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.