Metabolic Syndrome: Causes, Health Impact, and Prevention

Metabolic syndrome is a high-risk group of conditions affecting 12.5–31.4% of adults worldwide, with a higher prevalence in the Americas and Eastern Mediterranean regions. Most commonly, it occurs in people who have obesity. Evolving research aims to clarify what exactly causes metabolic syndrome and how to treat it, but people with the syndrome benefit from lifestyle modifications and preventive strategies that can help reduce its complications.

What is metabolic syndrome?

In 1988, American endocrinologist Gerald Reaven coined the term 'Syndrome X' to describe an interesting observation: certain health problems — including fat (lipid) abnormalities, high blood pressure (hypertension), and high blood sugar (hyperglycemia) tend to co-exist in people. Reaven further discovered that Syndrome X could be explained by the body’s inability to respond properly to insulin, the primary hormone responsible for regulating blood sugar concentration.

Over a decade later, in 1999, the World Health Organization (WHO) developed a new term for Syndrome X: metabolic syndrome (MetS). Today, MetS refers to a cluster of 3–5 health conditions that occur together, increasing the risk of various diseases such as heart disease and diabetes.

While MetS can be diagnosed independently, obesity and overweight play a significant role in the development of the disease. In a large U.S. study, only 8.6% of adults with normal weight had MetS, compared to 33.2% of adults with overweight and 61.6% of adults with obesity. Additionally, adults with both obesity and MetS had an increased risk of mortality compared to adults with obesity but not MetS.

How is metabolic syndrome diagnosed?

WHO was the first to propose a formal definition of MetS, but since then, additional diagnostic criteria have been considered. The most widely used definition for MetS comes from the National Cholesterol Education Program’s Adult Treatment Panel III. According to the 2005 guidelines, a person is diagnosed with MetS if they meet at least three of the following criteria:

• Elevated fasting blood glucose ≥ 100 mg/dL or drug treatment for elevated blood glucose
• Reduced HDL cholesterol < 40 mg/dL (men) and < 50 mg/dL (women), or drug treatment for low HDL cholesterol
• Elevated triglycerides ≥ 150 mg/dL or drug treatment for elevated triglycerides
• Elevated waist circumference ≥ 120 cm (men) or ≥ 88 cm (women); in people of Asian descent: waist ≥ 90 cm (men) or ≥ 80 cm (women)
• Elevated blood pressure ≥ 130/85 or drug treatment for hypertension

Since waist circumference is one of the diagnostic criteria for MetS, people with the condition commonly have an accumulation of fat around their abdomen, including high amounts of visceral fat surrounding the internal organs. This can take on an 'apple-shaped' body appearance.

What causes metabolic syndrome?

MetS is a complex condition, and its causes are not completely understood. Research shows that a combination of genetic, lifestyle, and environmental factors lie at the root of this condition. Together, these elements lead to insulin resistance and chronic inflammation in the body, which contribute to the development of MetS.

Insulin resistance and metabolic syndrome

Insulin is a hormone that plays an important role in the body, allowing cells to take in glucose from the circulation and use it to produce energy. MetS is more likely to occur when cells become resistant to insulin's effects.

One of the primary causes of insulin resistance is excess body fat. Fat cells produce molecules called cytokines that disrupt the ability of insulin to carry out its normal functions. For instance, a cytokine called tumor necrosis factor-alpha (TNF-alpha) inactivates insulin receptors and interferes with insulin signaling within cells.

Normally, insulin inhibits the breakdown of fat (lipolysis). In insulin-resistant states, increased fat breakdown leads to more circulating free fatty acids in the bloodstream. The abundance of free fatty acids in blood may cause an imbalance of lipid metabolism that may lead to the development of MetS.

In summary, a potential simplified explanation for the cause of MetS goes as follows:

1. Fat cells produce inflammatory cytokines.
2. An increase in inflammatory cytokines decreases the body’s sensitivity to insulin.
3. Decreased insulin sensitivity leads to increased circulating free fatty acid levels.
4. The abundance of free fatty acids in the blood causes abnormalities in blood sugar and blood lipid concentrations.

Genetics related to metabolic syndrome

MetS has a hereditary component, meaning that parents can pass on genes related to MetS to their offspring. One study suggests that nearly a quarter of MetS cases in Caribbean-Hispanic families may be explained by heredity. Race may account for some of these differences: the prevalence of MetS is highest among people identifying as Hispanic (40.4%) and lowest in those identifying as non-Hispanic Asian (26.2%).

