[Discussion] incretin is doing more work than we give it credit for
incretin is doing more work than we give it credit for — a position I have arrived at slowly and would like tested.
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.
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.
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.
Not medical advice, obviously, and nothing here is approved for human use. One person with a spreadsheet.
best — the order this archive was captured in
Speculation is welcome here if it is labelled. This one has been relabelled rather than removed.
Speculation is welcome here if it is labelled.
gastric_emptying_g is right that mechanism gives direction and not magnitude. Worth pinning.
half-life is why these are weekly and not daily
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a mechanism you can state is not a mechanism you have demonstrated
GIP is the arm people argue about because the biology is genuinely unsettled
Agreed — the incretin effect is the load-bearing concept and everything downstream reads differently once you have it.
Yes. The central component is the one that explains the reports on this site better than gastric emptying does.
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
preclinical is not clinical and rodents are not small people
Not convinced by the linearity assumption. Dose-response in this class is not linear and the trials show it.
receptor agonism is not the same as receptor activation in every tissue
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.
Same view. Tolerance developing to the gastric effect while the appetite effect persists explains most of what the side-effect board reports.
Do you have the paper, or a summary of it?
receptor distribution is why the side effects are where they are
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.
Which receptor arm are you attributing that to?
Which receptor arm are you attributing that to?
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.
Does the effect persist with continued dosing or does tolerance develop?
Is there any human data on that mechanism yet?
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.
Correcting my own comment: I attributed that to the GIP arm and the paper attributes it to the GLP-1 arm.
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.
tolerance to the gastric effect develops, appetite effect largely persists
Cosigning on GIP. The genuinely interesting thing is that the biology is not settled and the clinical result is nonetheless robust.
That study was in a rodent model. Worth stating, since the thread has been reading it as human data.
The half-life explanation was the thing that made weekly dosing intuitive for me rather than arbitrary.
That conflates receptor affinity with clinical potency. They are related and they are not the same thing.
- 1receptor agonism is not the same as receptor activation in every tissue12 comments in this branch · started by u/katrin_marchetti
- 2Speculation is welcome here if it is labelled. This one has been relabelled…8 comments in this branch · started by u/gastric_emptying_g