Metabolic dysfunction

Definition of metabolic dysfunction

In metabolic dysfunction, metabolism is dysregulated. Metabolism consists of processes in the body to use nutrients for energy and building blocks. Metabolic dysfunction typically manifests through increased fat storage around the waist, elevated blood sugar and blood pressure, fatty liver, and abnormal HDL cholesterol and triglyceride levels — which are associated with insulin resistance and low-grade inflammation. This greatly increases the risk of type 2 diabetes, atherosclerosis, cancer, dementia, and many other conditions.

Two mutually reinforcing factors, insulin resistance and low-grade inflammation, play a central role in metabolic dysfunction. You can read about how the various factors are connected in this article.

Metabolic dysfunction is strongly influenced by lifestyle: nutrition, exercise, stress, sleep, and toxic substances. This means that adjusting lifestyle can greatly improve metabolic health, reducing the risk of chronic diseases.

On this page, I summarize the scientific insights into the causes, consequences, and approach to metabolic dysfunction.

Author: Jaap Versfelt

Medical reviewer: Yvo Sijpkens, internist

Metabolic dysfunction and metabolic syndrome

Metabolism is the totality of processes in our body needed to produce energy, break down substances, and renew and maintain cells and tissues. Think, for example, of digesting food or storing energy in the body.

The terms metabolic dysfunction and metabolic syndrome are both used to indicate that metabolism is functioning less well. In general, metabolic dysfunction indicates that normal metabolism is disturbed, meaning the body cannot efficiently produce, store, or use energy. This can lead to phenomena such as insulin resistance and low-grade inflammation, which can manifest in elevated blood pressure, blood sugar, weight gain, and changes in triglyceride and HDL cholesterol values. Metabolic syndrome is the medically defined term used when three of the five mentioned risk factors are found in people.

Metabolic dysfunction is becoming more common

Metabolic syndrome is increasingly being diagnosed in the Netherlands. Where in the nineties 19 percent of men and 12 percent of women between 28 and 59 years old met the criteria, by 2020 this had doubled to 36 percent of men and 24 percent of women (Bos, 2007, Sigit, 2020).

Overweight among the Dutch also increased sharply. The number of people with obesity even tripled in the past forty years.

Year	Overweight (BMI > 25)	Obesity (BMI > 30)
1981	27.4%	4.4%
1991	36.2%	6.1%
2001	42.9%	9.2%
2011	47.2%	11.3%
2021	49.5%	14.0%
2022	50.0%	15.0%

Table 1. Development of overweight and obesity in the Netherlands (Vzinfo.nl)

It seems obvious that a change in our living environment and lifestyle is causing the explosive growth of metabolic dysfunction. Before I discuss lifestyle, however, I will first take a closer look at the mechanism behind metabolic dysfunction.

Underlying problems in metabolic dysfunction

Metabolic dysfunction is associated with two underlying, mutually reinforcing problems:

• Insulin resistance

• Low-grade inflammation.

Insulin resistance

Insulin resistance leads to metabolic dysfunction through various mechanisms:

In insulin resistance, there is reduced sensitivity of body cells to the hormone insulin. As a result, insulin is less able to maintain blood sugar levels.

• Excessive body fat around the waist Excessive body fat around the waist is a consequence of insulin resistance that promotes lipogenesis (fat storage) and inhibits lipolysis (fat breakdown) in adipose tissue, particularly in the abdominal region.

• High blood sugar levels High blood sugar levels (hyperglycemia) result from reduced glucose uptake by insulin-resistant muscle and fat cells and increased glucose production by liver cells. Consumption of carbohydrates then leads to hyperglycemia.

• Elevated blood pressure Insulin resistance causes elevated blood pressure through increased salt retention by the kidneys and increased activation of the sympathetic nervous system, leading to vasoconstriction.

• Abnormal triglyceride and HDL cholesterol levels This disturbance in lipid values occurs because in insulin resistance, triglyceride production is increased and breakdown is decreased. Insulin resistance and inflammation are also accompanied by reduced production and increased breakdown of HDL cholesterol, resulting in low HDL levels.

Deep dive: Insulin resistance and type 2 diabetes

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Read more about insulin resistance →

Low-grade inflammation

An infection or injury produces a strong inflammatory response of temporary nature. In low-grade inflammation, by contrast, the immune system is continuously mildly activated without direct symptoms. CRP (C-reactive protein) and sometimes the white blood cell count are only slightly elevated. Processed foods, chronic stress, inactivity, poor sleep quality, and smoking are all factors that contribute to an elevated inflammatory status. Visceral fat with hypertrophic fat cells contributes to metabolic dysfunction through the production of free fatty acids and cytokines such as TNF-alpha, IL-1beta, and IL-6 (Arkan, 2005) (Rohm, 2022). An unbalanced composition of the gut microbiome (dysbiosis) can lead to increased intestinal permeability, allowing bacterial components (lipopolysaccharides) to enter the bloodstream and cause inflammation.

