This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
Everything in post #27 holds. The case it does not cover is the one I have.
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 conclusion is tentative; the arithmetic underneath it is not.
The version of biased agonism that circulates here is a simplification of a simplification. It is not wrong, but it has lost the conditions under which it holds, and those conditions are where the interesting cases live.
Where a mechanism is proposed to explain an effect, the useful follow-up is what observation would distinguish it from the alternative. Most mechanistic threads here never get asked that.
I would rather say I do not know than round it up to an answer.
Post #34 answers the question as asked. The question underneath it is different.
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.
I would put a moderate confidence on that and no more.
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.
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 at related receptors within the secretin family is real and is one reason selectivity claims should be read against the panel that was tested rather than in general.
Summarising the biased agonism thread so far, since it is long and the answer is buried: the first reply has the method, the fourth has the correction to it, and the rest is people agreeing at length.
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.
That has been true for the cases I have seen and I have not seen many.
Adding the measurement that post #40 says would settle it.
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 have changed my mind on this once already, so take it as current rather than settled.
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 failure mode on biased agonism is boring rather than dramatic. It is almost always the step everyone assumes was done correctly because it is too simple to get wrong.
Reading back through, this was answered upthread and I missed it. My fault.
The arithmetic in post #44 is right; the assumption feeding it is the part to check.
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.
On reflection I would soften that slightly.
Answering the question post #47 raises rather than the one it answers.
Adding a reference point for biased agonism. Mine is a single case, collected without controls, and I am posting the method alongside it so it can be discounted appropriately.
Building on post #47 rather than restating it.
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.
Take the reasoning and check the arithmetic; I do not always get it right.
Post #47 put the caveat in the right place and I want to underline it.
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.
The honest answer is that it depends, and here is what it depends on.
Biased agonism is worth one more sentence than it usually gets, and the sentence is the one about how the number was arrived at.
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.
The general case is well covered; this is the awkward specific one.
Distinguishing three things in the biased agonism discussion that keep getting used interchangeably: the observation, the proposed mechanism, and the recommendation that gets attached to both.
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.
Not a strong opinion, just a consistent one.
Coming back to post #54, because the follow-up matters more than the original answer.
What I would tell a new member reading about biased agonism for the first time: the confident posts are not the reliable ones, and the reliable ones are longer.
Post #57 is right about the mechanism and I think understates the practical bit.
The strongest argument against my own position on biased agonism, stated as well as I can state it, since nobody else has yet.
Worth separating two things that post #57 runs together.
Cross-reactivity at related receptors within the secretin family is real and is one reason selectivity claims should be read against the panel that was tested rather than in general.
I would not lead a decision with this, but I would not ignore it either.
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.
Adding it in case it saves somebody the afternoon it cost me.