France has contributed many luminaries to science, including Pascal and Descartes, but maybe Metformin, a glucose-lowering medication taken by millions of people, deserves a place on this proverbial intellectual Mont Blanc as well.  Derived from the French lilac, Metformin continues to be a source of controversy and diarrhea for both scientists and patients across the world.  Smart people like to debate whether or not its inhibition of the electron transport chain really occurs at clinical doses, while others pontificate over the mechanism by which it modulates the nutrient sensor AMPK.  And anyone who has ever taken big doses of Metformin knows that it can almost make a colonoscopy bowel prep seem tame.

I historically haven’t really cared too much, but what I’ll say is that Metformin seems to blunt some of the beneficial effects of exercise, so although it’s not a useless tool by any means, it’s not my favorite.  But if Metformin is the catalyst to get people who haven’t run in a decade running to the bathroom, then maybe that’s a good thing.  At least it’s not a sulfonylurea.

But today, my good friend and brilliant cardiologist Dr. John Osborne (who is also living proof that Harvard and Yale CAN get along), shared this article that potentially gives us additional mechanistic insights into the Metformin Mystery.  Using mice with metformin-resistant mitochondria IN THE GUT, they found that the usual biologic effects of metformin (including glucose lowering and elevations in GDF15), were not elicited in response to the drug! 

There are some other interesting things in the article associated with glucose disposal, lactate generation, and lactoyl-phenylalanine production, but I sense you may be underwhelmed, so here are a few takeaways from this:

1. This study suggests that the beneficial effects of metformin are primarily due to its effects in the gut rather than the liver, although the downstream effects may result in suppressed hepatic gluconeogenesis.
2. Small intestine mitochondria produce citrulline, which is a precursor for NITRIC OXIDE (NO) production, but since metformin acts in the gut, citrulline production is depleted. (NO is a potent vasodilator and “Guardian of the Endothelium”).  This drop in citrulline has been demonstrated in several human studies of folks on metformin. Since we want to say “YES” to “NO” instead of having less NO, perhaps supplementing with citrulline could restore NO production for those taking metformin.  And perhaps with restored NO production, the deleterious effects of metformin on exercise adaptations could be mitigated as well (since exercise is instrumental in regulating NO production). 
3. BONUS ROUND: GDF15 is elevated by certain types of chemotherapies (cancer treatments) and in hyperemesis gravidarum (the fancy name for when pregnant gals puke their guts out…my Mom had this, which is why there is only one of me).  So the folks who get really sick when taking metformin can probably blame GDF15.

So if you’re taking metformin and your muscle volume is lagging behind your stool volume, maybe supplementing with some citrulline will make your muscles a little more solid than your bathroom output.  Or maybe it’s more complicated…for instance, GDF15 is also elevated in folks with heart failure, but inhibiting GDF15 pharmacologically just made things worse.  As always, there is much more to learn!