Metabolic Breakdown? Metabolic Syndrome, ME/CFS, Fibromyalgia and Long COVID

Are people with ME/CFS, fibromyalgia and long COVID at risk for major metabolic problems?

We hear a lot about metabolic problems (impaired fatty acid synthesis, preferential amino acid utilization, altered lipid metabolism) in chronic fatigue syndrome (ME/CFS) but surprisingly little about the other metabolic problems (metabolic syndrome, liver disease, and type II diabetes) that have become increasingly commonplace and receive much more attention.

Warning bells began chiming for me as I was reading Peter Attia’s “Outlive: the Science and Art of Longevity“. Peter Attia, who got his MD at Stanford, then spent five years as a general surgery resident at Johns Hopkins, opened a practice focused on longevity in 2014.

Metabolism has played a major role in Attia’s approach to longevity. It turns out that if you can get your metabolism under control, your risk of having many serious conditions that typically occur later in life (cancer, cardiovascular disease, Alzheimer’s) goes down dramatically.

One of the reasons Attia opened his longevity practice is his – disgust is not too strong of a word – at the way in what he calls “Medicine 2.0” modern medicine sweeps warning signs of a looming metabolic breakdown under the rug.  Stating that it “boggles” his mind, and is “beyond backwards”, Attia is clearly tweaked that doctors aren’t watching things like hyperinsulinemia (insulin resistance) as carefully as they do, say thyroid or cortisol levels.

Only when the patient reaches the stage where they have type II diabetes does anything significant often occur. By then, a lot of avoidable damage has already occurred.

Metabolic Syndrome

Metabolic syndrome is a good example of what Attia believes constitutes a massive failure of our medical system. If you meet three or more of the below criteria, you can join as many as 120 million other Americans who have metabolic syndrome:

• High blood pressure (>130/85)
• High triglycerides (>150 mg/dl)
• Low HDL cholesterol (<40 mg/dl in men or <50 mg/dl in women)
• Central adiposity (waist circumference >40 inches in men; >35″ in women)
• Elevated fasting glucose (>110 mg/dl).

Once you have metabolic syndrome, you’re at increased risk of a bunch of nasty conditions: atherosclerosis, high blood pressure, non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, sleep apnea, low-grade inflammation, increased risk of breast, liver and colorectal cancer, blood clotting disorders, type II diabetes, and – not surprisingly – reduced life expectancy.

Should you progress to type II diabetes – as 40% of the people with metabolic syndrome who don’t intervene do – you’re in a world of hurt. Again, you won’t be alone – about one in 9 people in the U.S. have type II diabetes – but your risk of heart attack, stroke, nerve damage, digestive, kidney, and vision problems, cancer, osteoporosis, and erectile dysfunction, etc., go up dramatically. It’s not a happy place to be.

Yet, Attia believes that simple interventions done early could prevent all that. If only the patients knew about them – which brings us to diseases like chronic fatigue syndrome (ME/CFS), fibromyalgia, and long COVID.

Metabolic Risk Factors in ME/CFS, Fibromyalgia, and Long COVID

The sedentariness, inability to exercise much, and problems sleeping are red flags suggesting that people with ME/CFS, FM, and/or long COVID may be at increased risk for metabolic syndrome, diabetes and other metabolic disorders. The relationship between being sedentary and these metabolic disorders is well known – as is how effective exercise is at battling them – but the sleep issue is less well known.

Several studies have found that reduced sleep results in increased fasting insulin levels the next day, but there are some qualifiers. The sleep restriction lasted one night, and was generally pretty intense (4 – 4.25 hrs), and studies exploring less sleep restriction (4-5.55 hours) found lower fasting insulin levels. Plus, one longer-term study which found no reductions in insulin sensitivity suggested that the body may be able to adapt.

Chronic Fatigue Syndrome (ME/CFS)

A large CDC study, “Chronic fatigue syndrome is associated with metabolic syndrome: results from a case-control study in Georgia“, (ME/CFS – 111; fatigued but not ME/CFS – 259; healthy controls – 123), found that people with ME/CFS were twice as likely as the healthy controls to meet the criteria for metabolic syndrome (MetS). Plus the more MetS criteria a person with ME/CFS met, the more fatigued they tended to be.

It was striking to see a recent UK Biobank preprint highlight, out of all its finding, evidence of “chronic inflammation, insulin resistance and liver disease”. Earlier in a hypothesis paper, Wirth and Scheibenbogen proposed that insulin resistance found in the muscles in people with ME/CFS “may only represent a broader disturbance of cellular metabolism”. If I have it right, they suggest that the mitochondrial problems in ME/CFS may be one driver of insulin resistance.

