Posting this under the heading it deserves: Biased agonism: a real phenomenon, an over-used explanation Everything below is what sits behind that.
Trying to work out what would count as evidence on biased agonism, 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?
Understood. Thank you for being specific about the limits of it.
Adding the boring version of biased agonism, because the interesting version keeps getting posted and the boring one is usually right.
Check the ordinary explanations, in order, and stop when one of them accounts for what you are seeing. Most of the time the second one does.
The confident answers on biased agonism and the well-sourced answers are not the same answers, which is the most useful thing I have learned reading this category.
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.
Filing this under things that are true until someone shows me otherwise.
For anyone finding this later: the short answer on biased agonism is that it depends on one thing, and the rest of the thread is people identifying which thing.
I read post #6 twice before replying, because I had assumed the opposite.
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.
Practical note on biased agonism: write down what you expect before you look. The number of times I have found what I went looking for is higher than chance would allow.
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.
Marking my uncertainty on biased agonism explicitly. I am confident about the direction, much less confident about the size, and not confident at all that it generalises past the case in the first post.
Post #13 is right about the mechanism and I think understates the practical bit.
Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.
Posting it because the silence on this was starting to look like agreement.
Right, and stated more narrowly than I would have dared to state it.
I had written a reply contradicting post #17 and deleted it. Here is what survived.
Glucose dependence is the property that distinguishes incretin-mediated insulin secretion from a sulfonylurea. It is also why hypoglycaemia risk from these compounds alone is low.
Anyone with a larger sample, please post it.
The claim about biased agonism upthread is stronger than its source supports. I have read the source. The source says "associated with" and the post says "causes".
I read post #20 twice before replying, because I had assumed the opposite.
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 am describing what is, rather than arguing for what should be.
Thank you for the correction. I would rather find out here than later.
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 call that likely rather than established.
Post #22 is right about the mechanism and I think understates the practical bit.
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.
I would want a second opinion before relying on that.
Coming back to post #24, because the follow-up matters more than the original answer.
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.
That is my reading. Someone else read the same page differently and was reasonable.
Biased agonism has a well-known answer and a correct answer, and the interesting work is establishing that they are the same. Nobody has done that here yet.
The arithmetic in post #26 is right; the assumption feeding it is the part to check.
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.
Scoping that to what I have actually seen rather than what I have read.