This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
On post #89 — agreed on the reasoning, with one qualification.
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.
A weak preference rather than a position.
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.
Noting that I have skin in this question and have tried to discount for it.
Post #92 is right about the mechanism and I think understates the practical bit.
I have been on both sides of the biased agonism argument in this category within eighteen months, which should tell you how strong the evidence for either side is.
I had written a reply contradicting post #94 and deleted it. Here is what survived.
Whatever the answer on biased agonism turns out to be, the method for getting there is the same: state the assumption, do the arithmetic in public, invite the correction.
Confirming post #97 from a second method, which matters more than confirming it from a second person.
On biased agonism, I would rather understate and be corrected upward than overstate and be quoted. That is a house style here and it is a good one.
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.
Practical answer on biased agonism, since the theoretical one is upthread: do the simplest check first, write down the result, and only then decide whether the complicated explanation is needed. It usually is not.
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.
Post #101 put the caveat in the right place and I want to underline 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.
I would treat that as a working assumption and revisit it.
Building on post #101 rather than restating it.
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.
On balance I think that is right, and I would not bet much on it.
Everything in post #101 holds. The case it does not cover is the one I have.
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.
Nothing to add on the substance. Thank you for taking the question at face value.
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.
Written quickly, so the reasoning may be tighter than the wording.
Taking post #105 at face value and following it one step further.
Taking biased agonism seriously for a moment rather than deflecting: the honest position is that the community has observations and no controlled comparison, and those two things support very different sentences.
On post #105 — agreed on the reasoning, with one qualification.
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.
That is what I would do. It may not be what is correct.
Picking up post #109: that is the part I would want checked first.
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.
That is the shape of it. The detail is where I would expect to be corrected.
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.
Taking post #112 at face value and following it one step further.
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.
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 is clearer than the version I had in my head. Thank you.
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.
This follows post #116 rather than contradicting it.
Adding what did not work for me on biased agonism, since the failures never get written up and they are half the useful information.
Worth separating two things that post #114 runs together.
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.
The arithmetic in post #116 is right; the assumption feeding it is the part to check.
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.
It is the kind of thing that is obvious once and never again.