What is Metabolic Syndrome?

What is Metabolic Syndrome?

Metabolic syndrome is a cluster of metabolic conditions that are major risk factors for the development of cardiovascular disease (CVD) and type 2 diabetes (T2D). Sometimes referred to as MetS, or metabolic syndrome X, metabolic syndrome is characterized by insulin resistance, dyslipidemia, hypertension, and visceral adiposity, all of which contribute to cardiometabolic health.

The conditions underlying MetS are connected through shared pathways including inflammation and oxidative stress.₁ Several modifiable lifestyle factors contribute to MetS development including poor diet, lack of exercise, and smoking habits, but non-modifiable factors also play a role, including genetics and epigenetics._2-4The definition of MetS, as well as diagnostic criteria, varies slightly among different health organizations.

The International Diabetes Federation states that central obesity must be present along with two or more other characteristics to diagnose MetS, whereas the World Health Organization requires that insulin resistance (IR) be present._2-4 The National Cholesterol Education Program developed its own criteria, consisting of clinical measures that are easy to obtain and strongly correlated with the underlying pathology of MetS.  The US National Cholesterol Education Program’s Adult Treatment Panel III (NCEP/ATP III) describes metabolic syndrome as the presence of three or more of the following metabolic disorders:_2-5

*Pharmaceutical treatment for high blood glucose, cholesterol, and TG levels, or hypertension count as a criterion for diagnosing MetS

Metabolic Syndrome Incidence & Prevalence

Metabolic syndrome affects between 25 to 33 percent of the United States adult population, depending on the guidelines used for diagnosis. It is associated with an increased risk of developing heart disease and T2D within five to ten years._2,3 Because the prevalence of MetS parallels the incidence of obesity and T2D, there is special concern about the rise in childhood obesity as well as the fact that many individuals with T2D are not aware they have diabetes.₃ Healthcare costs due to risk factors for MetS (BMI, hypertension, insulin resistance, poor diet, and smoking) were over $730 billion in the United States in 2016.₆ Beyond the United States, over one billion people are estimated to be affected by metabolic syndrome worldwide.₃

Metabolic syndrome prevalence and pathogenesis differ by race and sex. African American and Hispanic women both have higher rates of MetS compared to African American and Hispanic men.₂ Hispanic individuals also appear to have a higher prevalence of MetS overall.₂ Insulin resistance is more common in Hispanic adults while hypertension and dyslipidemia are seen more often in African Americans and Caucasians, respectively.₂

Factors Contributing to Metabolic Syndrome Development

The increasing prevalence of metabolic syndrome (and other chronic health issues) is due largely to low-quality diets common in the United States. Americans, as well as individuals in developed countries and those that have adopted Western dietary patterns in general, have more access to a greater abundance of calorie-dense, nutrient-poor diet choices than their ancestors did._2,7,8 Specifically, the Standard American Diet (SAD) is low in vegetables, fruits, and whole grains, but high in added sugars, saturated/trans fats, and sodium intake.₉ Consuming a low-quality diet contributes to each risk factor for MetS, as well as overall CVD risk, often through inflammatory pathways._2,10

Elevated blood glucose and insulin resistance

Consistently elevated fasting blood glucose levels are a sign of diabetes and increase the risk of heart disease.₁₀ T2D is characterized by insulin resistance which causes cells in the body to stop responding to insulin, resulting in chronically elevated levels of blood glucose. The combined presence of elevated glucose and insulin in the blood sends conflicting signals to cells throughout the body, impairing their metabolism including in the heart and blood vessels.

Insulin resistance also increases circulating levels of free fatty acids (FFAs) which can cause vasoconstriction, alter lipid metabolism, and signal the release of pro-inflammatory cytokines and adipokines from adipose tissue leading to low-grade, chronic inflammation._1,2,4 Chronic inflammation damages heart tissue and blood vessels, eventually leading to tissue fibrosis and atherogenesis.₄ Additionally, free fatty acids worsen insulin resistance by disturbing insulin signaling in various organs, including in the heart which leads to oxidative stress, impaired function, cardiac fibrosis, and myocardial cell death._4,11

Visceral adiposity

Overeating combined with a sedentary lifestyle results in visceral adiposity, or central obesity, which has negative effects on blood pressure, inflammation, hormonal signaling, insulin sensitivity, and lipid metabolism._2,4 Abundant fat stores in the abdominal region pose a greater risk for heart disease than in other areas of the body, such as the hips, because they are associated with higher inflammation which can negatively affect the health of blood vessels, pancreas, liver, and other organs involved in MetS and CVD._7,10,12

