The Relationship Between Insulin Resistance and Exercise

 A stunning new paper entitled “Molecular Choreography of Acute Exercise,” published on May 28^th, 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 exminations at 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 participants 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.

Take Home Message

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 TGFb). 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 signaling 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. The 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! But the response is weaker if you’re insulin resistant (4,5).

Resources:

1. https://pubmed.ncbi.nlm.nih.gov/32470399/
2. https://pubmed.ncbi.nlm.nih.gov/29057986/
3. https://pubmed.ncbi.nlm.nih.gov/27462049/
4. https://www.nobelprize.org/prizes/medicine/2009/illustrated-information/

Written in collaboration with Nicholas Norwitz, PhD

Beyond being an effective diet proven to assist in the reduction of body fat, reversal of diabetes, and potentially being useful in the management of other chronic diseases, the question remains: is the ketogenic diet actually good for the average person’s health in the long-term? The short answer is that we don’t really know because nobody has done a long-term controlled study in humans. However, some animal data (1) published in one of the world’s most prestigious scientific journals, Cell Metabolism, suggests that it very well might be helpful!

In the aforementioned study, healthy adult mice were split into three diet groups. One group ate a control diet containing moderate-carbohydrate mouse chow, another ate a diet that was low in carbohydrates but not quite ketogenic, and the third ate a proper ketogenic diet. Importantly, all three diets contained equal number of calories so caloric restriction could not impact the experimental results. Fascinatingly, the ketogenic diet group not only lived the longest (their median lifespan was 13% longer than the control mice) but also maintained the best physical strength and cognitive ability into old age!

The scientist also did biochemical tests on the mice to try to determine some of the mechanisms underlaying these data and found some interesting changes in DNA markers (DNA acetylation) and enzyme activity levels (including mTOR) that were consistent with the longevity and health-span results. (As an important aside, the low-carb group tended to perform between the control and ketogenic groups on most tests, including lifespan). While these data need to be replicated, and should be taken with a grain of salt because mice are not humans, they are at least consistent with the hypothesis that the ketogenic diet might be a generally positive lifestyle choice, even for healthy people.

https://www.cell.com/action/showPdf?pii=S1550-4131%2817%2930490-4

Written with the collaboration of Nicholas Norwitz, PhD

 It is quickly becoming common knowledge that ketone bodies are a better fuel for the brain than glucose. But it’s one thing to believe and another thing to understand. If you’re reading this, we figure you want to understand. Be warned, the next two paragraphs get a little bit technical. But we credit your intelligence and have confidence you’re up the challenge.

Let’s start with the big picture. Imagine your brain cells are like cars. Brain cells running on glucose are like a gas-guzzling Hummer H2s. They are clunky, inefficient, and produce a lot of pollution. By contrast, brain cells running on ketones are like new Tesla roadsters. They are faster, more efficient, and produce very little population. 

So, brain cells on glucose are slow and dirty Hummers, whereas brain cells on ketones are fast and clean Tesla roadsters. This analogy is meant to ground you, but it still doesn’t offer true understanding. Dig your trends into the asphalt and rev your engine because we are about to drive deep into your brain cells and talk mechanism!

Your brain cells’ car engine is called its “mitochondria.” Mitochondria are what turn glucose and ketones into energy. How they do so is complicated but involves converting the energy stored in glucose and ketone molecules’ chemical bonds into “high-energy electron particles.”

Let’s imagine these high-energy electron particles like bowling balls sitting at the top of a flight of stairs. To produce energy, your mitochondria brain cell engines roll the electron bowling ball down the stairs. Each bump releases energy that your brain cells can use to do work. You can think of the accumulated amount of noise produced with each “crash, crash, crash” as the amount of energy your brain gets from each electron particle.

In our bowling ball stair analogy, when your brain is using glucose the staircase is short and the stairs are made of wood. Therefore, there are fewer “crashes,” less energy is produced, and the wooden stairs are damaged in the process. (In brain cells, these processes are respectively referred to as a short “electron transport chain redox span” and elevated “reactive oxygen species” production.)

