opinions on combined therapy, glp + metformin?

[Meritocrat]

If someone isn't excessively hyperglycemic, taking metformin along with Reta or Tirz could be terrible. Metformin, like Rapamycin, has senolytic effects. Both of them inhibit mTor mechanism and it has been assessed that metformin interferes with strength adaptation. As such, the quick weight loss with GLP-1's can result in muscle loss. Adding metformin to the mix can worsen it.

Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial - PMC

Progressive resistance exercise training (PRT) is the most effective known intervention for combating aging skeletal muscle atrophy. However, the hypertrophic response to PRT is variable, and this may be due to muscle inflammation susceptibility. ...

pmc.ncbi.nlm.nih.gov

Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a - PMC

Skeletal muscle atrophy is a severe condition that involves loss of muscle mass and quality. Drug intake can also cause muscle atrophy. Biguanide metformin is the first‐line and most widely prescribed anti‐diabetic drug for patients with type 2 ...

pmc.ncbi.nlm.nih.gov

Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults | Aging

Evidence from clinical trials and observational studies suggests that both progressive resistance exercise training (PRT) and metformin delay a variety of age-related morbidities. Previously, we compl

www.aging-us.com

 

[AlexSilver]

Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a - PMC

Skeletal muscle atrophy is a severe condition that involves loss of muscle mass and quality. Drug intake can also cause muscle atrophy. Biguanide metformin is the first‐line and most widely prescribed anti‐diabetic drug for patients with type 2 ...

pmc.ncbi.nlm.nih.gov

Yeah but why do they do studies like this? In this one “Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a”,

They fed mice 250mg/kg. That’s the same as feeding a 200 pound man 110000 milligrams.

That’s absurd. I’m not surprised it causes atrophy at that concentration. You absolutely cannot compare to a human taking 500 or even 1000 mg to taking 110000mg. It’s not realistic. Such studies are hardly viable.

 

[AlexSilver]

I had been taking metformin for six years. I decided to take a treatment break when I started Reta and before my first cycle of MOTS-c.

I had also just read this article:

( https://pubmed.ncbi.nlm.nih.gov/27459533/ )

Metformin can raise cortisol levels. I linked this to the dawn phenomenon, which caused my fasting blood sugar to spike sharply for several hours.

The first noticeable effect the next morning when I woke up was that my legs no longer ached as if I had run 10 miles at night.

The dawn phenomenon has begun to fade and now occurs only once or twice a week, with a reduced amplitude.

May I ask what dosage you were taking for 6 years?

 

[AlexSilver]

It took me a moment to understand you were talking about glycemia and not some cowboy thingy. ;-)

Metformin has never had much effect on my blood sugar levels. It’s primarily a very good antioxidant that protects blood capillaries and peripheral nerves from the damaging effects of circulating glucose. It can reduce hepatic neoglucogenesis by about 30%, and around 2020, some lovely photos were published showing that it eliminates some of the glucose through the intestines.

Whoops, Sorry. Should have said Blood Sugar.

 

[Habibibi]

If someone isn't excessively hyperglycemic, taking metformin along with Reta or Tirz could be terrible. Metformin, like Rapamycin, has senolytic effects. Both of them inhibit mTor mechanism and it has been assessed that metformin interferes with strength adaptation. As such, the quick weight loss with GLP-1's can result in muscle loss. Adding metformin to the mix can worsen it.

Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial - PMC

Progressive resistance exercise training (PRT) is the most effective known intervention for combating aging skeletal muscle atrophy. However, the hypertrophic response to PRT is variable, and this may be due to muscle inflammation susceptibility. ...

pmc.ncbi.nlm.nih.gov

Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a - PMC

Skeletal muscle atrophy is a severe condition that involves loss of muscle mass and quality. Drug intake can also cause muscle atrophy. Biguanide metformin is the first‐line and most widely prescribed anti‐diabetic drug for patients with type 2 ...

pmc.ncbi.nlm.nih.gov

Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults | Aging

Evidence from clinical trials and observational studies suggests that both progressive resistance exercise training (PRT) and metformin delay a variety of age-related morbidities. Previously, we compl

www.aging-us.com

metformin does not inhibit mtor. It activates AMPK.

 

[Meritocrat]

metformin does not inhibit mtor. It activates AMPK.

It inhibits mTor BY its activation of AMPK and other mechanisms. Here's the AI version.

Metformin inhibits mTOR (specifically the mTORC1 complex) primarily by activating AMPK and lowering cellular energy status, and secondarily by blocking amino acid signaling. This downregulates cell growth and protein synthesis, which is how it exerts many of its metabolic and anti-cancer effects. [1, 2, 3]

The 3 Main Mechanisms

AMPK Activation (Energy Sensor): Metformin inhibits mitochondrial complex I, which depletes ATP and raises the cellular AMP-to-ATP ratio. This directly activates AMP-activated protein kinase (AMPK). Activated AMPK shuts down mTORC1 in two ways:
TSC1/TSC2 Activation: AMPK phosphorylates and activates the TSC2 tumor suppressor. This complex inactivates Rheb, a small GTPase required to turn on mTORC1.

RAPTOR Phosphorylation: AMPK directly phosphorylates RAPTOR, an essential scaffold protein of the mTORC1 complex, causing mTOR to be turned off. [1, 2, 3, 4, 5]

Amino Acid Starvation (Rag GTPase Inhibition): Metformin independently inhibits the Rag GTPases, which are required to anchor mTORC1 to the lysosomal surface. By blocking this recruitment, it prevents mTORC1 from being activated by cellular amino acid pools. [1, 2]

The REDD1/p53 Axis: In certain tissues (particularly under cellular stress), metformin increases the expression of REDD1 (Regulated in Development and DNA damage responses 1). REDD1 further binds and sequesters inhibitory proteins, preventing them from interfering with the TSC complex, thereby ensuring mTOR remains inactive.

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Metformin: An Inhibitor of mTORC1 Signaling

Recent progress in molecular medicine has identified the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1) as the central r

www.jscimedcentral.com

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.13780

https://aacrjournals.org/cancerres/article/71/13/4366/568093/Metformin-Independent-of-AMPK-Induces-mTOR