Metformin blunts exercise-induced gains in muscle, strength, and aerobic fitness | Rhonda Patrick

Now, the real question is, what if you were a healthy individual that exercises like you, me, and probably most of your friends in Silicon Valley are and you took metformin? Is there a synergistic effect, right? Is there an additive effect? Right. Like, that's the real question. And, I'll tell you, multiple, multiple randomized controlled trials now, not just 1, not just 2, not just 3, not just 4, more than that have shown that the Yeah. The opposite seems to be true where taking metformin in the context of either aerobic exercise or strength training exercises seems to blunt many of the positive effects of exercise. So, let me get a little more specific there.

There was a randomized controlled trial published, I believe it was a year ago or something, that was done because there had been multiple ones done in people with with type 2 diabetes or prediabetes showing that metformin could blunt some of the positive effects of exercise on insulin sensitivity and things like that. But, this is one of the first real randomized controlled trials done in healthy individuals that were at risk for type 2 diabetes but didn't have type 2 diabetes. They were basically given increasing doses of metformin starting from 500 milligrams and then increasing up to 2,000 milligrams depending on their body weight. This was a 4-week trial. So, it was about a month long. And, they were doing 45 minutes of aerobic exercise on elliptical 3 times a week.

Metformin prevented the exercise-induced improvements in cardiorespiratory fitness by 50%. Other randomized controlled trials have shown this to be true in people with type 2 diabetes. And also, there's one other study in health of active adults. So, that's really concerning. Cardiorespiratory fitness is one of the biggest predictors of disease and mortality. So that is really not good that metformin, you know, prevented it by 50%, you know. Wow. It also inhibited improvements in mitochondrial respiration and that may be something linked to some of— we— I didn't talk about all the mechanisms of metformin.

You know, one of the molecular mechanisms that's thought to play a role in improving, you know, all this glucose regulation and insulin sensitivity is the activation of an important pathway called AMP kinase. That pathway is activated by energy stress, and energy stress can be caused by things like exercise, can be caused by fasting or caloric restriction, or metformin. Another thing that metformin does, and it's actually even thought by some people that this is how AMP kinase is activated, is by basically disrupting a certain part of the mitochondria that generates energy called complex 1. You've got 5 complexes inside your mitochondria. They're basically just passing electrons around, and this is how you can make make energy in the form of ATP.

Well, metformin disrupts one of those complexes, mildly disrupts it, complex I. For the longest time, I wasn't hugely convinced by that because the majority of data was in vitro, meaning you dump metformin on cells in culture and this happened. And, it's like, well, that could be a really big dose-dependent thing. Most in vitro studies, you can show one thing and completely show an opposite thing if you were talking about what's called in vivo or at the level of the whole organism. Yeah. Mm-hmm. But there was a study published a few years like 2014 or '15 or something like that showing giving— if you fed rats very— actually they were rats that had type 2 diabetes and they were fed various doses of metformin, 30 milligrams per kilogram body weight, 100 or 300 milligrams, right?

Showed that at higher doses, 100 or 300 milligrams per kilogram body weight, metformin could decrease the mitochondrial oxidative capacity specifically linked to complex I. activity if they isolated muscle from these rats that were orally given these doses. So I was like, okay, that's kind of— that's evidence that it is obviously doing something that's physiologically relevant. So that could be why it's, you know, preventing cardiorespiratory fitness, which has been linked to mitochondrial function. It could be why it's— metformin's inhibiting adaptations with mitochondria. Metformin also diminished whole-body insulin sensitivity after aerobic exercise. But it wasn't like everything was bad.

So metformin didn't diminish other improvements from exercise like the decrease in HbA1c, which is like a long-term marker of blood glucose levels. It didn't affect fasting insulin or blood glucose or fat mass or skeletal muscle telomere length, which increased with exercise. So that's good. But it is concerning that it had all those negative effects, right? And these are in healthy people. Do you think this is something where eventually, you know, we— because we do want this activation of AMPK, right? That's a positive thing. So here's the thing. So activation of AMP— Can we pulse it? So the activation of— so here's the thing. That's the question, right? Well, what if you time your metformin, right? There's things to consider other than the half-life of metformin or, you know, the important thing is— so for example, exercise activates AMP kinase. The activation is relatively transient but the effects of exercise last about 48 hours.