I’ve written about metformin quite a few times over the years on the blog, and for several reasons. It is (for starters) obviously a frontline drug for treatment of Type 2 diabetes, a condition that has unfortunately become more and more common in the world as the world puts on more and more weight. (Side note: if any readers do get around to inventing a time machine, a fun afternoon excursion would be to zip back to the 1960s as Paul Ehrlich was writing The Population Bomb. He had predicted mass famines across the globe well before now, and food riots in the US and Europe. See if you can go back and persuade him to revise his famous opening sentence “The battle to feed the world is over” to “The battle to keep the world from getting too fat is over“, and let us know how that goes).

Another reason a drug discoverer would come back to metformin is that it’s a famous example of an extremely useful compound whose mechanism of action has never been fully worked out. Most people outside of medical research would probably imagine that we know how all our drugs work, but that is far from the case, and metformin is up near the head of the list. And even chemically, it’s a worthwhile topic: as I’ve said many times, the molecule is a standing rebuke to the instincts of medicinal chemists around the world, because I feel sure that most of us would have crossed it off a list of screening hits after seeing its structure. Metformin looks far more plausible as almost anything else – a fertilizer additive, a component of marine paint to keep barnacles from attaching to ship hulls, a veterinary deworming agent. Anything other than a multibillion dollar diabetes drug.

Finally, of course, it’s not just a diabetes drug, apparently. That ill-defined MOA bleeds over into other areas entirely, and over the years the compound’s been proposed to have connections (both positive and negative ones) with several other diseases. And if aging counts as a disease (I’m game), then that’s on the list, too. Metformin’s ability to slow the progress of Type II diabetes has been suggested as something that could be beneficial for aging in general, since cardiac/respiratory fitness, mitochondrial biogenesis, and many other metabolic processes are all impaired with age (and this idea is being put to the test). Another way to address those, of course, is with exercise, and the evidence for regular exercise ameliorating Type II diabetes (especially in its early stages) is overwhelming, as is the evidence that it improves overall health with age. There’s also the connection of insulin signaling and metabolism with aging in general (as shown by gene knockouts in model organisms, by the effects of caloric restriction, and by many other lines of evidence.

So why not get these two great therapies together? Well, people have tried that, naturally, but the results have not exactly been synergistic. In fact, if anything, metformin and exercise seem to be working against each other, and this new paper brings more detail to that story. The authors (a multicenter team in Illinois, Colorado, and Oklahoma) studied patients in their early 60s who had no chronic disease but had at least one risk factor for Type 2 diabetes, and who had never taken metformin. For twelve weeks, they engaged in a program of aerobic exercise, and took either metformin or a placebo along with that.

Exercise comes out looking good, as it generally does in such studies. Participants in the placebo group (exercise alone, in other words) lost fat mass, improved their oxygen handling, and decreased their fasting insulin levels. The metformin-plus-exercise group was a bit different, though: some of these metabolic measures improved, but in some cases by not as much, and there was a lot more scatter in the data. Indeed, when they gave participants an oral glucose tolerance test at the end of the study, the exercise group improved across the board, whereas the metformin-plus exercise group had about half the participants improve but the others actually get worse compared to the start of the trial.

Looking down at the cellular level (muscle biopsies, ouch), the differences became even more apparent. Exercise caused an increase in mitochondrial respiration in skeletal muscle, as advertised, but the metformin treatment definitely seemed to interfere with that process (as determined by a number of measures, and especially apparent in ADP titration experiments). The effect seems to be via some intrinsic mitochondrial function(s), rather than on protein synthesis. I’m reminded of the evidence showing that antioxidant treatment actually seems to negate some of the beneficial effects of exercise as well (a result that I keep expecting to make headlines, but which never does).

So there really does seem to be some conflict between the two mechanisms of improving insulin sensitivity, and that makes a person wonder about the whole idea of using metformin for general benefit in aging. It’s definitely helpful for patients who are already showing Type 2 diabetes, but what about the ones who aren’t? And especially, what about the ones who are already exercising? Both the trend for some improvements to be canceled out and the increased variability in the dual-treatment group are worth thinking about – you might, in a large population, end up with some people who aren’t affected by the combination and some who are being done real harm by it. At the very least, you’d want to see if there’s a way to figure out who that second group is up front, and needless to say at the moment we have no idea how to do that.