Noted, and thank you for writing it out rather than summarising it.
2 likes 5mo
Pharmacology · Receptor biology · continued
Amylin receptor signalling and satiety — what changed since posts 31–60
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.
A weak preference rather than a position.
0 likes 5mo
Collapsed as off-topic by two members at trust level 3 or above
Worth separating two things that post #29 runs together.
One caution on Amylin receptor signalling and satiety: everything above assumes the underlying documentation is what it claims to be. That assumption is doing real work and is rarely stated.
This follows post #32 rather than contradicting it.
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.
Adding the caveat now so it does not have to be extracted later.
14 likes 5mo
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.
Written in the hope of being told what I have missed.
0 likes 5mo
t.batista, post #9: 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. Posted with less confidence than the sentence structure implies. Go to post
The C-cell finding in rodent toxicology is a receptor-biology observation with a species-specific interpretation. It is the reason for a specific contraindication rather than a general concern.
Post #34 and I disagree about the size of the effect, not about the direction.
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.
Speaking for myself and not for anyone else who has posted here.
21 likes 5mo
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.
Not the whole picture, but the part of it I can speak to.
9 likes 5mo
Post #37 is the version of this I will quote in future. One addition.
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.
29 likes 5mo
Understood, and I withdraw the assumption I opened with.
0 likes 5mo
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.
That is the version I use. It may not be the version that is correct.
19 likes 5mo
k.okafor, post #11: 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 am confident about the direction and much less about the magnitude. Go to post
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.
I am not the right person to answer the follow-up to this.
This follows post #42 rather than contradicting it.
Since Amylin receptor signalling and satiety keeps coming up, it should probably be a maintained page rather than a recurring thread. I am happy to draft it if someone with more direct experience will review it.
2 likes 4mo
Worth separating two things that post #44 runs together.
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.
8 likes 4mo
y.ramos, post #42: Mechanistic plausibility has a poor record of predicting clinical outcomes across this whole field. It is a good reason to run the trial and a bad reason to skip it. Go to post
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.
m.adebayo, post #7: This follows post #5 rather than contradicting it. 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. Go to post
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.
Anyone who has looked at this more carefully, please correct the record.
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.
Marking that as an opinion rather than a finding.
0 likes 4mo
I had read the opposite somewhere and cannot now find where, which tells me something.
0 likes 4mo
c.balogun, post #17: 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. That distinction has done more work for me than anything else in this category. Go to post
Clear enough that I do not think I have a follow-up, which is unusual.
Tavares, post #6: Reading back through, this was answered upthread and I missed it. My fault. Go to post
Post #49 is the version of this I will quote in future. One addition.
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.
Answering the question post #52 raises rather than the one it answers.
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.
I would want to see it done twice before believing it once.
8 likes 4mo
Two things can be true about Amylin receptor signalling and satiety at once: the mechanism is plausible and the evidence for the size of the effect is thin. Most of the argument here is people defending the first against attacks on the second.
2 likes 4mo
Post #52 put the caveat in the right place and I want to underline it.
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.
0 likes 4mo
k.farrugia, post #12: The arithmetic on Amylin receptor signalling and satiety is the easy part and it is where the errors are, which is an uncomfortable combination. Show your working and someone will catch it. Go to post
Building on post #55 rather than restating it.
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.
A partial answer, offered because a partial answer beats none.
Amylin receptor signalling and satiety is one of those subjects where the general answer and the answer for a specific case diverge, and the thread will go in circles until someone says which one is being asked for.
4 likes 4mo
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.
The short version is the first sentence; the rest is why.
0 likes 4mo
Post #55 and I disagree about the size of the effect, not about the direction.
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.
I would not lead a decision with this, but I would not ignore it either.
1 like 4mo
m.yildiz, post #53: Answering the question post #52 raises rather than the one it answers. 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. I would want to see it done twice before believing it once. Go to post
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.
Adding it in case it saves somebody the afternoon it cost me.