This will be my first article as a ‘research pick’. I’ll try and somewhat regularly write brief articles on new studies published in the literature or discuss certain topics I see floating around on social media.
For this first research pick I’ll discuss the drug metformin as I’ve seen this floating around on Facebook over and over and over and over and over again.
Metformin is a drug used in the treatment of type 2 diabetes and polycystic ovary syndrome (PCOS). It decreases glucose production by the liver and increases insulin sensitivity to some extent. Now, I read in some posts on Facebook that it might inhibit your gains. Let’s put up front, if you’re diabetic, you shouldn’t stop using this even if it did inhibit your gains. But the main people who worry about this, are the ones with PCOS (without insulin insensitivity) who don’t really have to take it and a group of bodybuilders (again, without insulin insensitivity) who for some reason have an obsession with this stuff.
So where does the notion come from that metformin will hinder your gains? Well, it turns out that metformin activates a protein complex named AMP-activated protein kinase, or abbreviated, AMPK. In turn, AMPK is a negative regulator of a protein complex named the mechanistic target of rapamycin complex 1 (mTORC1). Bear with me, because here comes the punch line. mTORC1 is heavily involved in regulating skeletal muscle protein synthesis and thus muscle hypertrophy. I’ve published a review on mTORC1 a few years ago in JISSN (open access) which can be read here: Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance (I also briefly touch on the interaction between AMPK and mTORC1 in this paper).
Because AMPK is a negative regulator of mTORC1, it is somewhat fair to assume that that’s a really bad thing for your gains. However, this is an oversimplified picture. For starters, AMPK isn’t just a single protein complex. It’s actually a family (technically speaking ‘family’ might be the wrong word here) of protein complexes. You see, AMPK is made out of three parts, also called subunits. An α subunit, a β subunit, and a γ subunit. Each of these subunits is a protein, and each of them comes in various shapes and sizes sort to say (isoforms). There are two types of the α subunit, two types of the β subunit and three types of the γ subunit. Now if you try to make as much combinations as possible with these subunits to form different kinds of AMPK, you can generate 2 times 2 times 3 unique AMPKs (12 in total). In practice, only three out of these twelve possible combinations have been found in human skeletal muscle. Namely, α1/β2/γ1, α2/β2/γ1 and α2/β2/γ3.
Why am I telling you this? Because these three different AMPKs have different effects on the muscle cells. Only the α1-containing AMPK appears to attenuate muscle growth, whereas the other two containing the α2 subunit appear not to do so . As such, it is important to know which of these three AMPKs get activated by metformin or not. Ideally, I would bring you a paper which has examined this in the skeletal muscle of healthy adults. Unfortunately, I cannot find such a study. However, I’ve found something quite close to it, a study which examined this in the skeletal muscle of patients with type 2 diabetes . Not ideal, but a whole lot better than a rodent, drosophila or in vitro study.
In said study, they gave the patients a therapeutic dose of metformin for 10 weeks and took muscle biopsies pre-treatment and 4 and 10 weeks later to check both α1-containing AMPK and α2-containing AMPK activity. What they found was an increase in α2-containing AMPK activity, but not α1-containing AMPK activity. Which is great news for your gains, since as said before, only the α1-containing AMPK appears to attenuate muscle growth. Hurray.
That said, I want to comment a bit further on this whole thing. For one, the above study was in type 2 diabetics. This might not apply to non-type-2-diabetics. Furthermore, I’m assuming here that the α2-containing AMPK does not attenuate muscle growth. Although I base this on quite some research as described in reference number 1, this might still not be entirely true. Moreover, there might be some other way, outside of AMPK, how metformin might influence muscle hypertrophy, either positively or negatively. The thing is, to draw any definitive conclusions you’d need a study examining exactly that. Which does not exist as of this writing (in healthy individuals) and which I do not expect to be published ever anyways, since it’s not really interesting to investigate for research purposes. Finally, it’s also notoriously dangerous to draw clinical conclusions by isolating pathways like this. There are a great many things which influence the ultimate effects of molecules on cells.
Concluding, however, there simply does not appear to be an indication for metformin inhibiting your gains, but definitive studies are lacking. (And there are also definitive studies lacking whether or not an apple a day will influence your gains, so that isn’t really an argument against this anyways). So happily keep consuming your metformin people.
- Mounier, Rémi, et al. “Antagonistic control of muscle cell size by AMPK and mTORC1.” Cell Cycle 10.16 (2011): 2640-2646.
- Musi, Nicolas, et al. “Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes.” Diabetes 51.7 (2002): 2074-2081.