Metabolic Syndrome

Metabolic syndrome (MetS), sometimes called “insulin resistance syndrome” or “syndrome X”, refers to a cluster of interrelated risk factors for cardiovascular disease and type 2 diabetes, specifically enlarged waist circumference, elevated triglycerides, high blood pressure, low high-density lipoprotein cholesterol, and impaired fasting glucose.^[1] It’s estimated that the global prevalence of MetS is about 25%,^[2] while in the United States it’s nearly 35%.^[3]

Other than an enlarged waist circumference, which doesn’t always indicate the presence of MetS, there are typically no obvious signs or symptoms of the disease. Therefore, an evaluation by a medical doctor and blood work will be needed to determine the presence of MetS. In some cases, an individual will present with signs of specific risk factors, such as acanthosis nigricans (a darkening of the skin that appears in skin fold areas and is associated with insulin resistance) or xanthomas (yellowish-colored skin lesions that are associated with dyslipidemia).^[1]

To be diagnosed with MetS, an individual needs to have at least 3 of the following 5 risk factors:^[4]

• Enlarged waist circumference: ≥ 88 centimeters (35 inches) and ≥ 102 centimeters (40 inches) in women and men, respectively, with lower thresholds for Asian populations (≥ 80 centimeters and ≥ 85–90 centimeters in women and men, respectively)
• Elevated triglycerides: ≥ 150 mg/dL (1.7 mmol/L)
• High blood pressure: systolic ≥ 130 mm Hg and/or diastolic ≥ 85 mm Hg
• Low high-density lipoprotein cholesterol: < 50 mg/dL (1.3 mmol/L) and < 40 mg/dL (1.0 mmol/L) in women and men, respectively
• Impaired fasting glucose (or drug treatment of elevated glucose levels): ≥ 100 mg/dL (5.6 mmol/L)

The primary goal of clinical management is to reduce the risk of cardiovascular disease and type 2 diabetes.^[5] Lifestyle interventions (i.e., changes in dietary and physical activity habits and smoking cessation) are the initial strategy to treat MetS, followed by pharmacological therapy — if necessary — to improve individual risk factors. There are no guidelines from medical organizations for the pharmacological treatment of MetS; pharmacological treatment depends on the individual’s unique circumstances and may include a statin to improve blood lipids, a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or sodium-glucose cotransporter 2 (SGLT2) inhibitor to further reduce cardiovascular disease risk, metformin to increase insulin sensitivity, and/or a renin-angiotensin system (RAS) blocker to reduce blood pressure, among other drugs.^[6][7][8] In people with severe obesity, bariatric surgery is a highly effective option.

Maintaining a healthy body weight is central to the prevention and management of MetS. Virtually any calorie-restricted diet — irrespective of its macronutrient distribution or meal frequency — that the individual can adhere to has the potential to improve MetS risk factors.^[9] To achieve significant improvement of MetS risk factors, a weight loss of at least 5% of initial body weight is recommended, with greater improvements reported with further weight loss.^[10]

Regarding specific dietary patterns, the Mediterranean diet, which is rich in minimally processed plant foods and olive oil, has the most robust evidence of improving MetS risk factors and reducing the prevalence of MetS.^[11][12] The Dietary Approaches to Stop Hypertension (DASH) diet has also been shown to improve MetS risk factors, whereas a Western diet rich in red meat, saturated fatty acids, refined grains, and sugar is associated with an increased risk of MetS.^[13]

Because MetS is characterized by a cluster of cardiometabolic risk factors, a wide variety of supplements are of interest, including those purported to improve blood lipids, increase insulin sensitivity, decrease blood pressure, or reduce inflammation. Some of the most studied options are berberine, red yeast rice, fish oil, biotic supplements, curcumin, vitamin D, and garlic.^[14][15]

Regular exercise is important for the prevention and treatment of MetS. Sedentary behavior is associated with an increased risk of MetS,^[16][17] whereas higher cardiorespiratory fitness (i.e., VO₂max) is associated with a reduced risk of MetS.^[18] Additionally, regular exercise has been shown to improve each MetS risk factor.^[18] At a minimum, the physical activity guidelines of 150 minutes per week of moderate-intensity (or 75 minutes of vigorous-intensity) activity should be met.

Sleep hygiene interventions are also potentially useful because sleep deprivation increases hunger and energy intake and decrease insulin sensitivity.^[19] Moreover, short sleep duration (<6 hours per night) and sleep apnea are associated with an increased risk of MetS.^[20][21] Lastly, smoking cessation is recommended for the prevention and treatment of MetS.^[13]

MetS is caused by a combination of genetic^[22][23] and environmental factors, namely a high caloric intake and physical inactivity.^[24] The resultant excess adiposity — particularly in the intra-abdominal region (i.e., visceral fat) — leads to adipose tissue dysfunction and insulin resistance.

Expansion of visceral fat and insulin resistance increases circulating free fatty acids (FFAs), which infiltrate the liver and skeletal muscle and disrupt glucose and lipid homeostasis.^[24] The liver and skeletal muscle respond by increasing the breakdown of FFAs, which results in decreased glucose uptake in muscle along with increased glucose and triglyceride production and increased high-density lipoprotein clearance in the liver.^[25][15]

Additionally, expansion of visceral fat causes altered secretion of adipokines (i.e., hormones, cytokines, and other proteins secreted by fat tissue), including increased secretion of pro-inflammatory cytokines (e.g., interleukin-6, tumor necrosis factor alpha) and reduced secretion of adiponectin, contributing to a state of chronic low-grade inflammation and a deterioration in cardiometabolic health.^[26]