Is there any good data on Glucagon levels right after dosing various GLP1s?

[tubby]

Lilly was nice enough to report serum glucagon levels after the initial administration of retatrutide. See plot H here:

https://www.researchgate.net/figure/LY3437943-in-healthy-participants-in-a-phase-1-single-ascending-dose-clinical-study_fig1_362793202

From the chart, one can see that glucagon paradoxically increased at 0.1 mg dosing, but glucagon went down at all the other doses (0.3 mg and stronger).

Has anyone seem similar data following the FIRST dose of sema, tirz, or other similar peptides? I'm finding plenty of studies that give serum glucagon levels weeks/months into treatment, but that's pretty worthless information. By then significant weight has already been lost so it's impossible to untangle how much of the glucagon reduction was simply caused by the weight loss itself VS being an immediate response.

 

[Retazempic]

Same question. Also, does anyone have a good source explaining, in plain English, the biological mechanism of glucagon-agonist mediated weight loss? I understand the GLP and mechanisms, but I can’t figure out the glucagon piece. All I hear are general statements but nothing connecting the dots. I want to understand the cascade of reactions.

 

[tubby]

Same question. Also, does anyone have a good source explaining, in plain English, the biological mechanism of glucagon-agonist mediated weight loss? I understand the GLP and mechanisms, but I can’t figure out the glucagon piece. All I hear are general statements but nothing connecting the dots. I want to understand the cascade of reactions.

I have the same problem and find myself wondering if all of the "influencers" are making major conceptual errors when they try to explain how it's working.

At a high level it has to be something along the lines of:
Glucagon receptor agonist locks into a receptor somewhere in the body (presumably in or near the gut), creating a false "high-glucagon" alarm. From there the brain (or some other organ) picks up the signal and alters glucagon production (and likely other downstream hormonal cascades) as the result.

The question I'm left with is does the glucagon receptor agonist act to increase glucagon production or decrease glucagon production? And I had hoped that by being able to see how other GLP-1RAs affected glucagon level it might be possible to infer that (thus my original question).

If you believe social media influencers, "glucagon goes up and that increases fat burning," but that doesn't seem quite right. After all, in the phase 1 trial I linked to, glucagon clearly goes down following the injection. I mean this wouldn't be the first time lay-people pretending to be experts in internet videos got something wrong, so it's possible everyone making that claim is just mistaken.

The other possibility is that perhaps other GLP-1 agonists (e.g. sema or tirz) actually cause glucagon to drop even more post-injection than reta and reta is partially offsetting that effect. I have no reason to think this is the case, other than that it would allow the social media influcencer-style explanation for how reta works to be correct.

I you held a gun to my head and made me guess, I'd guess that the influencers are wrong and that the glucagon-agonist behavior of reta is DECREASING glucagon more than it otherwise would have from the GLP-1RA and GIP-RA action alone.

 

[Retazempic]

You literally have laid out my conundrum, and a sincere thanks for taking the time to write it out (and validating my confusion).

I’ve been trying to piece together various statements made by “doctors” on YouTube, and have come to the provisional conclusion that even if they’re all real doctors, most, if not all of them, don’t specialize in this enough to speak intelligently on it.

 

[tubby]

You literally have laid out my conundrum, and a sincere thanks for taking the time to write it out (and validating my confusion).

I’ve been trying to piece together various statements made by “doctors” on YouTube, and have come to the provisional conclusion that even if they’re all real doctors, most, if not all of them, don’t specialize in this enough to speak intelligently on it.

The problem is that although most are aware of what the different relevant hormones are, they haven't really ever tried to think of them in a fully integrated way (A causes B, causes C, leads to D), but are only looking at first order effect, which leads to some pretty stupid conclusions.

For example, GLP1s for diabetics are usually described as "lowering blood sugar by raising insulin," which is such a ridiculous claim that it's laughable. Sulfonylureas "lower blood sugar by raising insulin" and that's their only direct mechanism of action, as far as we know. Obviously that's not the mechanism through which GLP-1RAs are working, yet it gets repeated as if it were true. In fact, GLP1s ultimately lower insulin over time (due to weight loss). It would be funny that such ideas pass for descriptions, if it wasn't so tragic.

 

[tubby]

If you want an attempt at an explanation (which could be way off, I'll fully admit), I'll try to guess at one:

GLP-1RA and GIP-RA greatly decrease appetite, but in doing so likely INCREASE glucagon in the short-term. It's not that the drug directly increases glucagon, but simply that when someone cuts way back on what they're eating, that energy deficit has to come from stored energy in the body and glucagon is the hormone to make that happen. The body doesn't want to die so alpha cells start cranking out glucagon. Meanwhile, your brain is super confused because on one hand it's getting slammed with GLP-1/GIP ("I just ate, I'm full"), to which it's going to up insulin (AKA the storage hormone) release from beta cells to store that extra energy. At the same time, it's getting starvation signaling from everywhere else, so it's going to up glucagon production (AKA release stored energy signal). Over time, GLP-1 resistance develops in the brain and weight plateaus, as is seen with sema and tirz.

I'd suspect that what's different with reta is that within that context the glucagon-RA nudges glucagon down (instead of letting it rise) and somewhere in that tangled ball of signaling the insulin response to GLP-1 gets reduced. I say that because it's ultimately the ratio of insulin to glucagon that determines the net flow of energy at fat cells and the liver. And if glucagon goes down at a point where you're between meals, insulin has to follow it down for you to remain conscious and alive. Perhaps after a few days the brain gets a better handle on this new forced lower level of glucagon and is better at keeping insulin production in check (to avoid ongoing fatigue) and optimize for the new conditions. Whatever is happening, more weight seems to be lost before a plateau is achieved (and who's to say if a plateau exists at higher reta doses).

I'm sure there are still other hormonal signaling mismatches throwing a wrench in things (vs non-medicated weight loss). For example, normally when you go a day or so without food, growth hormone production gets ramped up, which I suspect isn't happening with any of the current injectables and is the motivation for the development of quadruple agonist formulations. And quite frankly, I wouldn't be surprised if these are getting slowly rolled out over time to ensure that there's always something better that's still under patent to give people a reason not to settle for the generic.

Again, this is all me speculating and my biochemistry is kind of weak so I could have blind spots here.

 

[Retazempic]

That’s as good a provisional theory as any. It certainly makes way more sense on its face than the glib treatment given to this topic on YouTube.

Hopefully, someone in this forum has come across a study or 2 that explains what is (or is believed to be) happening when all 3 agonists are combined.

Because right now, all I’m hearing from the “experts” is that they come together and work their power like Voltron or the Megazord.