GLP-1 receptor distribution: central and peripheral posts 91–99

Where I part company with post #89, and it is a narrow parting.

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.

The interesting part of this is the exception, and I do not understand the exception.

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.

Receptor distribution explains the side-effect profile better than anything else. GLP-1 receptors in the gastrointestinal tract and the area postrema account for most of what people report.

It is one reading of the data and not the only reasonable one.

Ghrelin receptor agonism drives growth hormone release in pulses and also increases appetite, which is the effect people most reliably report and least often want.

Noting that I have skin in this question and have tried to discount for it.

Right — I had this wrong and I am glad to have read it before it mattered.

Amylin signalling reaches satiety through a distinct receptor complex, which is the mechanistic basis for expecting an amylin analogue and an incretin agonist to add rather than overlap.

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