However, when your brain is using ketones, the staircase gets longer and the stairs turn into stainless steel. Therefore, more energy is produced as the high-energy electron bowling balls made from ketones crash down more stairs. What’s more, the stairs are now stronger and resistant to damage. (In brain cells, these processes are respectively referred to as an expanded “electron transport chain redox span” and decreased “reactive oxygen species” production.)

 Let’s review. At the big picture level, brain cells on glucose are like inefficient and dirty Hummers and brain cells on ketones are like efficient and clean Teslas. This is because, at the molecular level, glucose produces electron bowling balls that bounce down short wooden mitochondria staircases, creating less energy and more damage. By contrast, ketones produce electron bowling balls that bounce down long steel mitochondria staircases, creating more energy and less damage.

Written with the collaboration of Nicholas Norwitz, PhD

 “Autophagy” is a hot topic in nutrition science, particularly as relates to brain health. The discovery of autophagy-related genes was awarded the 2016 Nobel Prize in Physiology or Medicine, and autophagy is often touted as the abstract biological reason fasting is good for you. But for those who don’t have a medical or science degree, what the heck is autophagy?

Here’s a fun analogy! Imagine you’re running a bakery with no trash cans. Ideally, you’d love for every ingredient to be used and for every crumb of every pastry to be eaten. Unfortunately, that’s unrealistic. In other words, you need a way to dispose of the waste. Because you have no trash can, you have two options. First, you can grind up all the excess and try to flush it down the toilet. This could work for a bit, but it may not work forever. Plus, it’s pretty wasteful. Your second option is to get creative with the leftovers! Rather than flushing old bananas you meant to use for your banana foster, mash them up and bake them into banana bread. Rather than throwing out the stale sourdough, make crotons!

These two options (flush down the toilet or get creative and recycle) are akin to the options your brain bakery has for dealing with its cellular waste. It can try to flush excess down the toilet (by grinding it up using a molecular food processor called the proteasome and attempting to flush metabolic by-products out via out glymphatic system) or it can get creative and recycle the excess to make new and useful microscopic bits and pieces! You guessed it; the second option is “autophagy.”

Autophagy is a cellular recycling process in which waste (including old and damaged proteins and mitochondria) is wrapped into a package called an “autophagosome.” The autophagosome fuses with another package called a “lysosome” and the contents are broken down into their constituent parts. These parts can then be used to refresh and renew your brain cells!

So how do you activate autophagy in the brain? One sure-fire way to do so it through intermittent fasting. In mice, brain autophagy begins after about 24 hours of fasting. Unfortunately, we don’t yet know how long you need to fast to activate autophagy in the human brain (because the experiments we would need to perform to find the answer would require sacrificing human subjects). Other ways to potentially activate autophagy include achieving ketosis and through exercise. By combining these techniques (intermittent fasting, ketosis, and exercise), you can maximize autophagy, help optimize your brain health, and potentially protect yourself against diseases like Alzheimer’s disease, Parkinson’s disease, and migraines.

Your brain is a bakery. Get creative. Recycle ingredients. Don’t waste the yummy goods!

https://www.ncbi.nlm.nih.gov/pubmed/20534972

Written with the collaboration of Nicholas Norwitz, PhD

For decades, the advice for losing weight has been rather simple “Eat less, move more,” or even “Eat fewer calories than you burn!” However, despite the seeming simplicity of it and the willingness of millions to follow it, it seems that we just can’t get rid of those extra pounds. It could be, as many have put it, that the patients simply have no willpower or discipline to follow said rules -- or could it be that the advice itself is wrong? The fact that this weight-loss prescription has an estimated 99.4% failure rate (99.9% for the morbidly obese) seems to suggest that it is time to reconsider the efficacy of such a paradigm and come up with alternative models.

