GLP-1 receptor signalling: the GLP-1 receptor is expressed on beta cells (insulin secretion), on neurons (appetite and gastric motility), and on myocardium (contractility). Different tissues respond to the same signal in different ways.
2 likes 5mo
Pharmacology · Receptor biology · continued
Amylin receptor signalling and satiety — what changed since posts 31–60
This is a continuation of a long topic, addressed by post number rather than by page. Start at post 1.
I disagree with the reply above, and I think the disagreement is substantive rather than terminological.
The distinction being drawn does not survive when you look at the published data for this specific question. I would be glad to be shown wrong on this, because the version I am arguing against is more convenient.
0 likes 5mo
Collapsed as off-topic by two members at trust level 3 or above
On post #29 — agreed on the reasoning, with one qualification.
GIP receptor signalling: the glucose-dependent insulinotropic peptide receptor (GIP) is involved in glucose-stimulated insulin secretion. GIP agonism is thought to contribute to tirzepatide's effect but the mechanism is not fully settled.
post #33 answers the question as asked. The question underneath it is different.
Glucagon receptor agonism: glucagon receptor agonism increases energy expenditure and promotes hepatic fat oxidation. The mechanism is distinct from GLP-1 and GIP agonism and the clinical consequences are still being characterised.
14 likes 5mo
Cross-reactivity and selectivity: the compounds are not perfectly selective for their target receptors. Semaglutide has some activity on other receptors; tirzepatide activates both GLP-1 and GIP with different affinities. The off-target effects are part of the overall pharmacology.
0 likes 5mo
t.batista, post #9: Central versus peripheral action: GLP-1 agonism works through both central nervous system effects (appetite) and peripheral effects (gastric motility, insulin). The balance is not fully characterised. Go to post
Central versus peripheral action: GLP-1 agonism works through both central nervous system effects (appetite) and peripheral effects (gastric motility, insulin). The balance is not fully characterised.
Staff post. Actions described here are recorded in the public moderation log and may be challenged in Meta.
Worth separating two things that post #33 runs together.
Bias and desensitisation: receptors can be biased (preferentially activating some downstream pathways over others) and can desensitise over time (responding less to the same stimulus with repeated exposure). Both might affect long-term response to these compounds.
21 likes 5mo
Coming back to post #37, because the follow-up matters more than the original answer.
Species differences: rodent studies show the same compounds produce effects in rodents that predict human effects reasonably well for semaglutide and tirzepatide. The track record is less clear for novel compounds with less human data.
0 likes 5mo
Picking up post #37: that is the part I would want checked first.
Pharmacological class effects: all GLP-1 agonists slow gastric emptying and suppress appetite. Those are class effects, not unique to one compound. Effects that differ between compounds are usually about potency or receptor selectivity.
29 likes 5mo
This follows post #38 rather than contradicting it.
Amylin receptor signalling: amylin promotes satiety and slows gastric emptying through a receptor distinct from GLP-1. The hypothesis behind combination therapy is two complementary satiety mechanisms.
0 likes 5mo
Bias and desensitisation: receptors can be biased (preferentially activating some downstream pathways over others) and can desensitise over time (responding less to the same stimulus with repeated exposure). Both might affect long-term response to these compounds.
4 likes 5mo
Thank you for the correction. I have edited my earlier post with a note rather than silently, so the thread still makes sense to read. The error was mine and it was the kind that comes from remembering a figure instead of looking it up.
19 likes 5mo
k.okafor, post #11: GLP-1 receptor signalling: the GLP-1 receptor is expressed on beta cells (insulin secretion), on neurons (appetite and gastric motility), and on myocardium (contractility). Different tissues respond to the same signal in different ways. Go to post
Glucagon receptor agonism: glucagon receptor agonism increases energy expenditure and promotes hepatic fat oxidation. The mechanism is distinct from GLP-1 and GIP agonism and the clinical consequences are still being characterised.
Picking up post #42: that is the part I would want checked first.
Long-term receptor changes: very little is known about what happens to receptor expression, signalling, and downstream effects over years of exposure to these compounds. That is exactly the knowledge gap phase 3 trials exist to fill.
2 likes 4mo
Coming back to post #44, because the follow-up matters more than the original answer.
Two things before anyone answers the substance.
First, the context in the first post is clear and specific. Second, the question is framed so that an answer can actually address it. Both are the norm here and both matter more than they sound.