Various proteins involved in the control of blood sugar levels, blood pressure, and lipid metabolism may all contribute to the development of MetS. For instance:

• ADIPOQ, the gene that encodes the protein adiponectin, which helps to increase fat cell sensitivity to insulin. Certain variants of ADIPOQ lead to decreased adiponectin production, contributing to insulin resistance.
• AGT, which encodes a protein called angiotensinogen important in water retention and blood pressure regulation. Increased angiotensinogen levels contribute to hypertension.
• APOC3, which encodes apolipoprotein C-III (a protein involved in lipid metabolism). Apolipoprotein C-III slows down the removal of triglycerides from the bloodstream, leading to elevated triglyceride levels.

Some genes may also contribute to more than one component of MetS. For example, NR3C1 encodes a glucocorticoid (steroid) receptor involved in multiple biological processes; thus, certain variants have been linked to hypertension, obesity, and insulin resistance.

A unifying genetic profile for MetS, however, has not yet been identified. Since only a fraction of MetS is explained by genetic differences, other risk factors are also at play.

Lifestyle factors related to metabolic syndrome

Increased body weight leading to overweight or obesity is a significant risk factor for MetS, and even small body weight increases, when not addressed, could contribute to the development of MetS. One study showed that an increase in weight of just 2.25 kg (5 lbs) is associated with a 20–37% increase in the risk of developing MetS over a 16-year period.

Abdominal obesity is particularly important. One study found that even individuals who were not diagnosed with obesity but who had abdominal obesity in terms of waist circumference were more likely to have hypertension, low HDL cholesterol, and high triglyceride levels.

Poor dietary habits (such as excess calorie intake or consumption of highly processed foods and drinks), low physical activity, and decreased sleep quality are some of the lifestyle factors that contribute to overweight or obesity.

Gut microbiome and metabolic syndrome: is there a link?

The gut microbiome refers to the billions of microorganisms present in the gastrointestinal tract. These organisms have been implicated in numerous biological processes related to health. In recent years, connections have been made between the gut microbiome and MetS.

In a 2019 study, researchers assembled the existing data and proposed a model to explain how imbalances in the gut microbiome (‘gut dysbiosis’) can lead to MetS. When the gut microbiome is disrupted through a poor diet (high in processed foods and drinks), the cells of the intestines become more permeable and release inflammatory metabolites into the bloodstream. These substances then may travel to the fat tissue and liver, where they can cause chronic inflammation and insulin resistance and contribute to increased free fatty acids in the circulation, leading to MetS.

Recent research suggests that an enzyme called gamma-glutamyl transpeptidase (GGT) may be an important link between the gut microbiome and MetS. Elevated GGT levels may be associated with an increased risk of MetS. A study found that individuals with MetS and high GGT levels had a less diverse gut microbiome compared to those with MetS and GGT levels in the reference range.

Additionally, those with MetS and high GGT levels had increased numbers of 'harmful bacteria' and fewer numbers of 'beneficial bacteria.' While it is not possible to prove cause-and-effect, these results show that GGT is an important marker that may help identify gut microbiome differences with respect to MetS.

Animal studies suggest that supplementation with prebiotics and probiotics may lead to improvements in components of MetS, including improved lipid profiles and increased insulin sensitivity.

Evidence from clinical studies is promising but mixed. A 2018 systematic review and meta-analysis of clinical trials showed that supplementation with probiotics and prebiotics may reduce body weight and waist circumference, although they do not appear to alter body fat or body mass index. However, scientific evidence is contradictory regarding whether prebiotic and probiotic supplementation generates improvements in blood pressure and lipid and blood glucose levels.

Dietary interventions appear more promising. A Western diet (rich in saturated fats, trans fats, and simple sugars and low in dietary fiber from fruits, vegetables, and whole grains) has been potentially linked to insulin resistance and imbalance in the gut microbiome. By contrast, the Mediterranean diet (rich in vegetables, fruits, lean proteins, and healthy fats and low in simple sugars and red meats) has been shown to improve lipid profiles, insulin sensitivity, and the composition of the gut microbiome.

Researchers, however, concede that further research is needed to fully understand how dietary patterns affect the composition of the gut microbiome and how these, in turn, can improve or reverse MetS.

Is metabolic syndrome related to chronic stress?

Chronic stress may contribute to the development of MetS.

In a 2019 systematic review and meta-analysis, researchers discovered that adults in high-stress groups had a 45% higher chance of having MetS compared to adults in low-stress groups. Work-related stress was a particularly strong predictor, increasing the risk of MetS by 69%.

