the half-life question that gets asked weekly, answered properly
the half-life question that gets asked weekly, answered properly. Making the case below, and I expect to lose some of it in the comments.
Long half-life in this class comes from structural modification that promotes albumin binding and resists enzymatic degradation. Weekly dosing is a consequence of the molecule, not a convenience decision.
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.
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.
Would rather be corrected in public than confident in private.
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.
Retitled to distinguish preclinical from clinical, which the original ran together.
Small fix — it slows gastric emptying, it does not halt it, and the distinction matters for the mechanism you are proposing.
dose response is not linear and nobody should assume it is
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.
GIP receptor biology is genuinely unsettled — there is a live argument about agonism versus antagonism at the receptor — and the clinical results are
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
albumin binding is most of the half-life story
Spent an evening on the receptor distribution literature and the side-effect map suddenly stopped looking random.
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.
Do you have the paper, or a summary of it?
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
Is there any human data on that mechanism yet?
Started reading limitations sections first. It has changed how much weight I give to almost everything posted here.
incretin effect first, then everything else in this board makes sense
That study was in a rodent model. Worth stating, since the thread has been reading it as human data.
Correcting my own comment: I attributed that to the GIP arm and the paper attributes it to the GLP-1 arm.
receptor distribution is why the side effects are where they are
Read the primary paper after arguing about the summary for a fortnight. The discussion section said almost the opposite of what the thread had concluded.
Is that from a human study or a preclinical model?
the peripheral and central stories are not in competition
Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.
- 1incretin effect first, then everything else in this board makes sense8 comments in this branch · started by u/greta_lokken