Revisiting: GLP-1 receptor distribution: central and peripheral posts 61–67

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.

Where I would look next, rather than where I would stop.

Following this. I have the same question and no better information than the first post.

Everything in post #60 holds. The case it does not cover is the one I have.

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.

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.

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.

That is the honest state of it as of this week.

Building on post #63 rather than restating it.

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.

I would put a moderate confidence on that and no more.