Receptor desensitisation as a tolerance hypothesis, and its weak evidence — setting out what I have, and where I think it stops being reliable.
Trying to work out what would count as evidence on receptor desensitisation, before collecting any. This is the part I usually skip and it is the part that makes the rest useful.
If two explanations predict the same observation, observing it does not help. So: what observation would separate them?
Taking the opening post at face value and following it one step further.
Half-life extension by albumin binding through a fatty acid chain trades free fraction for duration. It is an engineering solution with a cost, and the cost is that the bound fraction is not active.
The honest answer is that it depends, and here is what it depends on.
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.
That holds under the stated conditions and I have stated them.
Worth separating two things that post #3 runs together.
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.
Same conclusion as the reply above, reached differently, which is mildly reassuring.
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.
That is clearer than the version I had in my head. Thank you.
Bias and desensitisation: receptors can be biased (preferentially activating some downstream pathways over others) and can desensitise over time (responding less to the same stimulus with repeated exposure). Both might affect long-term response to these compounds.
I have deliberately not rounded that, because the rounding is where the argument starts.
This follows post #12 rather than contradicting it.
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".
Worth separating two things that post #10 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.
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.
Adding this to the thread rather than to the wiki, because I am not confident enough for the wiki.
On post #14 — agreed on the reasoning, with one qualification.
Two sentences on receptor desensitisation and then I will stop, because the rest is speculation and the thread is better without mine.
What is documented is narrow. What is inferred from it is broad. The gap between them is where every argument here lives.
Post #16 is the version of this I will quote in future. One addition.
Filing a mild objection to the consensus on receptor desensitisation. Mild because I might be wrong; an objection because nobody has addressed the case that does not fit.
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.
Answering the question post #19 raises rather than the one it answers.
Receptor desensitisation was covered in the wiki last year and the page has a review date on it, which is a better starting point than my memory of a thread.
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 interested in a counterexample if anyone has one.
Post #23 is the version of this I will quote in future. One addition.
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.
Saving this. It is the version I will quote when the question comes round again.
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.
The mechanism is plausible, which is not the same as established.
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.
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.
Worth saying I have only my own numbers here, and n is small.
Picking up post #27: that is the part I would want checked first.
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.