Receptor desensitisation as a tolerance hypothesis, and its weak evidence

Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.

Take the reasoning and check the arithmetic; I do not always get it right.

Right, and stated more narrowly than I would have dared to state it.

I read the earlier replies on receptor desensitisation twice before writing this, because I had assumed the opposite and wanted to be sure I was disagreeing with what was said rather than what I expected.

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.

I am describing what is, rather than arguing for what should be.

This follows post #41 rather than contradicting it.

The number people quote for receptor desensitisation is a central estimate presented without its interval, and the interval is wide enough that the estimate is nearly uninformative on its own.

That reframing is the whole thing. The facts I already had.

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.

If anyone has run this properly I would rather read that than my own guess.

Where the receptor desensitisation reasoning breaks down for me is the step from the group result to the individual case. That step is almost never argued for.