8 likes 4mo
y.ramos, post #42: Bias and desensitisation: receptors can be biased (preferentially activating some downstream pathways over others) and can desensitise over time (responding less to the same stimulus with repeated exposure). Both might affect long-term response to these compounds. Go to post
Central versus peripheral action: GLP-1 agonism works through both central nervous system effects (appetite) and peripheral effects (gastric motility, insulin). The balance is not fully characterised.
m.adebayo, post #7: post #6 is right about the mechanism and I think understates the practical bit. Amylin receptor signalling: amylin promotes satiety and slows gastric emptying through a receptor distinct from GLP-1. The hypothesis behind combination therapy is two complementary satiety mechanisms. Go to post
Cross-reactivity and selectivity: the compounds are not perfectly selective for their target receptors. Semaglutide has some activity on other receptors; tirzepatide activates both GLP-1 and GIP with different affinities. The off-target effects are part of the overall pharmacology.
GIP receptor signalling: the glucose-dependent insulinotropic peptide receptor (GIP) is involved in glucose-stimulated insulin secretion. GIP agonism is thought to contribute to tirzepatide's effect but the mechanism is not fully settled.
0 likes 4mo
I read post #48 twice before replying, because I had assumed the opposite.
GLP-1 receptor signalling: the GLP-1 receptor is expressed on beta cells (insulin secretion), on neurons (appetite and gastric motility), and on myocardium (contractility). Different tissues respond to the same signal in different ways.
0 likes 4mo
c.balogun, post #17: Practical note that does not fit anywhere else. Whatever you conclude from this topic, write down what you did and when. The single most useful thing in your own records is not any individual result; it is that they are dated and consecutive. Go to post
Bias and desensitisation: receptors can be biased (preferentially activating some downstream pathways over others) and can desensitise over time (responding less to the same stimulus with repeated exposure). Both might affect long-term response to these compounds.
Tavares, post #6: Having read the exchange above, I think I was wrong earlier in this topic and I want to say so plainly rather than quietly editing. The correction was fair and I had been repeating something I had not checked carefully enough. Go to post
post #51 is right about the mechanism and I think understates the practical bit.
Amylin receptor signalling: amylin promotes satiety and slows gastric emptying through a receptor distinct from GLP-1. The hypothesis behind combination therapy is two complementary satiety mechanisms.
I read post #51 twice before replying, because I had assumed the opposite.
Practical note that does not fit anywhere else. Whatever you conclude from this topic, write down what you did and when. The single most useful thing in your own records is not any individual result; it is that they are dated and consecutive.
8 likes 4mo
Central versus peripheral action: GLP-1 agonism works through both central nervous system effects (appetite) and peripheral effects (gastric motility, insulin). The balance is not fully characterised.
2 likes 4mo
On post #51 — agreed on the reasoning, with one qualification.
GLP-1 receptor signalling: the GLP-1 receptor is expressed on beta cells (insulin secretion), on neurons (appetite and gastric motility), and on myocardium (contractility). Different tissues respond to the same signal in different ways.
0 likes 4mo
k.farrugia, post #12: Glucagon receptor agonism: glucagon receptor agonism increases energy expenditure and promotes hepatic fat oxidation. The mechanism is distinct from GLP-1 and GIP agonism and the clinical consequences are still being characterised. Go to post
post #55 answers the question as asked. The question underneath it is different.
Long-term receptor changes: very little is known about what happens to receptor expression, signalling, and downstream effects over years of exposure to these compounds. That is exactly the knowledge gap phase 3 trials exist to fill.
Glucagon receptor agonism: glucagon receptor agonism increases energy expenditure and promotes hepatic fat oxidation. The mechanism is distinct from GLP-1 and GIP agonism and the clinical consequences are still being characterised.
4 likes 4mo
Thank you for the correction. I have edited my earlier post with a note rather than silently, so the thread still makes sense to read. The error was mine and it was the kind that comes from remembering a figure instead of looking it up.
0 likes 4mo
Worth separating two things that post #55 runs together.
Practical note that does not fit anywhere else. Whatever you conclude from this topic, write down what you did and when. The single most useful thing in your own records is not any individual result; it is that they are dated and consecutive.
1 like 4mo
m.yildiz, post #53: I read post #51 twice before replying, because I had assumed the opposite. Practical note that does not fit anywhere else. Whatever you conclude from this topic, write down what you did and when. The single most useful thing in your own records is not any individual result; it is that they are dated and consecutive. Go to post
GIP receptor signalling: the glucose-dependent insulinotropic peptide receptor (GIP) is involved in glucose-stimulated insulin secretion. GIP agonism is thought to contribute to tirzepatide's effect but the mechanism is not fully settled.