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Insulin Resistance Blocks the Benefits of Exercise
New Report Suggests (May 2020)

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A stunning new paper entitled “Molecular Choreography of Acute Exercise,” published on May 28th, 2020 in the prestigious journal Cell ( 1), reported that insulin resistance blocks the benefits of exercise.

But before we tell you about exactly what this paper discovered, let’s review what they did. For this study, scientists took 36 participants with different degrees of insulin resistance and made them exercise.

Before exercise, as well as 2, 15, 30, and 60 minutes after exercise, the scientists took bloods from the participants and did an incredible array of “multi-omic” tests on each sample. These weren’t your standard lab blood tests. Far from it! These were in-depth examinations of the participants’ transcriptomes, metabolomes, proteomes, lipidomes, and immunomes. These “omes” (hence the term “multi-omics”) were then integrated with each other, as well as with more information about the participants, to get an unprecedented look at how exercise impacts the human body at a systems level.

The study reported many incredible results (10 of which we highlight in the take home messages below), but let’s focus most heavily on one.

The human body is supposed to respond to exercise with cellular responses that collectively make the body adapt and get healthier, but, in the authors’ own words, “most of these processes were dampened and some were reversed in insulin-resistant participants.” For example, the “fitness inflammatory signature” that is supposed to occur 15-minutes after exercise as a signal to the body to adapt, was blunted in insulin-resistant participants, even though insulin-resistant subjects had greater inflammation at baseline.

30% of proteins and 10% of other metabolites even diverged in opposite directions in insulin-resistant subjects, as compared to healthy insulin-sensitive subjects. These opposite responses included the “protein ubiquitination pathway” (important in cellular cleanup, similar to autophagy) and omega-3 fatty acid signaling (yes, those healthy fats in fish are signaling molecules).

In layman’s terms, this suggests that when a person is insulin-resistant and exercises, some of the “good molecules” that are supposed to go up, go down instead, and vice versa for the “bad molecules.” From a fifty-thousand-foot view, this makes sense. Insulin resistance is a marker of metabolic dysfunction. Why should we expect a body with a dysfunctional metabolism to respond adaptively to exercise?

Does this mean if a person is overweight and insulin-resistant s/he shouldn’t exercise? Not exactly. But it does suggest metabolic health is a predecessor of exercise. In other words, if you’re overweight and insulin resistant, it’s important to get your nutrition in order first. Food is more than fuel.

Insulin resistance, which is strongly associated with being overweight, blocks the benefits of aerobic exercise at the cellular level.

Top 10 Findings From the Paper

Rather than give our standard take home messages, here are our top 10 findings from the paper:

  1. Insulin resistance, which is strongly associated with being overweight, blocks the benefits of aerobic exercise at the cellular level.

  2. The “fitness inflammatory signature” refers to the acute inflammatory response that is supposed to occur about 15 minutes after exercise to signal to the body to adapt. (It appears to be driven by the molecules IL-5 and TGFβ). This response is blunted in insulin-resistant individuals.

  3. While most fatty acids decreased in response to exercise because they were burned as fuel, the omega-3 fats, EPA and DHA, went up after exercise. This is likely because omega-3 act as anti-inflammatory signalling molecules and initiate an adaptive response to compensate for the inflammatory effects of exercise.

  4. In insulin-sensitive participants, the “protein ubiquitination pathway,” which important in cellular cleanup, like autophagy, went up. In insulin-resistant participants, it went down!

  5. There was a wide variation among participants in responses of the hunger and fullness hormones, ghrelin and leptin, to exercise. This predicts exercise will make different people hungry (or not) to varying degrees.

  6. Exercise stimulated the release of thyroid hormone, the metabolism boosting hormone.

  7. Exercise stimulates the release of insulin. This response is meant to drive glucose as fuel into muscles during exercise. However, the insulin spike in response to exercise is overblown in insulin-resistant individuals, suggesting they are more likely to go hypoglycemic in response to exercise.

  8. Exercise stimulates an increase in fatty acid binding proteins that help the heart and skeletal muscles suck up fat and burn it for fuel.

  9. Hippuric acid is a marker of gut microbiome diversity ( 2), which is assumed to be good. Hippuric acid also predicts maximum oxygen consumption (peak VO2), which is among the best predictors of longevity ( 3).

  10. Telomeres are the measuring sticks of cellular age. Telomerase is the enzyme that builds up telomeres. (The discovery of telomerase won Elizabeth Blackburn, Carol Greider, and Jack Szostak the 2009 Nobel prize in Physiology or Medicine). Telomerase signaling was increased for 60 minutes after exercise, suggesting exercise helps to reverse cellular aging! However, the response is weaker if you’re insulin resistant ( 4,  5).

If you’re overweight and insulin resistant, it’s important to get your nutrition in order first so that your body is metabolically ready for exercise. Food is more than fuel.

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Nicholas Norwitz
MD-PhD candidate at Oxford University

Nicholas Notwitz

Nicholas Norwitz is a Harvard medical student and Oxford PhD researcher who specializes in ketone metabolism. He a rising star in the scientific community, with peer-reviewed publications on topics ranging from brain health to bone health to heart health to gut health.

Informed by his own medical history, he has an infectious passion for food as medicine and a drive to find innovative ways to teach the general public about the latest nutrition science.

