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Aging and Lifespan

Metformin and Exercise

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.

17 comments on “Metformin and Exercise”

  1. dearieme says:

    The danger of a bad memory: I was convinced I’d been told that metformin came from feverfew. But WKPD tells me it comes from “French lilac or goat’s rue”. So I would have been wasting my time munching feverfew. Could I have confused it with this?
    https://www.ncbi.nlm.nih.gov/pubmed/24125916

    “more and more common in the world as the world puts on more and more weight”: no doubt. But in Britain it has also got more and more common because (i) the definition was changed in a direction that made it commoner, and (ii) the GPs of the NHS were given handsome financial rewards for every case they diagnosed.

    1. luysii says:

      Dearieme: Excellent point. Distinguish (in the USA) obesity (BMI > 30) from overweight (BMI between 25 and 30). In fact over age 50 the lowest mortality occurs with BMIs in the ‘overweight’ range. For details

      https://luysii.wordpress.com/2019/03/05/if-you-are-over-50-its-healthier-to-be-overweight-than-not/

      1. Barry says:

        these mortality comparisons by BMI are bedeviled by people who are lean or emaciated because of underlying disease.

        1. luysii says:

          The data is based on 3 million people — have a look — https://jamanetwork.com/journals/jama/fullarticle/1555137?__rtqa=f4c5e818aba04f769cfc65207b2199b9

          I doubt that the 1% of the cohort which would be expected to die each year would seriously skew the results.

          1. MTK says:

            A problem I have with BMI are the labels of “overweight” and “obese” themselves. Even ignoring the fact that BMI does taking into account body type and composition, these labels skew how we think about BMI.

            If one removes those labels and just looks at the numbers and correlations then none of it seems particularly counterintuitive, i.e. optimal BMI rises with age. It’s only when you deem >25 “overweight” that one starts to think something is amiss.

        2. Scott says:

          BMI is just a crappy metric all around. It compares your weight to the square of your height. Whatever happened to the square-cube rule, where something twice the size is 8x the weight?!?

          Shaquille ONeal and Yao Ming were considered obese by BMI when they were playing. Shaq is 7’1″ and 324lbs for a BMI of 31.5, Yao Ming must have lost weight since the last time I looked since he’s now 7’6″ and 310lbs for a BMI of 26.9. Sun Mingming is 7’9″ and 370lbs for a BMI of 30.1, and Manute Bol was 7’7″ and 201lbs for a BMI of 20.0.

          When I got out of boot camp I was 6’0 and 178lbs for a BMI of 24.1. I had a 30″ waist, a 48″ chest, and a 17″ neck. Several doctors I have told that have told me that I was underweight at that time, given my barrel chest. Now, sure I’m overweight. A broken back makes it hard to do cardio, I’ve blown up to 275, but I still only wear a size 50 suitcoat.

  2. luysii says:

    MTK — well the people had Harvard had a problem NOT calling a BMI > 25 overweight. Here is a bit more repartee on the subject —

    “Naturally this did not sit well people who’d staked their research careers on telling people to lose weight. One study by a Harvard guy removed 900,000 people from the JAMA study. Robert Eckel, an endocrinologist at University of Colorado in Denver made the great comment that “It’s hard to argue with data. We’re scientists. We pay attention to data, we don’t try to un-explain them.””

  3. sgcox says:

    Any idea what happened to Retractionwatch ?
    My guess somebody took revenge..

  4. 1234 says:

    Could some one suggest whether should I be not taking Metformin while I am exercising ( say in summer) and take it in the winter when I am not that active outdoor? I am confused! I thought they should after all be synergistic as both of them lower the blood glucose levels.
    Should I be cutting the dosage of Metformin to factor in the exercise part, once 500mg instead of 2X 500mg? Looks like I would have to either shift to something compatible with exercise or just go with exercise!

    1. Lauren says:

      You should certainly take what you healthcare provider has prescribed to you but it is important to see what blood sugar response is to exercise and if Metformin is causing a negative effect. I am trainer at GlucoseZone and work with many people with diabetes who are on Metformin and still see results and improvements in their diabetes metrics. The best thing to do is to continue to exercise and make sure you are doing the right exercise at the time based on your blood sugar.

  5. Tim says:

    “Metformin looks far more plausible as almost anything else – a fertilizer additive, a component of marine paint to keep barnacles from attached to ship hulls, a veterinary deworming agent.” I love it when the sense of humor shines thru!

  6. Charlie says:

    Isn’t this just that mitochondria don’t have much of a stress response system , so you need to stress out the cell to turn it on. Metaforim may just be blocking part of that

  7. Terry says:

    Rosiglitazone stimulates mitochondrial biogenesis in diabetic adipose, and increases the types of fuel mitochondria can utilize. We thought we knew the MOA of rosiglitazone, but evidently it does more than suspected. Bring back phenotypic screening…

  8. Lane Simonian says:

    Exercise and metformin both activate the AMP-activated protein kinase. So too does resveratrol. And the combinations of these may have a negative impact on some people.

    Also long term activation of this kinase may result in health problems especially in those with already existing health problems.

    https://blogs.sciencemag.org/pipeline/archives/2017/08/03/ampk-time-to-think-hard

    https://onlinelibrary.wiley.com/doi/full/10.1111/j.1471-4159.2011.07331.x

  9. D says:

    Quite: Metformin looks most like something that some obscure branch of life leaves caked on cliffs which can be mined and turned into plastic explosive.

  10. MN says:

    its in the genes why there is a differential response, trust me on this (I’m in the genetics business). They should have genotyped the exercise study participants first…

    https://www.ajmc.com/newsroom/different-responses-to-metformin-its-in-the-genes-study-finds

  11. Sean Maguire says:

    Peter Attia has some intersting and informed perspective on metformin, anti aging and exercise.
    https://peterattiamd.com/metformin-and-exercise/

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