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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