Central fat stores tend to be enriched in white adipocytes (fat cells) compared to other fat depots that contain more brown adipocytes. Brown adipocytes are the most active, secreting hormones that affect appetite, satiety, and energy metabolism while white adipocytes secrete pro-inflammatory hormones and mediators.₃ Adipokines, hormones secreted by adipose tissue, can negatively affect vascular function, work as pro-inflammatory agents, and contribute to IR.₁₃ Adipokines and FFAs released from fat tissue also impair cellular pathways, dampening their function and increasing oxidative stress.₁₃ The location of excess fat in the abdomen provides a direct path for FFA to travel directly to the liver via splanchnic circulation, where they accumulate and can cause non-alcoholic fatty liver disease.₄

Dyslipidemia

Dyslipidemia, or the imbalance of blood lipids including high levels of TGs and low-density lipoprotein (LDL) or low levels of high-density lipoprotein (HDL), increases the risk of heart disease.₁₀ Increased TG and LDL allows for greater interaction between lipids and plaque formation, resulting in increased fat deposition which contributes to atherosclerosis. Low HDL level is a risk factor for MetS because HDL is involved in the transport of cholesterol back to the liver, helping remove it from circulation.

Dyslipidemia is closely connected to glucose metabolism and insulin resistance. Impaired insulin signaling increases lipolysis, increasing FFA levels that are circulating through the body.₄ Because FFAs are required for TG synthesis, insulin resistance can lead to an increase in TG synthesis as well as LDL production.₄ When these molecules are found in excessive levels, they can significantly worsen atherosclerotic plaque formation.

Hypertension

Inflammation, caused by visceral adiposity or insulin resistance, negatively impacts endothelial function, elevating blood pressure.₂ High blood pressure threatens the integrity of artery walls in the heart, increasing the risk for plaque buildup, which can lead to heart disease.₂ Endothelial function can also be affected by oxidative stress, hyperglycemia, FFAs, inflammatory cytokines and adipokines, which are abundant in MetS.₁₃

Genetic and epigenetic modifications

Genetics play a role in MetS, but it is likely much smaller than people like to believe. A study investigating over 300,000 people found 97 different genetic locations related to BMI. However, those 97 genetic loci accounted for less than three percent of total BMI variation, indicating that the genetic component is relatively small compared to lifestyle factors.₁₄

Epigenetics, changes in gene expression that do not involve changes to DNA sequence, likely play a much larger role than genetics in promoting the development of MetS. Maternal nutrition as well as obesity status can significantly impact the risk of developing obesity, and possibly MetS, later in life. Maternal nutrition can cause epigenetic changes that affect growth factors, appetite control, glucose metabolism, and adipogenesis in offspring.₃ Similarly, the presence of obesity in parents can cause epigenetic changes in male and female reproductive cells as well during development in utero that results in obesity in the offspring later in life.₃ Mechanistically, obesity in the parent results in altered DNA methylation of the IGF2, leptin, and TNF genes in the offspring, all of which can contribute to inflammation and obesity.₃

How Nutrition Helps Manage Metabolic Syndrome

The Mediterranean Diet can prevent or reduce MetS due to the presence of many health-promoting nutrients that work on every component of MetS._4,7 It is rich in fruits, vegetables, whole grains, lean protein, and healthy fats and low in processed foods, sugar, and saturated fat. Several nutrients found in the Mediterranean Diet provide support for managing risk factors related to metabolic syndrome, including protein, fiber, healthy fats, magnesium, and phytonutrients.

Protein

The body requires protein for a variety of functions, including building muscle and synthesizing hormones and enzymes. Obtaining protein from lean sources, as well as from protein blends with a low glycemic index, can provide essential amino acids while avoiding the detrimental effects of saturated fat, sodium, and a carbohydrate-induced spike in blood glucose levels. Conversely, most sources of protein in the Standard American Diet (SAD) also contain high amounts of saturated fat, sodium, and preservatives in the form of red and processed meats. Saturated fat can contribute to dyslipidemia and plaque formation while excess sodium can increase blood pressure and harm blood vessel integrity.₁₅

