Biased agonism: a real phenomenon, an over-used explanation posts 121–136

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.

This follows post #119 rather than contradicting it.

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.

Worth separating two things that post #119 runs together.

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.

I disagree with the reply above, and I think the disagreement is substantive rather than terminological.

The distinction being drawn does not survive when you look at the published data for this specific question. I would be glad to be shown wrong on this, because the version I am arguing against is more convenient.

Coming back to post #123, because the follow-up matters more than the original answer.

Cross-reactivity and selectivity: the compounds are not perfectly selective for their target receptors. Semaglutide has some activity on other receptors; tirzepatide activates both GLP-1 and GIP with different affinities. The off-target effects are part of the overall pharmacology.

Picking up post #123: that is the part I would want checked first.

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.

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.

I read post #127 twice before replying, because I had assumed the opposite.

Species differences: rodent studies show the same compounds produce effects in rodents that predict human effects reasonably well for semaglutide and tirzepatide. The track record is less clear for novel compounds with less human data.

I disagree with the reply above, and I think the disagreement is substantive rather than terminological.

The distinction being drawn does not survive when you look at the published data for this specific question. I would be glad to be shown wrong on this, because the version I am arguing against is more convenient.

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.

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.

Picking up post #130: that is the part I would want checked first.

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.

Coming back to post #132, because the follow-up matters more than the original answer.

Practical note that does not fit anywhere else. Whatever you conclude from this topic, write down what you did and when. The single most useful thing in your own records is not any individual result; it is that they are dated and consecutive.