setting out what I have, and where I think it stops being reliable.
An honest uncertainty about GLP-1 receptor distribution rather than a disguised assertion.
I do not know the answer and I have not been able to find one. What I have is the shape of the question, which may be worth more than my guess at the answer.
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 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.
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.
Picking up post #7: that is the part I would want checked first.
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.
Worth reading the earlier posts in this thread before acting on mine.
That reframing is the whole thing. The facts I already had.
Narrowing post #7, because the general version has more than one answer.
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 step people skip is the one I have spelled out.
Narrowing post #8, because the general version has more than one answer.
Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.
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.
The evidence for this is thinner than the way I have phrased it suggests.
Post #12 answers the question as asked. The question underneath it is different.
An update on my earlier GLP-1 receptor distribution post: the pattern held for another six weeks and then stopped, which I did not predict and cannot explain.
I read post #15 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.
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.
Written from notes rather than memory, which is why the numbers are specific.
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.
A modest claim, modestly supported.
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.
That is what I would do. It may not be what is correct.
I read post #18 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.
Same conclusion as the reply above, reached differently, which is mildly reassuring.
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.
Picking up post #19: that is the part I would want checked first.
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.
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.
Adding this to the thread rather than to the wiki, because I am not confident enough for the wiki.
Fair, and the limits you put on it are the part I will remember.
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.
I have no interest in any supplier named above.
I had written a reply contradicting post #25 and deleted it. Here is what survived.
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.
That is the version I would defend. It is not the version I started with.
Receptor distribution explains the side-effect profile better than anything else. GLP-1 receptors in the gastrointestinal tract and the area postrema account for most of what people report.
I would treat the number as indicative rather than as a measurement.
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 have separated what I observed from what I concluded, which does not always happen.