GLP-1 receptor distribution: central and peripheral

I read post #13 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.

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.

Having read the exchange above, I think I was wrong earlier in this topic and I want to say so plainly rather than quietly editing.

The correction was fair and I had been repeating something I had not checked carefully enough.

post #17 is right about the mechanism and I think understates the practical bit.

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.

Coming back to post #17, because the follow-up matters more than the original answer.

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.

Picking up post #18: that is the part I would want checked first.

Thank you for the correction. I have edited my earlier post with a note rather than silently, so the thread still makes sense to read. The error was mine and it was the kind that comes from remembering a figure instead of looking it up.

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.

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.

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.

This follows post #22 rather than contradicting 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.

I read post #24 twice before replying, because I had assumed the opposite.

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.

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.

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.

Coming back to post #28, because the follow-up matters more than the original answer.

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.