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Comments (8)

In your blog post it just mentions exercise but not the specific type of exercise. Did the study share whether it was referring to steady state cardio, hiit and/or weight lifting? Do you think the results would be the same no matter what type of exercise one was doing? Thanks!

Reply

For these type of studies steady state is the standard. Easier to study. Yes, for this study I suspect the findings are generalizable.

Reply

Very nicely written. Thank you for this. Question: does the fact about omega 3 going up after exercise as a compensatory response mean I should eat salmon after a run?

Reply

Really great question! I’m going to say yes, but not for the reasons you’d conclude from the above blog post. I would guess that the DHA you get from eating salmon after exercise isn’t going to get into your blood quickly enough to be useful in the compensatory response to the “fitness inflammatory signature” although I could be wrong on that point.
More importantly, I’m going to quote from a 2019 review in Frontiers in Nutrition. “Recently, data have emerged demonstrating a positive influence of omega-3 fatty acid intake on skeletal muscle. For instance, there are reports of clinically-relevant gains in muscle size and strength in healthy older persons with omega-3 fatty acid intake as well as evidence that omega-3 fatty acid ingestion alleviates the loss of muscle mass … The primary means by which omega-3 fatty acids positively impact skeletal muscle mass is via incorporation of EPA and DHA into membranes [of skeletal muscle cells]. Enrichment of EPA and DHA in these membranes is linked to enhanced rates of muscle protein synthesis and decreased muscle protein breakdown.”
Basically, the above is saying that the omega-3s in fish help in muscle building and recovery by getting used to make and shape muscle cell membranes. There’s also probably an anti-inflammatory effect that is beneficial, at least in protecting against muscle breakdown, as well. There’s actually a lot of clinical evidence that omega-3s are good for muscles, but not much is known about the exact mechanisms.
Moral of the story: eat your salmon (Wild Alaska Sockeye is the healthiest because it has the most “astaxanthin” antioxidant that makes the salmon pink-red.)
www.ncbi.nlm.nih.gov/pmc/articles/PMC6742725/

Reply

I heard being on a ketogenic diet for a long time can make you insulin resistant. Myth?

Reply

Yes, to the best of my knowledge it’s a myth, but a complicated one. Here’s the deal… people talk about two types of insulin resistance, “pathological insulin resistance” and “physiological insulin resistance.”
Pathological insulin resistance is the bad type and is associated with diseases like diabetes and being overweight. It occurs when your body is exposed to too much glucose and insulin and starts to ignore the insulin signal similar to how you might habituate the sound of a fan that is constantly on in the background while you work.
Physiological insulin resistance is a “good” adaptation, in which, because you’re eating low-carb, your muscles don’t suck up as much glucose so that little bit of glucose that is there can go to the brain. This is the adaptation you want, otherwise your muscles would burn sugar and then your body might have to break down muscle to make more glucose for the brain, as ketones can’t fuel the brain 100% (60-70% max). BUT…
Physiological insulin resistance, although it’s a term thrown around, isn’t actually insulin resistance. Instead, your body, when you’ve been low carb for a while, decides not to release as much insulin in response to glucose. This isn’t insulin resistance because if you give a low-carber an injection of insulin her/his response will be as strong as normal or stronger. In fact, people who have been low carb for a while are profoundly insulin-sensitive, in general.
What I’m saying, in two sentences, is that being low carb makes you insulin sensitive, not insulin resistant. The nuance is that you can become temporarily and adaptive “glucose intolerant,” which is fine and is an adaptation that can be reversed if you slowly re-expose yourself to carbs.
Hope that helps. Good question!

Reply

That’s all amazing. I was particularly interested in the note about hippuric acid as is fascinated by the microbiome. What more do you know about it?

Reply

I’ll be honest, the hippuric acid comment in the paper caught me of guard. I’d never heard of it myself, which surprised me because I’ve read a lot of microbiome literature. Before writing the blog post, I read up a bit on the molecule.
It turns out, it’s not so black and white as high hippuric acid is good. It’s true that
Hippuric acid been reliably reported to associate positively with microbiome diversity and negative with metabolic syndrome, but these are just associations drawn from studies done in animals and people on higher carb diets. The findings may not apply to low-carb and keto. There are a few more caveats…
Hippuric acid levels are associated with diets rich in whole grains and fruits, which I personally don’t consider to be universally healthy foods. They are certainly not low carb. That said, you/your bacteria can also make hippuric acid from the polyphenols in coffee and tea (particular the catechins found in green and black tea).
Hippuric acid is a glycine-bound form of benzoic acid. In fact, the addition of glycine is the rate limiting step of hippuric acid synthesis. For this reason, glycine supplementation (and presumably the consumption of glycine rich foods like bone broth, collagen peptides, and pork rinds) boosts hippuric acid levels.
Finally, hippuric acid has also been used as a urine measure of toxin exposure, particularly to toluene, which is found in permeant marker and some glues. So, if you eat glue, your hippuric acid may go up, but that’s probably not going to protect your microbiome nor metabolic syndrome.
In truth, the hippuric acid comment was the single comment in the blog post I almost didn’t include. I chose to include it in the end because, as stated above, the information is correct and I think it’s a worthwhile “fun fact,” if nothing else.
As you can see, there is a bit too much nuance about hippuric acid to include above in the main text so I’m really glad you asked this question. Thank you.
pubmed.ncbi.nlm.nih.gov/29057986/
pubmed.ncbi.nlm.nih.gov/23342949/

Reply