three years of pharmacology threads, summarised so you do not have to read them
Something I keep coming back to: three years of pharmacology threads, summarised so you do not have to read them.
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.
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.
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.
Happy to answer the boring questions. Those are usually the ones worth asking.
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.
incretin effect first, then everything else in this board makes sense
Not convinced by the linearity assumption. Dose-response in this class is not linear and the trials show it.
Speculation is welcome here if it is labelled. This one has been relabelled rather than removed.
Is that from a human study or a preclinical model?
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.
dose response is not linear and nobody should assume it is
gastric emptying slows, it does not stop
a mechanism you can state is not a mechanism you have demonstrated
Disagree. That is a preclinical finding in a rodent model and you are stating it as human pharmacology.
the peripheral and central stories are not in competition
Agreed — the incretin effect is the load-bearing concept and everything downstream reads differently once you have it.
Cosigning on GIP. The genuinely interesting thing is that the biology is not settled and the clinical result is nonetheless robust.
Started reading limitations sections first. It has changed how much weight I give to almost everything posted here.
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.
GIP is the arm people argue about because the biology is genuinely unsettled
Careful — you have a plausible mechanism and no evidence that it is the operative one in the case you are describing.
What does the discussion section say about the limitation you are glossing?
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