Biased agonism: a real phenomenon, an over-used explanation — what changed since — setting out what I have, and where I think it stops being reliable.
What changes if the standard account of Biased agonism is wrong? I ask because I have been treating it as settled and I noticed this week that I could not say why.
Working through the consequences rather than the evidence, since others here are better placed on the evidence.
Confirming the opening post from a second method, which matters more than confirming it from a second person.
Since Biased agonism 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.
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.
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.
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.
That is one dataset and I would not build a rule on it.
Post #3 is right about the mechanism and I think understates the practical bit.
Reporting rather than recommending, on Biased agonism. What happened is above. Whether it should have is a different question and not one I am qualified to answer.
Worth separating two things that post #3 runs together.
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.
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.
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.
That is what I would do. It may not be what is correct.
Building on post #12 rather than restating 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.
Useful. I had the fact and not the reason, which turns out to be the important half.
The arithmetic in post #12 is right; the assumption feeding it is the part to check.
One more thing on Biased agonism that took me far too long to see: the two figures people quote are not measuring the same quantity. Once you notice that, the apparent contradiction disappears.
Answering the question post #15 raises rather than the one it answers.
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.
That is all I can say without guessing.
Biased agonism is a question about a distribution, not about a value, and treating it as a value is what produces the confident wrong answers.
I would call the community position on Biased agonism likely rather than established, and I would be comfortable defending that hedge.
Adding the measurement that post #16 says would settle 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.
That distinction has done more work for me than anything else in this category.
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.
Caveat: everything above assumes the paperwork is what it says it is.
Answering the question post #19 raises rather than the one it answers.
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.
A modest claim, modestly supported.
Biased agonism 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.
Filing a mild objection to the consensus on Biased agonism. Mild because I might be wrong; an objection because nobody has addressed the case that does not fit.
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.
Small point, but it is the one that usually catches people.
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.
It is one reading of the data and not the only reasonable one.
I had written a reply contradicting post #23 and deleted it. Here is what survived.
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.
Confirming post #27 from a second method, which matters more than confirming it from a second person.
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.
Worth one more sentence than it usually gets.
The reason Biased agonism is hard to answer is that the obvious measurement and the relevant quantity are not the same thing, and substituting one for the other is silent.
Post #27 answers the question as asked. The question underneath it is different.
Biased agonism: I would want to see the raw numbers rather than the summary before agreeing. Summaries lose exactly the information that would settle this.