The traditional equation suggests that the fat in our bodies is a result of (calories in) minus (calories out): a simple explanation, but fatally flawed. The first mistake it makes is that it does not distinguish between types of calories, it simply assumes that the only important variable is the number of calories consumed. But do olive oil and sugar have the same metabolic responses from the body? No! While the former is absorbed through the small intestine and transported to the liver, causing neither a rise in insulin nor in blood glucose levels, the latter (sugar) does raise both, provoking a response from the pancreas. It is quite clear that not all calories are created equal.

This model also assumes that fat storage is unregulated by hormones. Actually, every vital function and system of the human body is autonomically regulated by hormones: blood glucose by insulin and glucagon, height by human growth hormone (HGH), sexual maturity by estrogen and testosterone, body temperature by thyroxine, and countless others. The gastrointestinal, respiratory, circulatory, hepatic and renal systems (just to provide a few examples) are all tightly regulated by hormones and are certainly not controlled consciously. On the other hand we are led to believe that the growth of fat cells is essentially unregulated, so that the simple act of eating will result in fat growth.

This is far from the truth, as nowadays they are still discovering new hormonal pathways in the regulation of fat growth; the most famous of all is leptin, although others play a role in it too, like adiponectin, hormone-sensitive lipase, lipoprotein lipase and adipose triglyceride lipase. This also makes us realize that, given that hormones regulate fat growth, then obesity is a hormonal disorder, not a caloric one.  

This also connects to the myth that the decision to eat or not, or even to feel hungry is mostly if not entirely conscious. The truth is that we consciously decide to eat in response to hunger signals that are hormonally mediated, in that same fashion we stop eating when the body sends signals of satiety, also hormonally mediated. This explains why we may respond to the same smell of delicious food in a different fashion before and after having a large meal; of course the smell is the same, but the body’s response is not. This is indeed also under automatic control, just as you cannot decide consciously when you need to breathe or pump blood.

Perhaps the most important mistaken assumption of the calorie-counting model is that it assumes that the caloric intake and expenditure (calories in and calories out respectively) are two completely independent variables, and not linked together. This is said in part because although energy intake is very easy to measure (by the food you eat), energy expenditure is more complicated, being the sum of basal metabolic rate, thermogenic effect of food, non-exercise activity thermogenesis, excess post-exercise energy consumption and exercise. In reality, the problem of fat-storing is one of energy distribution, with too much energy being divested to producing fat instead of heat, muscle or bone production (just to mention some), so many obsess about calorie input when output is far more important; and, worst of all, the truth is we cannot decide the ways in which the body spends that energy

Many experts however ignore this and choose to focus solely on exercise as the only way energy is spent. They assume the fact that the rest of energy expenditure remains constant and that caloric expenditure is not linked in any way to caloric intake, so their theory is that if you eat less and are spending the same amount of energy (or even more, with the exercise) you have to lose weight. This is false, these two processes (intake and expenditure) are linked, and total energy/caloric expenditure is not constant. In fact it can go up or down by as much as 50% depending upon the caloric intake (among other factors) to maintain energy balance. So, for example, a 40% reduction in calorie intake is counterbalanced by a 40% reduction in calorie expenditure. In simpler terms: Calories Out does respond to Calories In, and in ways that are out of our conscious control, so if you consume less calories, your body is going to adjust to spend less energy, with the net result being no weight-loss at all.

This was demonstrated by one of the most ambitious nutrition studies ever done: the Women’s Health Initiative. This randomized trial evaluated the calorie-reduction, low fat approach for weight-loss in almost 50,000 women. One group of these women was encouraged through intensive counseling to reduce their daily caloric intake by 342 calories and to increase their level of exercise by 10%, the expected result was that they would lose an average of 32 pounds every single year. However, when the final results 7 years after came, to the surprise and disappointment of the health experts, virtually no weight loss had occurred despite good compliance of the subjects, not even a single pound.