Increased levels of triglycerides – a key component of insulin resistance – have been found several times in ME/CFS.

Fibromyalgia

Several fibromyalgia studies have found an increased incidence of metabolic syndrome (MetS). A large 2020 fibromyalgia study, “Coexistence of fibromyalgia and metabolic syndrome in females: The effects on fatigue, clinical features, pain sensitivity, urinary cortisol and norepinephrine levels: A cross-sectional study“, found that people with FM had a 4 times higher risk for metabolic syndrome than healthy controls. (Twenty-four percent of FM patients and 8% of healthy controls met the criteria for metabolic syndrome.) High triglyceride levels, in particular, were signaled out, and pain levels appeared to be associated with MetS patients as the FM patients with MetS had the highest pain ratings as well.

The authors attributed the increase in metabolic syndrome to pain-associated disability, sleep disturbances, inactivity and increased weight. Other studies have found increased rates of insulin resistance, diabetes mellitus, higher triglycerides and total cholesterol. Even though body mass indexes were similar between FM patients and the healthy controls, the FM patients had a higher waist/hip ratio and a higher insulin resistance rate – indicating they were probably more predisposed to metabolic problems.

Uncontrolled hypertension was common – and related to quality of life measures – and many patients were not getting high blood pressure medication. The authors warned that the combination of MetS and fibromyalgia produced “an important risk factor for cardiovascular diseases and mortality“.

Likewise, a large Danish study, “Lipid metabolism and functional somatic disorders in the general population. The DanFunD study“, which examined people with ME/CFS, chronic widespread pain (CWP), irritable bowel (IBS), and bodily distress syndrome (BDS), found a positive association between these syndromes and elevated glucose, HbA1c, insulin levels, and insulin resistance. Obesity was not a major factor.

Tracking Your Metabolism with Medicine 3.0

Instead of waiting for metabolic syndrome or type II diabetes to show up, Attia proposes a “Medicine 3.0” approach that attempts to nip metabolic problems in the bud. This part of the blog will explain more about the metabolic issues in question and will highlight the metabolic tests Attia uses. While many of us may not be able to get all these tests done, most of us can probably get some of them done.

People with enough resources to pay for these tests themselves should be able to order most of them without a doctor’s prescription.

The Fat Storage Problem

When we eat carbohydrates, insulin shuttles the glucose produced either into the muscles – if you are exercising – or into the fat cells lying under our skin – if you’re not exercising. At this point, even if you accumulate a lot of fat under the skin, it’s essentially harmless.

Things change when the body starts housing the fat elsewhere in your abdomen, liver, heart, pancreas, muscle tissues, and the blood – where it will start showing up as high triglycerides (one of the metabolic criteria). Now you have pathologic fat – fat which secretes pro-inflammatory cytokines (TNF-a, IL-6).

Healthy fat storage rates range dramatically from person to person. One person may be able to store a lot of fat safely under their skin while another can store very little. This variability in the ability to store fat safely or not goes a long way to explain while some obese people can be healthy metabolically while some skinny people are not. Everyone who is obese, though, will have some form of insulin resistance.

It’s why – diverging from standard medical practice – Attia requires his patients to undergo a DEXA body scan every year to determine how much visceral (bad) fat they’re carrying. Attia believes that storing fat in the muscle cells (instead of under the skin) is the trigger for the development of insulin resistance.

Shulman has found that the best predictor for insulin resistance in muscle was the presence of fat in the muscles. (Fat under the skin is fine; fat buildup in the muscle cells, liver cells, etc., is not.)

The fact that insulin resistance starts in the muscle and then moves to the liver is not great news for exercise-intolerant or inhibited ME/CFS, FM, and long-COVID patients.

Attia Metabolic Test #1 – DEXA Body Scan

Attia requires his patients to undergo a DEXA body scan in order to determine how much visceral fat they’re carrying. If they’re carrying a lot, the goal will be to get those fat levels down. The scan appears to be surprisingly affordable ($100-$300).

The Canary in the Coal Mine – Hyperinsulinemia, or Insulin Resistance

“Hyperinsulinemia is the canary in the coal mine.” —Peter Attia

Insulin resistance occurs when the muscle, fat, and liver cells increasingly “become dead” to insulin; i.e. they no longer respond to insulin’s signal to store glucose in them. With that, as glucose starts building up in the bloodstream, the pancreas, desperate to get glucose levels in the blood down, secretes even more insulin. That works at first – glucose is kept under control – but it’s a sign that the cells are starting to buckle metabolically.

