[Discussion] we are measuring half-life at the wrong time and calling it noise
we are measuring half-life at the wrong time and calling it noise, and I am aware this is a minority view on this board. 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…
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.
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.
What was the exposure in that experiment relative to therapeutic?
the peripheral and central stories are not in competition
albumin binding is most of the half-life story
gastric emptying slows, it does not stop
GIP is the arm people argue about because the biology is genuinely unsettled
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.
GIP receptor biology is genuinely unsettled — there is a live argument about agonism versus antagonism at the receptor — and the clinical results are
Adding the caveat the paper itself makes in its limitations section, which is stronger than anything in this thread.