#62

Yes, but I think the idea is that those two interventions are not necessarily additive. Because say you are doing D+E, and now you add MET. Well, the if addition of MET suddenly degrades the effectiveness of exercise, then you are now no longer having effective D+E. Also, even if the muscles are not worse off with MET (which is highly speculative), certainly aerobic benefits are degraded and the insulin sensitivity benefits of exercise are similarly degraded. At which point, you would like in preference want first D+E as the most effective, and use MET only as a monotherapy, i.e. without exercise (which to be fair, most people would default to).

#63

The observations of efficient muscles with Ex+Met are not “highly speculative”, however, regarding insuline sensitivity, I am not so sure. If it is similar to the issue of less muscle build, I will continue with 250mg before meals (max 2/d), because I am clearly building sufficient muscle on it.

“use MET only as a monotherapy, i.e. without exercise (which to be fair, most people would default to)”

??? Clearly, exercise does no harm when taking metformin. Metformin makes resistance training more difficult, but so is putting on more weight on the barbells! We do not tell people to reduce the weight they lift because it makes the exercise easier. And that is how I see the added difficulty by metformin, namely increasing the resistance (like more weight) but with the additional benifit of more efficient rather than merely bigger muscles.

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#64

Sorry to jump into the middle of your conversation but this “metformin is bad for exercise adaptation” has gotten accepted as a fundamental truth a bit prematurely. The guy who got metformin approved by the FDA says that metformin only has effects on the liver. He said, “no molecule of metformin ever got into a muscle”. (He was a recent guest on Attia’s podcast).

Now, I don’t know about you but to me that makes me think, “then how can metformin have detrimental effects on exercise adaptation?” I no longer worry about it. I take metformin a few days every 2 weeks around my rapa dose.

Any ideas?

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#65

ChatGPT does not agree

Metformin is a widely used drug for type 2 diabetes, and it distributes into various tissues in the body, but not all equally. Here’s a breakdown of where metformin can go:

Tissues Metformin Can Get Into:

  • Liver: Major target tissue – metformin suppresses glucose production here.
  • Intestines: High concentrations accumulate in the gut; may play a role in its glucose-lowering effects.
  • Kidneys: Metformin is excreted unchanged through the kidneys, so it accumulates here too.
  • Muscle: Enters skeletal muscle where it increases glucose uptake.
  • Adipose (fat) tissue: Can enter, though effects here are less well understood.
  • Heart: Some evidence it reaches cardiac tissue.
  • Mitochondria (within cells): Especially in the liver and muscle cells; it inhibits mitochondrial complex I, affecting energy metabolism.

Tissues Metformin Doesn’t Penetrate Well:

  • Brain/Central Nervous System: Very limited penetration due to the blood-brain barrier.
  • Fatty tissues: While it can enter, the uptake is relatively lower compared to more perfused tissues like the liver or kidney.

Its uptake into cells often depends on organic cation transporters (OCTs) – proteins that actively move metformin into tissues.

#66

Metformin itself does not need to get into muscle or any other tissue to have an effect. Metformin most certainly impacts muscle and other tissues.

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

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#67

Also, just to make clear, I am not urging anyone to not use metformin for any reason. Metformin has been cleared by the FDA, and if your physician prescribes it, you should follow your physician’s advice. I am not a doctor and I don’t offer medical advice.

I am explaining why I personally don’t take metformin at this time, and have no plans to do so, unless compelling research comes out that changes my mind.

As I understand it, the evidence is that metformin negatively affects exercise adaptations, and this is one of the reasons why I don’t want to take it. However if you see benefits, I am very happy for you. YMMV.

#68

Thanks. I cannot understand what they did in your referenced study. It looks like only a portion was done in a live animal (vs. in a dish). And the part they did “in vivo” is hard to understand how the metformin got into the tissues that were tested.

This could all be true but if Ralph DeFronzo PhD, the guy who got metformin approved by the FDA is correct, metformin does not get into muscle of human beings. Any effects are occurring in liver (and maybe kidney, I can’t remember exactly)

That said I don’t know that means metformin doesn’t affect exercise adaptation, it just means it isn’t happening in the muscle. Perhaps the higher lactate (from the liver) is causing a stress signal that is too much…or some such indirect effect. Or, in my experience, metformin made hard exercise feel harder, which lowered how hard I could go, which no doubt lowered my adaptation to exercise because I didn’t exercise as hard.

But don’t worry. I’m not seeking your approval to take metformin. I’m just sharing potentially useful information for people to consider in their calculus.

Here’s the podcast in case you are interested.

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#69

I am puzzled (and should be given I am not a scientist), but does it matter that metformin doesn’t get into the muscle to explain metformin’s impact on exercise adaptation?

According to the following: Reczek, Colleen R., et al. "Metformin targets mitochondrial complex I to lower blood glucose levels." Science Advances 10.51 (2024): eads5466.

Metformin is a cost-effective oral medication generally administered twice daily to humans to reduce blood glucose levels. The molecular mechanisms by which acute metformin administration lowers blood glucose are not fully understood

Our data illustrate the necessity of mitochondrial complex I inhibition for the blood glucose–lowering effects of metformin

Any other glucose inhibitor discussed in the video such as SGLT1 or SGLT2, or not discussed like acabose would seem superior given the drawbacks to the holistic mitochondria inhibition. This same researcher in the video has published papers on acabose so I am puzzled (again) why he even mentions metformin other that for all practical purposes it is free. Too many drawbacks to it use, at least for active people.

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