It is no surprise then that this great rebuke of the caloric-reduction approach was simply ignored, with no effort to adjust that model or to look for better explanations on the part of its defenders; the studies and statistics that have proved time and time again that this effort leads to failure on the vast majority of cases were forgotten and discarded, recurring to the same old strategy of blaming the patients for said failure: “It is them who are not complying, it is them who do not have the willpower to live healthy”. Having said that, this story does not end here, as we have not yet answered the most important question of all regarding this issue, because…if calories do not cause obesity, then what does? This, dear readers, we will examine in detail in another article very soon, to give it the attention it deserves.

[This article was written based on information found in The Obesity Code and The Diabetes Code, both by Jason Fung].

In the world of nutrition and health, it is very common for a new diet, a new method or a new “miraculous cure” to appear almost every day. Apart from being rationally skeptical of any kind of definitive cure for anything, I think we should be able to overcome the ever-present ad novitatem fallacy (the idea of something being better or superior just because it is new) and look to the past –as well as to the present- for answers.

A good example of past traditions being useful in the way we conceive health is the revival of fasting, a practice that goes back in a medical context to the father of modern medicine himself, Hippocrates. Even though it has been present as part of our lives as humans in almost every culture and religion for millennia, fasting (more specifically intermittent fasting) has made a comeback since 2012 with the help of doctors such as Michael Mosley, Jason Fung, and journalist Kate Harrison, among others.

But what is intermittent fasting? In a nutshell it consists of the voluntary abstinence of food for certain periods, be it hours or even days. The main objective of the fast is to deprive the body of glucose, so that it turns to other sources of energy such as glycogen (excess glucose stored in the liver) and fat, the last functioning as the long term food energy storage. This not only helps the body to burn said fat and lower insulin levels, but also produces other many benefits, depending on the fasting regime you are following.

One is the production of ketone bodies, which is one of the products of said breakdown of fat stores (called triglycerides); ketones can then be used to supply approximately 75% of the brain’s energy needs, as they are capable of crossing the blood brain barrier (a thing that not all forms of fat can do). Another positive is that not only do the insulin levels go down -and blood glucose too, in a span as short as 24 hours- but regular fasting, by routinely lowering insulin levels, can improve insulin sensitivity; this is very important because the main factor driving type-2 diabetes is insulin resistance, and regular fasting can help significantly with this.

Another byproduct of this is that fasting rids the body of excess salt and water, as insulin causes salt and water retention in the kidney; this in turn helps to reduce blood pressure slightly, while decreasing LDL-cholesterol and triglyceride levels. It is also beneficial for losing weight, first by producing results that are almost twice as better as those of bariatric surgery patients. But even in studies comparing fasting approaches to caloric restricted diets, the fasting groups not only lost more weight generally, but lost twice as much of the dangerous visceral fat.

Talking about cancer, fasting provides many benefits. It lowers the activity of IGF-1, a hormone associated with cell proliferation in many cancers; it also lowers pro-inflammatory cytokines like IL-1β and IL-6, both known cancer promoters. On the other hand it promotes mechanisms in our body that can help fight cancer, like limiting cell growth and proliferation, or promoting autophagy, a process where damaged or inefficient cells are sacrificed for economizing purposes, including the dysfunctional mitochondria in cancer cells.

Finally, it can improve your cognitive readiness. When you eat, blood goes to your digestive system to deal with the great influx of food, leaving less blood for brain function, this helps to explain why you may feel sleepy and not very alert after eating large meals; fasting does precisely the opposite, allocating more blood to your brain.

Now we know that fasting has been around for many millennia for a reason, not only as a significant part of religious rituals, but because it has many benefits for our health, of which the ones shown before are just only one part of the picture of what this practice can do for us. Of course, as always, if you have found this could be an option that seems suitable for you, we encourage you to start with the assistance and guidance of a nutritional expert or a physician. In the following articles we will expand on this subject, tackling common myths surrounding this practice and the best ways to start.