Fiber

Both types of dietary fiber – soluble or insoluble – are beneficial for metabolic health. Soluble fiber can delay gastric emptying, resulting in slower glucose absorption which prevents spikes in blood glucose that can lead to insulin resistance over time.₇ Delayed gastric emptying can also help with appetite and weight loss because it allows time for appetite hormones to reach the brain where they signal satiety and inhibit food intake.₇ Finally, soluble fiber reduces bile acid reabsorption, requiring the body to produce new bile acid which uses cholesterol as a building block and therefore decreases circulating cholesterol levels in the process.₇

Insoluble fiber cannot be utilized by the body but can be digested by bacteria in the gut microbiome. These microbiota ferment insoluble fibers, producing short-chain fatty acids (SCFAs), that provide energy to intestinal cells, improve the composition of the gut microbiome, and exert anti-inflammatory effects.₇ Not surprisingly, fiber intake is linked to lower levels of obesity and lower risk for MetS and heart disease._16-19

Healthy fats

The Mediterranean Diet is a rich source of omega-3 fatty acids, a group of polyunsaturated fatty acids (PUFAs) that help resolve dyslipidemia and its underlying mechanisms. They decrease unhealthy cholesterol levels, promote healthy inflammation, improve beta-cell function, and support healthy blood pressure._7,20 Omega-3 fatty acids also decrease lipogenesis and increase fatty acid oxidation, helping to utilize fat instead of storing it in the body where it can contribute to visceral adiposity, insulin resistance, and inflammation.₂ The SAD, on the other hand, is low in PUFAs but contains high levels of saturated and trans fats, which contribute to inflammation in the body.

Vitamins and minerals

Many vitamins and minerals work as cofactors for essential cellular processes, including energy metabolism, oxidative balance, and inflammation resolution. As such, sufficient intake can help cellular-level processes run smoothly and prevent the accumulation of metabolic by-products including reactive oxygen species (ROS) and homocysteine, which contribute to poor cardiovascular health.₂₁ The minerals magnesium and potassium are especially important for healthy blood pressure. Magnesium promotes vasodilation while potassium helps blood vessel walls relax and triggers the kidneys to excrete excess sodium, which also helps decrease blood pressure._7,22 Additionally, vitamins A, C, and E (and their metabolites) are powerful antioxidants, helping to maintain oxidative balance which can improve insulin signaling and blood pressure.₇

Phytonutrients

Phytonutrients are associated with reduced risk of heart disease deaths, due in part to their beneficial effects on inflammation, blood pressure, gut microbiome health, insulin signaling, lipid metabolism, and energy expenditure._7,23,24 A specific group of phytonutrients, flavonoids, have therapeutic value in the treatment and management of MetS.₁ Flavonoids have demonstrated anti-inflammatory, antioxidant, anti-atherosclerotic, and anti-diabetic activities, helping to counteract underlying pathways that contribute to MetS.₁ Flavonoids also interact with glucose metabolism pathways, decreasing insulin resistance, inflammation, and oxidative stress.₁

Whole-grain oats are rich in fiber and phytonutrients, making them especially beneficial for cardiometabolic health. Consumption of whole grain oats has long been connected to supporting healthy glucose metabolism and metabolic health due to soluble and insoluble fiber content.₂₅  A large systematic review and meta-analysis revealed that higher oat intake (>5.7g/day) was significantly associated with a lower risk of T2DM compared to lower intake (<1.3g/day).₂₆ Similarly, the highest intake of oats was associated with a significantly lower risk of dying from any cause.₂₆

A unique phytochemical class identified in oats called avenanthramides has been reported to influence glucose uptake through interaction with bitter taste receptors in the gastrointestinal (GI) tract.₂₇ Activation of these intestinal GI taste receptors results in an enteroendocrine hormone influence on glucagon-like peptide 1 (GLP-1), insulin, glucagon, ghrelin, and cholecystokinin (CCK) – all important regulators of glucose uptake, storage, and release. Regulation of specific bitter receptor signaling in the extraoral tissues may reduce the risk factors associated with metabolic diseases.

Other phytonutrient-rich plants with known benefits for cardiometabolic health include:_2,4

Metabolic Syndrome describes a cluster of health conditions that contribute to the risk of developing cardiovascular disease. The components of MetS contribute to CVD development through shared pathways- inflammation, oxidative stress, and aberrant cellular signaling. Genetics and epigenetics play a role in the development of MetS and CVD, although diet and lifestyle choices largely drive the risk. Whereas the SAD promotes inflammation, MetS, and CVD, a Mediterranean-style diet full of fruits and vegetables, omega-3 fatty acids, and phytonutrients can help prevent and even reverse MetS and CVD risk, with greater adherence resulting in greater reversal._3,4

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