Insulin resistance and low-grade inflammation are closely linked in a vicious cycle. With aging, their effect becomes amplified.

Consequences of metabolic dysfunction

Metabolic dysfunction has a major impact on our physical and mental health. The risk of a range of diseases is greatly increased in people with insulin resistance and low-grade inflammation. In this chapter, I discuss the effect of metabolic dysfunction on:

• Obesity

• Type 2 diabetes

• Atherosclerosis

• Cancer

• Dementia

• Parkinson’s

• Migraine

• Polycystic ovary syndrome (PCOS)

• Erectile dysfunction.

Obesity

Insulin resistance is accompanied by elevated levels of the hormone insulin (hyperinsulinemia). This elevated level prevents fat from being properly used as an energy source. High insulin levels also promote storage of energy from food as fat. Therefore, insulin resistance contributes to overweight.

It doesn’t stop there. In obesity, there is often accumulation of abdominal fat. The enlarged fat cells in the abdomen then secrete pro-inflammatory molecules. These molecules impair insulin function, further increasing insulin resistance (Weisberg, 2003) (Rohm, 2022).

Additionally, obesity is associated with changes in the gut microbiome and increased intestinal permeability. This permeability is another cause of low-grade inflammation (Furman, 2019).

In short, insulin resistance and low-grade inflammation not only contribute to obesity but are subsequently also reinforced by obesity, further increasing metabolic dysfunction.

Type 2 diabetes

As we have seen, inflammation and obesity contribute to insulin resistance, the precursor to diabetes. Insulin resistance is accompanied by elevated insulin levels (hyperinsulinemia). Over time, insulin resistance and overload of beta cells in the pancreas become so severe that glucose levels begin to rise. Then there is type 2 diabetes.

Atherosclerosis

Research shows that lifestyle factors account for 90 percent of the risk of cardiovascular disease. Diabetes and related factors such as high blood pressure and large waist circumference are important factors here (Yusuf, 2004). Hyperinsulinemia and hyperglycemia contribute to the development of atherosclerosis in combination with elevated blood pressure, disturbances in fat balance, elevated inflammation levels, clotting, and narrower, less flexible blood vessels. Inflammatory substances from macrophages such as IL-1b (interleukin-1 beta), tumor necrosis factor alpha, and interleukin-6 play an important role here (Rohm, 2022).

Deep dive: Cardiovascular disease

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Cancer

People with hyperinsulinemia are twice as likely to die from cancer (Tsujimoto, 2017). Women who are insulin resistant, for example, have a 2 to 3 times higher risk of dying from breast cancer. Men who are insulin resistant and have a high waist-to-hip ratio even have an 8 times greater risk of prostate cancer.

Dementia

The link between insulin resistance in the brain and dementia is so strong that Alzheimer’s is sometimes referred to as type 3 diabetes (Accardi, 2012). Type 2 diabetes increases the chance of dementia by 69 percent (Jin-Tai Yu, 2020). The connection between insulin resistance and dementia was also shown in a study conducted in Finland examining risk factors for dementia. Surprisingly, the study found that insulin resistance is a greater risk factor than age in predicting dementia risk (Kuusisto, 1997). It is becoming increasingly clear that the first brain abnormalities can begin in middle age.

Parkinson’s

There is a significant association between insulin resistance and Parkinson’s disease. A significant percentage of Parkinson’s patients have type 2 diabetes (8-30 percent according to the study Aviles-Olmos, 2012) and are insulin resistant (50-80 percent). Parkinson’s is characterized by loss of dopamine-producing neurons in the brain. Insulin resistance inhibits this dopamine production in the brain.

Migraine

A study among insulin-resistant middle-aged women showed they had migraine three times as often as their healthy peers. If they were also obese, the chance of migraine was even thirteen times higher (Fava, 2013). Furthermore, 69 percent of participants in a clinical trial experienced a halving of migraine frequency when using the supplement alpha-lipoic acid, which counteracts both insulin resistance and inflammation (Cavestro, 2018).

