Receptor desensitisation as a tolerance hypothesis, and its weak evidence — the long version posts 31–60
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Confirming post #31 from a second method, which matters more than confirming it from a second person.
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.
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.
Old habit: I write down the expected answer before I calculate it.
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.
I have said this before in a thread nobody could find, so it is worth repeating.
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Coming back to post #31, because the follow-up matters more than the original answer.
Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.
Adding this to the thread rather than to the wiki, because I am not confident enough for the wiki.
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 would put this at better than even and not much better.
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.
The general answer and the answer for your case may diverge here.
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.
That is the version I would defend. It is not the version I started with.
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 have deliberately not rounded that, because the rounding is where the argument starts.
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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.
Following, with nothing to contribute beyond having asked the same thing elsewhere.
Coming back to post #43, because the follow-up matters more than the original answer.
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.
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.
One more caveat and then I will stop qualifying: the sample selected itself.
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.
I would want the raw data before agreeing with my own summary of it.
Post #44 answers the question as asked. The question underneath it is different.
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.
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.
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.
Happy to be the one who is wrong here if it settles the question.
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Post #46 describes the usual case. This is about the unusual one.
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.
Post #49 and I disagree about the size of the effect, not about the direction.
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.
The confident version of this sentence would be wrong, so here is the hedged one.
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.
Worth reading the earlier posts in this thread before acting on mine.
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.
Narrowing post #53, 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.
The answer changed when I changed how I was measuring, which was informative.
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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.
Marking that as an opinion rather than a finding.
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.
I read post #53 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.
A single observation, in a thread that deserves better than single observations.
Post #57 answers the question as asked. The question underneath it is different.
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 be glad to be shown a cleaner way of putting this.
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.