someone explain incretin to me like I have not read a paper in years
someone explain incretin to me like I have not read a paper in years. Searched first, found three threads that contradict each other, hence the post.
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.
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.
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.
That is everything I have. The rest is opinion and I have tried to keep it out.
best — the order this archive was captured in
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.
What was the exposure in that experiment relative to therapeutic?
Went looking for human data on a mechanism everybody here asserts. Found preclinical work and one small study. That was clarifying.
Went looking for human data on a mechanism everybody here asserts.
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
Disagreeing with this specific inference — that is a preclinical result being read as human pharmacology.
the peripheral and central stories are not in competition
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.
Was completely wrong about the gastric emptying story in a thread here two years ago. Someone corrected me with a citation and I have not made that mistake since.
Was completely wrong about the gastric emptying story in a thread here two years ago.
swirl_dont_shake is right that mechanism gives direction and not magnitude. Worth pinning.
What does the discussion section say about the limitation you are glossing?
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
Careful — you have a plausible mechanism and no evidence that it is the operative one in the case you are describing.
mechanism explains a direction, not a magnitude
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 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.
The half-life explanation was the thing that made weekly dosing intuitive for me rather than arbitrary.
Started reading limitations sections first. It has changed how much weight I give to almost everything posted here.
Started reading limitations sections first.
This is the concept everything else on this board is downstream of.
Push back: a receptor being expressed in a tissue does not tell you the agonist reaches it at therapeutic exposure.
Left up and flaired Explainer. This is the standard of post the board was created for.
dose response is not linear and nobody should assume it is
- 1The mental model, in four steps, that makes the rest of this site legible.…7 comments in this branch · started by u/dose_creep_dan