Chronically elevated insulin usually results in weight gain, and increases the risk of atherosclerosis – and puts one “well down the track toward type 2 diabetes”.

Attia has described elevated insulin as “the foundation upon which the major three chronic diseases sit”. He believes charting insulin resistance is as important, if not more important, than charting glucose levels.

If the insulin resistance continues, the pancreas can become exhausted and stop producing as much insulin, causing blood glucose levels to rise and stay risen. Now you’re looking at some serious stuff: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), dyslipidemia (high triglyceride levels), and eventually type 2 diabetes.”

Plus, insulin resistance also disrupts the functioning of AMPK (adenosine monophosphate-activated protein kinase), a master regulator of cellular energy levels within the cells, which has been found impaired in both ME/CFS and FM.

Gerald Shulman, Professor of Medicine, Cellular & Molecular Physiology, and the Director of the Diabetes Research Center at Yale, reports that metabolic-associated fatty liver disease is the leading cause of NASH (non-alcoholic steatohepatitis), liver fibrosis, cirrhosis, end stage liver disease and will soon be shown to be the most common cause of liver cancer.

In fact, Shulman believes that insulin resistance is driving the huge increase in cancers associated with obesity (breast, colon, pancreatic, and liver cancers) and agrees that insulin resistance is a foundational problem for many serious diseases.

“…  lf we can understand insulin resistance, then that’s going to be the best way to fix diabetes, type 2 diabetes, heart disease, we’re going to make a big impact there, fatty liver disease and slow down cancers.” —Gerald Shulman

Attia is so taken with the opportunity that catching hyperinsulemia in its early stages presents that he proposes that it “might have a greater impact on human health and longevity than any other target”.

Attia Metabolic Test #2 and #3 – Fasting Glucose/Insulin and Oral Glycemic Load Tests

Fasting glucose/insulin tests are fairly commonly done, but Attia wants to push the envelope further and do oral glucose tolerance or glycemic load test (OGTT) which provides a big hit of glucose (via a drink), then assesses insulin and glucose levels in 30 minute intervals over two hours.

Attia is looking for a bigger-than-normal jump in glucose and insulin levels followed by sustained elevated levels over the two-hour test period. Those elevations indicate that the muscles have been unable to absorb the glucose provided; i.e. insulin resistance is present.

Attia Metabolic Test #4 – Uric Acid

High uric acid levels can worsen insulin resistance, promote inflammation, promote the progression of metabolic disorders, impair fat metabolism, promote visceral fat accumulations, are associated with triglyceride levels, and contribute to fatty liver disease

Attia Metabolic Tests #5-9 – Homocysteine, ALT Liver Enzymes,  Triglycerides/HDL Cholesterol, VLDL

• Homocysteine – generates oxidative stress, can disrupt insulin signaling, and is associated with elevated triglyceride levels, damages the blood vessels, impairs blood flows to the brain, and promotes neuroinflammation and visceral fat accumulations.
• ALT (alanine aminotransferase) Liver Enzyme – the liver regulates both blood glucose levels and fat (lipid) metabolism. In metabolic syndrome, the liver may start pouring out bad fats, such as triglycerides, that compound the problem. The liver readily gains fat as metabolic problems proceed, leading potentially to, first, non-alcoholic fatty liver disease (NAFLD), then non-alcoholic steatohepatitis (NASH, liver fibrosis, and eventually cirrhosis. Increased alanine aminotransferase (ALT) levels are commonly found in non-alcoholic fatty liver disease (NAFLD). Several recent studies suggest the liver may be involved in ME/CFS.
• Triglyceride/HDL Ratio – Attia believes that triglyceride levels which are more than twice the HDL cholesterol levels constitute a “very big red flag”.A high TG/HDL ratio is strongly associated with metabolic disorders such as metabolic syndrome and insulin resistance. It is “widely recognized as a surrogate marker for insulin resistance” and is associated with increased risk of atherosclerosis, heart attack, and stroke, and promotes (once again) visceral fat accumulations.
• High Triglyceride Levels – Attia believes that the currently accepted threshold for “normal” (150 mg/dL) triglycerides is too high, and that “elevated triglycerides are an under-appreciated warning of poor metabolic health. He proposes that triglyceride levels above 100 mg/dL should be considered abnormal. Triglycerides impair glucose transport into the cell.
• Very-Low-Density Lipoproteins (VLDL) – VLDLs transport triglycerides, cholesterol, and other fats (lipids) in the bloodstream. Increased VLDL levels are strongly associated with metabolic syndrome.