PCOS

Polycystic ovary syndrome (PCOS) is a common cause of female infertility affecting millions of people worldwide. Research shows that in women with type 2 diabetes, PCOS occurs eight to ten times more often than in women without type 2 diabetes (Diamanti-Kandarakis, 2012). Insulin plays a crucial role in PCOS particularly by stimulating ovarian androgen production, disrupting the hormonal balance needed for ovulation and explaining symptoms such as acne and hirsutism.

Erectile dysfunction

Men with insulin resistance have an increased risk of erectile dysfunction, which worsens as this dysregulation increases (De Berardis, 2003). Free testosterone may also be decreased, with consequences for libido. Erectile dysfunction can be considered a canary in the coal mine for vascular problems elsewhere in the body.

Deep dive: Erectile dysfunction

Erectile dysfunction is often an early warning sign - on average 5 years before heart problems. Discover how ED relates to metabolic dysfunction and what you can do about it.

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Other diseases

The list above is far from exhaustive. Metabolic dysfunction is linked to a whole range of conditions. Think also of gout, psoriasis, sarcopenia (muscle loss), gallstones, fatty liver with an associated cascade of liver diseases, reflux esophagitis, kidney stones, kidney failure, acne, and skin tags. Virtually all mental problems, even at a young age, are related to metabolic dysfunction.

Determining metabolic dysfunction

The probability of the presence of insulin resistance can be reasonably well estimated with the following questions:

• Is there more fat around the abdomen (waist circumference > 102 cm for men and > 88 cm for women)?

• Is blood pressure elevated (systolic > 135 mm Hg, diastolic > 85 mm Hg)?

• Are there patches of darker colored skin (acanthosis nigricans) or skin tags?

• Is there polycystic ovary syndrome (PCOS) or erectile dysfunction?

• Is there a family history of heart disease, high blood pressure, or type 2 diabetes?

• Are there thick ankles?

Additionally, there are a number of blood values that a doctor can have tested that indicate insulin resistance:

• High fasting glucose (> 5.5 mmol/L)

• High fasting triglycerides (> 1.7 mmol/L)

• Low HDL cholesterol (men: < 1.03 mmol/L, women: < 1.29 mmol/L).

With a ‘yes’ to one of these characteristics or blood values, there is probably insulin resistance. With a ‘yes’ to two or more of these questions, the person is almost certainly insulin resistant.

To determine insulin resistance with complete certainty, more blood values are needed. These are some of the most common methods to directly test insulin resistance, with the corresponding healthy values:

• Rising HbA1c value > 40 mmol/mol

• Fasting insulin measurement > 6 uU/ml

• HOMA-IR index, calculated from measurements of fasting glucose and fasting insulin. A value above 1.5 is consistent with insulin resistance

• Oral glucose tolerance test: insulin > 30 uU/ml, 1 to 2 hours after ingestion of a glucose solution (75 grams)

• Elevated ALT and GGT values, >40 U/l. This indicates fatty liver.

Repeatedly elevated white blood cell count (leukocytes > 7) or slightly elevated CRP (> 1) is a signal for low-grade inflammation, which often accompanies insulin resistance.

How lifestyle contributes to metabolic dysfunction

As we have seen, metabolic dysfunction is becoming more common. This makes it likely that our living environment is a cause. A large number of factors play a role. The most important are nutrition and exercise.

Nutrition

Eating ultra-processed food has many negative effects on our health. A French study (Rico-Campa, 2019) in which 170,000 people were followed for 10 years showed strong associations between consumption of ultra-processed food and increased risks of type 2 diabetes, cardiovascular disease, cancer, depression, and gastrointestinal disorders. The participants in the study who ate and drank the most ultra-processed foods had a 62 percent higher mortality risk compared to those who consumed the least.

Over the past fifty years, consumption of ultra-processed food rich in refined fats, sugars, and white flour has increased sharply. 61 percent of the energy intake of the average Dutch person now consists of this industrially produced food (Vellinga, 2022). Examples of ultra-processed food include supermarket bread, sunflower and rapeseed oil, milk substitutes, breakfast cereals, meat substitutes, and diet drinks.

Ultra-processed food stimulates low-grade inflammation in the body. Refined fats and carbohydrates can cause oxidative stress, activating inflammatory processes (Dickinson, 2008). Another example of how ultra-processed food causes inflammation is through higher levels of advanced glycation end products (AGEs), when proteins and fats are exposed to sugars during the production process.

Deep dive: Ultra-processed food

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Exercise

Lack of physical activity is associated with higher levels of inflammatory markers such as CRP (C-reactive protein) (Furman, 2019). Muscles that are stressed through walking, running, or strength training release substances (such as myokines) that reduce inflammation. This helps improve insulin sensitivity. Additionally, regular physical activity can enable muscles to take up glucose independently of insulin, which helps keep blood sugar levels more stable and reduce the risk of insulin resistance.

