[Adam]

What is 600mcg 2x day?

None

[Adam]

Excellent and very insightful question — and one that’s come up in a few clinical discussions about Retatrutide (LY3437943).

Here’s a detailed breakdown of why Retatrutide can sometimes raise fasting glucose or HbA1c in certain individuals, while other GLP-1 receptor agonists like semaglutide or tirzepatide usually lower them:

⸻

🧬 1. Retatrutide isn’t only a GLP-1 agonist

Retatrutide is a triple agonist — it targets:

• GLP-1 receptor

• GIP receptor

• Glucagon receptor

That last one — the glucagon receptor — is the key to this paradox.

⸻

🔥 2. Glucagon receptor activation increases hepatic glucose output

• Glucagon stimulates gluconeogenesis and glycogenolysis in the liver.

• This increases hepatic glucose release → higher fasting blood glucose.

• Even though GLP-1 and GIP reduce glucose by enhancing insulin secretion and slowing gastric emptying, the glucagon receptor agonism counteracts this effect to some extent.

⸻

🧩 3. Why include glucagon agonism at all?

It seems counterintuitive, but it’s intentional:

• Glucagon receptor activation raises energy expenditure, promotes fat oxidation, and reduces body fat mass.

• It’s part of why Retatrutide produces remarkable weight loss (up to 24%+), greater than tirzepatide.

• The trade-off: a transient or mild elevation in fasting glucose or HbA1c in some individuals.

⸻

⚖️ 4. Why it affects some people more than others

• Baseline insulin sensitivity: People who already have impaired β-cell function or insulin resistance may not compensate as effectively for the glucagon-induced hepatic glucose release.

• Dosing phase: Early in treatment (dose-escalation phase), transient glucagon-driven glucose rises are more likely before the full GLP-1 and GIP effects dominate.

• Body composition: Leaner individuals with lower hepatic fat may exhibit a stronger glucagon-to-glucose effect.

⸻

📈 5. What the trials show

In Eli Lilly’s Phase 2 study (published in NEJM, 2023):

• Some participants showed slight increases in fasting plasma glucose and HbA1c, particularly at higher doses (12–16 mg).

• However, these changes were small, and the overall metabolic benefit (weight loss, insulin sensitivity, lipid profile) remained strongly positive.

⸻

💡 6. Contrast with other incretin drugs

Drug Mechanism Glucose effect

Semaglutide GLP-1 agonist ↓ FPG, ↓ HbA1c

Tirzepatide GLP-1 + GIP agonist ↓↓ FPG, ↓↓ HbA1c

Retatrutide GLP-1 + GIP + Glucagon agonist ↓ overall, but can ↑ FPG or HbA1c in some due to glucagon activity

⸻

🧠 Summary

Retatrutide’s mild glucose-raising effect in some people is:

A side effect of its glucagon receptor agonism, which increases hepatic glucose production — a trade-off for higher fat loss and energy expenditure.

With continued use, improved insulin sensitivity and reduced fat mass often normalize or even lower glucose levels over time.

⸻

Would you like me to show how Retatrutide’s receptor balance compares numerically to semaglutide and tirzepatide (e.g., GLP-1:GIP:GCGR activity ratios)? That helps visualize exactly why its effects differ metabolically.

None

[Adam]

I asked in ref to the glucogen component as I assumed you must of tried tirz to make that comparison . I’m still confused though. The hard part is none of my pals that are really good docs understand it either , I have asked them a fair bit and now they are back to asking me what I think haha. That’s my reading for the day to try to figure out what’s going 😂

I asked ChatGPT? Is that cheating the question? LOL

It explains why this is sometimes seen.

None

[Adam]

The temptation to add Reta is real at a very low dose (micro dose)! I’m am toying with the same.

I dont like the increases in RHR though, which seem to be common.

None

[Adam]

Which body parts do you feel need coming up over the next push up phase?

None

[Adam]

Adam my modified set up is based on my needs for volume per body part , in that I need 4-5 sets per exposure , to grow well , I can do that with my set up , so why would I fuck around with rir stuff? The whole point of the modified full body is when your too big for normal full body that you make the adjustment on the 2-3 body parts that can’t do high frequency and moderate volume

Was just thinking what variables you can change to get more frequent pressing, or whatever body parts take longer to recover, whilst maintaining exposure and lowering recovery demands.

Failure seems to be something that has remained constant in your training, so you could argue that works and must remain.

None

[Adam]

Have you experimented with not going to failure and going 1RIR or 2RIR with muscle groups that take longer for you to recover from?

You state pressing takes more time, so are the recovery demands the same for 2-3 sets with 1RIR as they are for 1 straight set to failure?

I recall you tried RIR and said it didn’t work at the time on the split you were using. Could a different split mean 1-2RIR works?

None

[Adam]

Did you have soreness in the pec the day after?

Do you lower load the next time you do it?

None

[Adam]

Is TBJP Gyms replacing TBJP x Shed?

None

[Adam]

Will you be speaking about whats happened with James?

None

[Adam]

So you have a competition next year in mind if you know when prep is starting?

None

[Adam]

Ooo I just realised it’s the chappy that posted on here that made the initial post , that was 260 first show ? Was it Peter ? He is a nice chap , so that initial post defo isn’t a dig imo

I’m not sure if traininsane11 is a here, I think he is. Yes, he competed recently and is a big fella.

I am Swifto at PM, I replied/defended you on the ‘retard’ comment 🙂

Thank you for posting.

None

[Adam]

I know you probably dont care, but you were mentioned here recently at PM. Some of us had your back to 🙂

https://www.professionalmuscle.com/forums/index.php?threads/just-to-clarify-big-dosages-still-work-%F0%9F%98%85.183878/

I apologise in advance for interrupting your log.

professionalmuscle.com

Just to clarify big dosages still work 😅

More of a fun post than anything Anyone who didn’t follow JP from the early years may think he’s full of shit with the TRT+ DHT phase that he’s been a big part of But here’s a pic dating back … Continue reading

None

[Adam]

Have you tried methylene blue?

None

[Adam]

Yes ! But honestly That’s not good bodybuilding ! When I do that , that is just me making it work , but the reality is this :

When your programming is in that sweet spot , where you have let’s say even just two rotations for PPL , or 3 for UL , and your not doing too much total session volume so your not a fucking zombie outside the gym , and you go in with even just moderate up for it energy, your going to get progressive overload . Then you do that over 6 months , and you never get so hyped you end up being exhausted , and you just tick along tick along , you will make insane progress . Really good bodybuilding is picking exercises that build a shit ton of muscle with less fatigue , doing them well and being consistent . That sillyness I do before sets , is basically just a result of me being a bit fucked up and using that as an outlet for it , defo don’t confuse it for anything more than that . Me being a zombie too, is the same , reallt it’s just me needing to trash myself because I want to feel dead . That’s why I’m not a good onstage bodybuilder! I could be , and I plan to be in the next couple years as I can highlight my own weaknesses , but it’s going to take a lot of work from me to overcome my own emotional attachments to things to reach my goals

What emotional attachments do you think you must overcome?

None