[Discussion] can we stop arguing about gastric emptying until somebody posts a number
Slightly embarrassed to be asking this, but: can we stop arguing about gastric emptying until somebody posts a number.
Asked a question here that I thought was stupid and got three papers back. Best thread I have been in on this site.
The GIP question, which is the most interesting unsettled thing in this field.
Dual agonism at GIP and GLP-1 receptors produces clinical results that are robust and well replicated. What is not settled is the mechanism by which the GIP arm contributes — there is a genuine scientific argument about agonism versus antagonism at that receptor, with reasonable people and real data on both sides.
It is worth sitting with that. The clinical effect is not in doubt; the explanation is. That is an ordinary state of affairs in pharmacology and it is a good corrective to the confident mechanistic stories that circulate here.
Why mechanism talk keeps misleading people, including me.
A mechanism tells you a direction. It does not tell you a magnitude, a timescale, or whether the pathway is operative at the exposures involved. "Receptor X is expressed in tissue Y" is a fact; "therefore effect Z in a person" is a hypothesis with several missing steps.
The corrective is boring and it works: ask whether the evidence is preclinical or human, ask what exposure was used, and read the limitations section before the abstract. Most of the confidently wrong posts on this board — several of them mine — skipped all three.
Ask me anything specific. Anything general I will probably get wrong.
best — the order this archive was captured in
The mental model, in four steps, that makes the rest of this site legible.
One: gut hormones amplify the insulin response to food. Two: agonists at those receptors act peripherally on insulin secretion and gastric emptying, and centrally on appetite. Three: structural modification gives them a long half-life, so exposure is smooth and weekly. Four: tolerance develops to some effects and not to others.
From those four, most of what the experience boards report falls out: why the side effects cluster early, why they settle at a stable dose, why appetite reduction persists, and why the scale and the appetite move on different clocks.
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.
Speculation is welcome here if it is labelled. This one has been relabelled rather than removed.
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.
the central appetite effect is doing more work than the gut effect
Not convinced by the linearity assumption. Dose-response in this class is not linear and the trials show it.
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.
Are we talking about receptor affinity or clinical potency?
Push back: a receptor being expressed in a tissue does not tell you the agonist reaches it at therapeutic exposure.