Other factors

A large number of other factors contribute to low-grade inflammation, insulin resistance, and thus to metabolic dysfunction. Think of:

• Smoking Smokers have a significantly higher insulin spike in their blood when they eat carbohydrates than non-smokers.

• Alcohol Excessive alcohol consumption increases the risk of insulin resistance through fatty liver, inflammatory reactions in the body, and disrupted hormone balance.

• Lack of sleep One week of too little sleep already makes our body 30 percent more insulin resistant. Sleeping half as long as normal for two days can even make healthy people insulin resistant.

• Chronic stress Through activation of the hypothalamus/pituitary/adrenal axis, cortisol contributes to appetite, elevated blood sugars, inflammation, and thus to insulin resistance and hyperinsulinemia.

• Environmental pollution Over the past two hundred years, there has been an enormous increase in exposure to various harmful substances such as air pollution, hazardous waste, and industrial chemicals (such as the microplastic PFAS). An estimated two thousand new chemicals are introduced each year in everyday products such as food, personal care products, medications, household cleaners, and garden products. These chemicals can promote inflammatory processes.

Effective interventions to address metabolic dysfunction

With lifestyle adjustments, you can address metabolic dysfunction. Think of eating healthier, getting enough sleep, relaxing, and exercising more. All these adjustments promote sensitivity to insulin and reduce inflammation.

Central to this is our nutrition. When we eat carbohydrates (bread, pasta, rice, fruit, soft drinks, etc.), these nutrients are converted to glucose. On average, Dutch people eat about 213 grams of carbohydrates per day. That is 43 percent of our energy intake. As described earlier, an excess of (refined) carbohydrates contributes to the development of insulin resistance. With inactivity, even 50 to 100 grams of carbohydrates per day can be too much.

It is therefore logical that limiting carbohydrates can reverse insulin resistance. This is what therapeutic carbohydrate restriction looks like in practice:

• Reduce intake of ultra-processed food The first step is eliminating added sugars such as glucose and fructose, refined starch (as in almost all packaged food products from supermarkets), and the pro-inflammatory seed oils (sunflower oil, rapeseed oil, soybean oil, etc.). Whole foods (meat, fish, eggs, dairy, vegetables) lead to satiety and thus energy restriction.

• Choose foods with low glycemic load A number of foods contain carbohydrates that cause high insulin spikes and thereby increase insulin resistance. These are foods with a high glycemic load, where the food contains many carbohydrates that are quickly absorbed by the intestine. Think of potatoes, pasta, and rice. Foods that cause fewer insulin spikes are meat, fish, milk, eggs, many fruits including apples, pears, grapefruits, olives, and avocados, vegetables such as broccoli, lettuce, and carrots, and nuts such as peanuts and cashews. In this table you will find the glycemic load of more than one hundred foods.

• Limit the amount of carbohydrates Depending on individual tolerance for carbohydrates and food products, there is more or less room for whole grain products, starchy vegetables, fruit, and honey. To determine how many (or how few) carbohydrates someone can handle, a continuous glucose meter is a useful tool. Ideally, the glucose rise after a meal is less than 1.6 mmol/L. For many patients with insulin resistance, this means they must limit carbohydrates to less than 50 grams per day.

• Limit the number of eating occasions Limiting the number of eating occasions becomes easier when someone eats fewer carbohydrates. After eating or drinking many (refined) carbohydrates, there is first a rapid glucose and insulin spike followed by a sharp drop in blood glucose. This glucose dip can be accompanied by a new need to eat. With whole foods, two to three eating occasions per day are sufficient.

• Limit the amount of fat Whole protein-rich foods naturally contain sufficient fat. Too much fat in the diet means an energy burden and hinders the release of stored fat as an energy source.

In the box below, more about the evidence underlying the advice to eat fewer carbohydrates.

The evidence for the importance of limiting carbohydrates

For people with insulin resistance or (pre-)diabetes, what the average Dutch person eats in carbohydrates (213 grams per day) is quickly too much. Carbohydrate restriction can then help. There are many studies showing that people with (pre-)diabetes benefit more from a carbohydrate-restricted diet than from avoiding fat. For those interested, here is an overview of three meta-analyses (collections of randomized controlled trials or RCTs) and six individual RCTs that all show that therapeutic carbohydrate restriction works:

Goldenberg, 2021, meta-analysis of RCTs, 1,357 participants

Sainsbury, 2018, meta-analysis of RCTs, 2,412 participants

Saslow, 2017, RCT, 25 participants

Saslow, 2017, RCT, 68 participants

Snorgaard, 2016, meta-analysis of RCTs, 1,376 participants

Tay, 2015, RCT, 115 participants

Hussain, 2012, RCT, 163 participants

Nielsen, 2008, RCT follow-up, 31 participants

Westman, 2008, RCT, 84 participants.