Using a Continuous Glucose Monitor (CGM)

CGMs are available only through prescription and they are not inexpensive ($10/day), but Attia states that using them for a month or two is all that’s needed. Attia has his clients use them to determine which foods – at which times – send glucose levels soaring. Every five minutes, it takes a reading. Attia believes CGMs are far more effective than hemoglobin A1c measurements. The goal is to use the CGM to lower glucose levels and to minimize the variability (spikes) in your glucose levels.

Attia stated that three monitors (Medtronic, Abbott, Dexcom) produce “clinical grade” results and he likes Dexcom best because it can be calibrated.

Treatment

Diet

Many people with ME/CFS/FM and/or long COVID may be ahead of the game because they already have a good diet. Attia thoroughly explored keto diets, and has come to believe that outside of broad outlines (reduced carbohydrates, plentiful vegetables, and fruits, few processed foods, high fiber, sufficient protein, etc.), diets are individual; i.e., different diets work for different people.

Note that if you’re overweight, losing even small amounts of weight (5-10%) can help reduce triglyceride levels.

A Focus on Fructose 

Fructose deserves mention all on its own. Fructose metabolizes into uric acid which is associated with fat gain, inflammation, insulin resistance, etc.

It turns out that fructose is metabolized differently than glucose. When confronted with high levels of fructose, the ATP levels inside a cell drop rapidly, causing us to feel hungry. Plus, high levels of fructose can overwhelm the gut – sending fructose to the liver where it can end up as fat, and impair glucose regulation, etc.

(The fructose/uric acid/fat gain scenario is believed to result from an evolutionary adaptation that occurred when the fruit-loving apes needed to find a way to store fat as the climate cooled. From then on, eating fructose translated into fat storage).

While fructose is the kind of sugar found in fruits, eating fruits is not generally a problem because the fructose enters the bloodstream slowly. (Drinking apple juice, or fruit smoothies, is another matter.)

Note, though, that pure table sugar isn’t much better than fructose; it contains about the same amount of fructose as high-fructose corn syrup. Agave syrup is very high in fructose while blackstrap molasses and maple syrup are very low.

Sweetener	Fructose Content (% by weight)	Notes
Table Sugar (Sucrose)	~50%	Table sugar is sucrose, which is a 1:1 combination of glucose and fructose.
Molasses	~29-40%	Varies by type (light – 29-35%, dark – 20-30%, blackstrap – 10-20%); contains other nutrients like iron and calcium.
Honey	~38-41%	Fructose content is slightly higher than glucose, contributing to its sweetness.
High-Fructose Corn Syrup (HFCS 55)	~55%	Commonly used in sodas; contains 55% fructose and 45% glucose.
Agave Syrup	~56-90%	Known for its high fructose content; varies depending on processing methods.
Maple Syrup	~1-4%	Primarily sucrose; contains only small amounts of free fructose and glucose.
Coconut Sugar	~3-9%

 

Improving One’s Metabolic Health

Ways to reduce insulin resistance – increase fiber intake, eat carbs with protein/fats, eat low glycemic index (GI) foods, take in healthy fats (monounsaturated and polyunsaturated fats – olive oil, avocados, etc.), stay hydrated, lose weight if overweight, get as good sleep as possible, manage stress (meditation, yoga, deep breathing exercises), try intermittent fasting, try drugs (metformin, thiazolidinediones (e.g., pioglitazone)).

Ways to lower high blood glucose levels – eat frequent small meals, increase fiber intake, eat carbs with protein/fats, low glycemic index (GI) foods, drugs (Metformin, Sulfonylureas, SGLT2 inhibitors, GLP-1 agonists), supplements (cinnamon, berberine (works similar to metformin), magnesium, chromium)

Ways to reduce triglyceride levels – Statins, fibrates (fenofibrate and gemfibrozil). niacin (Vitamin B3), high dose Omega-3 Fatty Acid Supplements – can all reduce triglyceride levels. Note that prolonged, high-dose niacin (particularly sustained release) can damage the liver, and niacin can impair insulin sensitivity and increase uric acids levels in the blood.

Metformin

Metformin has got to be one of the most interesting drugs around. Not only can it improve glycemic control and insulin sensitivity but it has immune-enhancing capabilities that suggest it may be helpful in chronic pain.

A recent review paper, “Metformin: A Prospective Alternative for the Treatment of Chronic Pain“, stated: “Data strongly suggest that metformin could open a new avenue for the treatment of pathological pain. The authors believe that metformin’s ability to inhibit mTOR expression may be helping it regulate the activity of out-of-control sensory neurons that are causing so much pain in FM and other diseases. (High glucose levels can damage the nerves across the body.)

