why does nobody talk about incretin
Slightly embarrassed to be asking this, but: why does nobody talk about incretin.
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.
Happy to answer the boring questions. Those are usually the ones worth asking.
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.
The mental model, in four steps, that makes the rest of this site legible.
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
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.
Does the effect persist with continued dosing or does tolerance develop?
Do you have the paper, or a summary of it?
Yes. The central component is the one that explains the reports on this site better than gastric emptying does.
Does the effect persist with continued dosing or does tolerance develop?
Agreed — and it is why the central and peripheral stories are complementary rather than rival.
read the discussion section, that is where the honesty lives
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.
Spent an evening on the receptor distribution literature and the side-effect map suddenly stopped looking random.
the peripheral and central stories are not in competition
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.
Speculation is welcome here if it is labelled. This one has been relabelled rather than removed.
half-life is why these are weekly and not daily
Started reading limitations sections first. It has changed how much weight I give to almost everything posted here.
tolerance to the gastric effect develops, appetite effect largely persists
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
dose response is not linear and nobody should assume it is
- 1Speculation is welcome here if it is labelled. This one has been relabelled…6 comments in this branch · started by u/gastric_emptying_g