glucagon receptor agonism raising energy expenditure — how solid is that
glucagon receptor agonism raising energy expenditure — how solid is that. Making the case below, and I expect to lose some of it in the comments.
Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.
Started reading limitations sections first. It has changed how much weight I give to almost everything posted here.
Went looking for human data on a mechanism everybody here asserts. Found preclinical work and one small study. That was clarifying.
Ask me anything specific. Anything general I will probably get wrong.
best — the order this archive was captured in
Receptor expression in a tissue is necessary but not sufficient for an effect. You also need the agonist to reach it at relevant exposure, and that is where a lot of confident mechanism talk falls down.
Tried to build a mental model from mechanism alone and produced a confident prediction that the trial data flatly contradicted.
Small fix — it slows gastric emptying, it does not halt it, and the distinction matters for the mechanism you are proposing.
Left up and flaired Explainer. This is the standard of post the board was created for.
That study was in a rodent model. Worth stating, since the thread has been reading it as human data.
The incretin effect is the observation that oral glucose provokes a larger insulin response than intravenous glucose at matched glycaemia, and the difference is mediated by gut hormones. That is the foundation the whole class sits on.
receptor distribution is why the side effects are where they are
receptor agonism is not the same as receptor activation in every tissue
Tolerance to the gastric effect develops with continued exposure while the appetite effect largely persists. That single fact explains most of the "it settles but it still works" pattern the side-effect board reports.
Agreed — the incretin effect is the load-bearing concept and everything downstream reads differently once you have it.
the central appetite effect is doing more work than the gut effect
GLP-1 receptor agonism acts both peripherally — insulin secretion in a glucose-dependent way, slowed gastric emptying — and centrally, on appetite regulation. The central component is the better explanation for sustained intake reduction.
GIP receptor biology is genuinely unsettled — there is a live argument about agonism versus antagonism at the receptor — and the clinical results are robust regardless, which is an uncomfortable and interesting position.
a mechanism you can state is not a mechanism you have demonstrated