Plus, metformin has been found to have many positive effects on the gut, including increasing the levels of butyrate and short-chain fatty acids, and bulking up the integrity of the gut wall – three areas of concern in these diseases. A recent article proposed repurposing metformin to reduce inflammation and oxidative stress, and enhance gut barrier integrity and the gut microbiome in inflammatory bowel disease.

At least five studies/papers on metformin and fibromyalgia/chronic pain have been published. The fact that metformin reduced chronic pain and fatigue in a large UK study suggests insulin resistance may indeed play a role. One study even asked, “Is insulin resistance the cause of fibromyalgia? A preliminary report.“

Exercise

It had to be exercise that, as Attia stated, provides the biggest boost to longevity. Attia noted that “peak aerobic cardiorespiratory capacity” (VO2 max) is “perhaps the most powerful marker for longevity”. Studies have found that having a below-average VO2 max is a greater risk factor for overall mortality than smoking. (Ouch!)

All is not lost, however. Endurance training is, of course, a key part of complete exercise programs – and an hour or two of brisk walking does wonders for insulin resistance and glucose problems. Some people with fibromyalgia may be able to manage that, but that’s clearly out for most people with ME/CFS.

Strength training that mostly taxes the anaerobic energy production system, on the other hand, may be achievable for many more people. Simply building muscle mass and, even more importantly, muscle strength can have surprising physiological benefits.

For years I thought strength training was impossible – perhaps because I pushed too hard or because I had not started my stretching routine or maybe I was just not ready for it. Now I know, that at least for me, strength training is not only possible but helpful. While I doubt that any one of us can do the kind of strength training that Attia advises, many of us may be able to do something.

I’ve found that using exercise bands and doing simple exercises like bent knee pushups and core exercises can be done – if approached slowly – and will quickly increase my strength and even build a surprising amount of muscle pretty quickly. For me, the benefits of doing quite limited exercise a couple of times a week include increased well-being, resilience, ability to concentrate, etc.  Sometimes when I’m lagging, I find that doing a mini workout with an exercise band or a few bent knee pushups can perk me up. All from engaging in what is essentially an anaerobic form of exercise.

The type 2 muscle fibers that strength training improves atrophy quickly when we are inactive and as we get older. Endurance training – even if you could do it – won’t do anything for these muscle fibers – only strength training will get them back.

Strength training takes on an extra emphasis as we age because bone density, particularly for women, diminishes on a parallel path to muscle mass and strength training stimulates the growth of bone. Studies report that osteoporosis is increased in fibromyalgia (and therefore probably is in ME/CFS as well). It doesn’t take much strength training to improve bone density.

First note that any exercise should be done following a meal in order to get the glucose from the meal into the muscle tissues.

Attia focuses strength training around increasing one’s grip strength, lifting and putting down weights slowly and with control, doing exercises that require pulling, and doing things like step-ups, hip thrusters, and deadlifts that strengthen the legs and lower back.

Attia also focuses on “eccentric exercises” which focus on slowly doing the “down” phase of, say, a bicep curl or weight lift. Slow and sure – the opposite of an aerobic workout. Attia also finds that breathing is important (a blog on breathing is coming up), talks about doing “toe yoga” to improve stability and balance and much more in his comprehensive coverage of exercise.

Conclusion

Given the difficulty exercising, the sedentariness, and the sleep problems diseases like ME/CFS/FM and long COVID impose it was no surprise to see studies suggesting high rates of metabolic syndrome may be present. Indeed, it would have been surprising not to see them.

Pete Attia MD puts metabolic problems at the very crux of many of the chronic diseases that damage our health and shorten our lifespans. He believes our medical system should be actively searching out and identifying and treating metabolic problems well before they reach the metabolic syndrome stage.

Not everyone will agree with Attia’s aggressive approach but for those who do Attia provides guidelines on what to look for.  Ultimately we need to solve these diseases to eliminate the risk of metabolic breakdown and thankfully research is focusing more and more on the metabolism. Until then we have what we have. While Attia’s favorite remedy for metabolic issues – exercise – is beyond the reach of people with these diseases, other options – small amounts of strength training, better diets, supplements, and drugs may help.

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This blog says a lot about what Health Rising does. Virtually no one talks about the looming metabolic problems that people with ME/CFS, FM, and long COVID may face. Perhaps because this type of metabolic problem isn’t considered a possible cause of these illnesses, studies are rare.

The cost to unsuspecting patients, however, is potentially huge and that’s why we took so much time to get into the weeds about this unusual issue. If that works for you please support us!

 

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