A 2009 study corroborated these findings, showing that people who experienced stressful work- or finance-related events had an increased likelihood of MetS compared to people without those experiences. Additionally, the greater the number of stressful life events they had, the more likely they were to have insulin resistance, obesity, and elevated triglycerides.

The link between stress and MetS might be explained by the production of inflammatory cytokines under stressful conditions, concluded by the authors of a 2023 study. Specifically, they found that stress caused an increase in inflammation explained nearly 62% of the connection between stress and MetS.

The authors suggest that the remaining percentage might be explained through the indirect effects of stress. Chronic stress can cause people to engage in negative health behaviors such as poor dietary choices, low physical activity, poor sleep, and increased tobacco use, all of which can lead to MetS by increasing inflammation.

These findings suggest that stress reduction strategies may be a valuable way to protect against MetS.

Does metabolic syndrome have any symptoms?

MetS is generally considered a ‘silent’ condition because it does not directly cause any symptoms.

The components of MetS — high blood pressure, high blood sugar, and altered blood lipid levels — are asymptomatic on their own, but they can sometimes lead to disease progression or complications that manifest in symptoms.

• For example, in a condition called hypertensive emergency, an extreme elevation in blood pressure (≥180/120) can disrupt the function of organs, leading to symptoms such as headache, blurry vision, or trouble breathing.
• In people with worsening blood sugar control, type 2 diabetes can develop, causing symptoms such as excessive thirst or hunger, frequent urination, or blurred vision.
• Elevated triglyceride levels can also increase the risk of heart disease and stroke, which can cause symptoms such as chest pain or weakness in the extremities.

Lastly, since people with MetS tend to suffer from obesity, they may indirectly experience symptoms associated with obesity, such as fatigue or breathlessness with light exercise.

Since MetS is asymptomatic by itself, a formal medical assessment is required to diagnose the condition.

Long-term health effects of metabolic syndrome

Without proper treatment, MetS may increase the risk of heart disease (including heart attacks), type 2 diabetes, and stroke. The more components of MetS a person has, the more likely type 2 diabetes will occur. People diagnosed with MetS may also face a higher risk of premature mortality.

Even individuals with a healthy weight range do not escape these risks; as long as they have MetS, this population is more likely to develop type 2 diabetes and heart disease.

While these are the most common disease associations, MetS may also increase the risk of other health-related problems such as nonalcoholic fatty liver disease, chronic kidney disease, and Alzheimer’s disease.

People with MetS have a significantly worse quality of life compared to people without the condition, negatively impacting physical health, daily work, personal life routines, sexual life, and diet-related distress.

Prevention and treatment of metabolic syndrome

Experts recommend the same strategy to prevent and manage MetS: significant lifestyle modification focused on weight reduction, which may improve insulin sensitivity. Foundational behavioral changes include maintaining a healthy diet and getting proper physical activity. All five components of MetS have been shown to improve with lifestyle and diet modification.

The Mediterranean diet offers a multitude of benefits, including the ability to aid weight loss, lower blood pressure, improve lipid profiles and insulin resistance, and lower inflammatory biomarker levels in blood.

Other diets that may contribute to improving MetS include the Dietary Approaches to Stop Hypertension (DASH) diet, a low glycemic index diet, and a high-fiber diet.

These diets may all help with caloric management, enabling you to eat fewer calories than you expend, leading to weight loss.

The American Heart Association recommends at least 150 minutes of moderate-intensity aerobic exercise or 75 minutes of vigorous aerobic exercise per week, along with resistance training at least two days per week. Combining aerobic and resistance training may lead to greater reductions in cardiovascular disease risk factors compared to either aerobic or resistance training alone.

Those who are unable to exercise can still derive benefits from reducing sedentary behavior. One study of adults with MetS showed that a reduction of sedentary behavior by one hour a day with an increase in physical activity improved insulin resistance after three months of practice.

For those who are unsuccessful in reversing MetS with lifestyle modifications, medical treatment may be necessary. These include medications to lower blood pressure, control blood sugar, and improve blood lipid levels, as well as bariatric surgery in eligible patients to manage weight and improve blood sugar control.

Final thoughts

Being diagnosed with metabolic syndrome can be overwhelming. The good news is that it can be preventable, manageable, and even reversible with lifestyle modifications and medical treatment. Understanding metabolic syndrome can empower you to take action and change what is in your control in order to live a healthier life.