Conclusion

As Dutch people, we have become unhealthier at a rapid pace. The proportion of people with overweight in the population has risen to 50 percent, the number of people with obesity quadrupled over the past 40 years. At the same time, since the nineties, the number of people with metabolic syndrome doubled to 36 percent of men and 24 percent of women.

This metabolic dysfunction is recognizable by a large waist circumference, high blood pressure, abnormal fat values, and elevated glucose or liver values in the blood. Two factors — insulin resistance and low-grade inflammation — reinforce each other and contribute to metabolic dysfunction.

Parallel to this, the burden of chronic diseases has increased significantly over the past 50 years. Think of type 2 diabetes, high blood pressure, cardiovascular disease, cancer, dementia, Parkinson’s, multiple sclerosis, PCOS (infertility in women), etc. These conditions have in common that they arise from metabolic dysfunction that has existed for years.

Metabolic dysfunction is associated with a large number of lifestyle factors such as nutrition, exercise, stress, sleep, and toxic substances. Adjusting lifestyle can greatly improve metabolic health and reduces the risk of all the mentioned chronic diseases. A successful lifestyle intervention has a favorable effect on existing conditions with a decrease in complications and other diseases, and thus provides an improvement in quality of life.

In a webinar for Je Leefstijl Als Medicijn, Yvo Sijpkens explained metabolic dysfunction. Watch it here.

Veelgestelde vragen

What are the main causes of metabolic dysfunction?

Metabolic dysfunction is primarily caused by modern lifestyle factors. The main ones are: overconsumption of ultra-processed food (61% of average Dutch energy intake), lack of exercise, chronic stress, sleep deprivation, smoking, excessive alcohol consumption, and exposure to environmental pollutants. These factors contribute to insulin resistance and low-grade inflammation, the two main mechanisms behind metabolic dysfunction.

How can I recognize if I am insulin resistant?

Insulin resistance can be recognized by: increased fat storage around the waist (waist circumference >102 cm for men, >88 cm for women), elevated blood pressure (>135/85 mmHg), dark skin patches (acanthosis nigricans), skin tags, PCOS or erectile dysfunction, family history of heart disease/diabetes, and thick ankles. Blood values indicating insulin resistance are: fasting glucose >5.5 mmol/L, triglycerides >1.7 mmol/L, and low HDL cholesterol (<1.03 mmol/L for men, <1.29 mmol/L for women).

Which lifestyle changes help prevent type 2 diabetes?

The most effective lifestyle changes for diabetes prevention are: reducing ultra-processed food (added sugars, refined starch, seed oils), choosing foods with low glycemic load, limiting carbohydrates (often to below 50g per day for people with insulin resistance), limiting eating occasions to 2-3 per day, regular physical exercise, good sleep hygiene, stress management, and avoiding smoking and excessive alcohol consumption.

Why is abdominal fat more dangerous than fat in other places?

Abdominal fat (visceral fat) is more dangerous because fat cells in the abdomen secrete pro-inflammatory molecules that impair insulin function. These fat cells produce free fatty acids and cytokines such as TNF-alpha, IL-1beta, and IL-6, which worsen insulin resistance. Abdominal fat is therefore directly linked to an increased risk of type 2 diabetes, cardiovascular disease, cancer, dementia, Parkinson's, and other chronic conditions.

What are the proven effects of carbohydrate restriction on metabolic problems?

Multiple studies show that carbohydrate restriction is effective for metabolic problems, especially for people with (pre)diabetes. Nine studies (3 meta-analyses and 6 RCTs) with a total of more than 5,000 participants show that therapeutic carbohydrate restriction is more effective than fat restriction for improving metabolic health. This works because carbohydrate restriction reduces insulin spikes, decreasing insulin resistance and allowing the body to better burn fat as an energy source.

What role does chronic inflammation play in health problems?

Chronic (low-grade) inflammation plays a central role in metabolic dysfunction and the resulting health problems. Processed foods stimulate inflammatory processes through oxidative stress and formation of advanced glycation end products (AGEs). Ultra-processed food can also lead to a disrupted gut microbiome and increased intestinal permeability, allowing bacterial components to enter the bloodstream and cause inflammatory reactions.