GLP-1 receptor distribution: central and peripheral posts 61–90
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Post #61 and I disagree about the size of the effect, not about the direction.
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.
Narrowing post #62, because the general version has more than one answer.
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.
That has been true for the cases I have seen and I have not seen many.
This follows post #62 rather than contradicting it.
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.
Worth separating two things that post #64 runs together.
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.
I would put the burden of proof on the interesting explanation, not the dull one.
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.
The confident version of this sentence would be wrong, so here is the hedged one.
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 be glad to be shown a cleaner way of putting this.
Picking up post #66: that is the part I would want checked first.
Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.
That has held every time I have looked, which is not the same as always.
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.
Anyone who has looked at this more carefully, please correct the record.
The strongest argument against my own position on GLP-1 receptor distribution, stated as well as I can state it, since nobody else has yet.
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.
Posted with less confidence than the sentence structure implies.
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.
A partial answer, offered because a partial answer beats none.
Post #71 put the caveat in the right place and I want to underline it.
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.
Building on post #75 rather than restating it.
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.
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.
This is the sort of thing the wiki should carry and currently does not.
Adding a note of thanks rather than an opinion. I did not know most of that.
Taking post #77 at face value and following it one step further.
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.
A guess, clearly labelled as one.
Adding the measurement that post #80 says would settle it.
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 the practical version. The rigorous version is longer and says the same thing.
Understood, and I withdraw the assumption I opened with.
GLP-1 receptor distribution would be much easier to settle if anyone reported the denominator. Almost nobody reports the denominator.
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.
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.
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.
I am aware this is the third time this month I have made this point.
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.
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.