three years of receptor threads, summarised so you do not have to read them
Thinking out loud about this: three years of receptor threads, summarised so you do not have to read them.
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.
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.
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.
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
Glucose-dependent insulin secretion is why hypoglycaemia risk is low as monotherapy: the effect scales with glycaemia rather than acting unconditionally.
Do you have the paper, or a summary of it?
Are we talking about receptor affinity or clinical potency?
Left up and flaired Explainer. This is the standard of post the board was created for.
glucagon agonism sounds paradoxical until you read the energy expenditure work
Cosigning on GIP. The genuinely interesting thing is that the biology is not settled and the clinical result is nonetheless robust.
incretin effect first, then everything else in this board makes sense
Correction: that is glucose-dependent insulin secretion, which is why hypoglycaemia risk is low as monotherapy. Not the same claim as you made.
Tried to build a mental model from mechanism alone and produced a confident prediction that the trial data flatly contradicted.
That conflates receptor affinity with clinical potency. They are related and they are not the same thing.
Does the effect persist with continued dosing or does tolerance develop?
The half-life explanation was the thing that made weekly dosing intuitive for me rather than arbitrary.
Cosigning on GIP.
This is the concept everything else on this board is downstream of.
Small fix — it slows gastric emptying, it does not halt it, and the distinction matters for the mechanism you are proposing.
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.
albumin binding is most of the half-life story
Is there any human data on that mechanism yet?
a mechanism you can state is not a mechanism you have demonstrated
That study was in a rodent model. Worth stating, since the thread has been reading it as human data.
What does the discussion section say about the limitation you are glossing?
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.
Push back: a receptor being expressed in a tissue does not tell you the agonist reaches it at therapeutic exposure.
the peripheral and central stories are not in competition
Is that from a human study or a preclinical model?
Is that from a human study or a preclinical model?
Disagreeing with this specific inference — that is a preclinical result being read as human pharmacology.
gastric emptying slows, it does not stop
Disagreeing with this specific inference — that is a preclinical result being read as human pharmacology.
nadia_fonseca is right that mechanism gives direction and not magnitude. Worth pinning.
the central appetite effect is doing more work than the gut effect
- 1glucagon agonism sounds paradoxical until you read the energy expenditure work10 comments in this branch · started by u/niels_roos
- 2What does the discussion section say about the limitation you are glossing?9 comments in this branch · started by u/asks_dumb_questions