Metabolic syndrome

Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).

Metabolic syndrome is associated with the risk of developing cardiovascular disease and type 2 diabetes.<ref name="Mayo-metabolic">Template:Cite web</ref> In the U.S., about 25% of the adult population has metabolic syndrome, a proportion increasing with age, particularly among racial and ethnic minorities.<ref name="Falkner-2014">Template:Cite journal</ref><ref name="pmid23810877">Template:Cite journal</ref>

Insulin resistance, metabolic syndrome, and prediabetes are closely related to one another and have overlapping aspects. The syndrome is thought to be caused by an underlying disorder of energy utilization and storage, but the cause of the syndrome is an area of ongoing medical research. Researchers debate whether a diagnosis of metabolic syndrome implies differential treatment or increases risk of cardiovascular disease beyond what is suggested by the sum of its individual components.<ref name="Anagnostis2023">Template:Cite journal</ref>

Signs and symptoms

The key sign of metabolic syndrome is central obesity, also known as visceral, male-pattern or apple-shaped adiposity. It is characterized by adipose tissue accumulation predominantly around the waist and trunk.<ref>Template:Cite web</ref> Other signs of metabolic syndrome include high blood pressure, decreased fasting serum HDL cholesterol, elevated fasting serum triglyceride level, impaired fasting glucose, insulin resistance, or prediabetes. Associated conditions include hyperuricemia; fatty liver (especially in concurrent obesity) progressing to nonalcoholic fatty liver disease; polycystic ovarian syndrome in women and erectile dysfunction in men; and acanthosis nigricans.<ref>Template:Cite journal</ref>

Neck circumference

Neck circumference has been used as a simple surrogate index of upper-body subcutaneous fat. Values >Template:Cvt (men) and >Template:Cvt (women) are considered high risk for metabolic syndrome, and large neck circumference more than doubles risk.<ref>Template:Cite journal</ref> In adults with overweight/obesity, clinically significant weight loss may protect against COVID-19,<ref>Template:Cite journal</ref> and neck circumference has been associated with increased risk of mechanical ventilation and mortality in hospitalized COVID-19 patients.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Complications

Metabolic syndrome can lead to type 2 diabetes, cardiovascular diseases, stroke, kidney disease and nonalcoholic fatty liver disease.<ref>Template:Cite web</ref> It is also associated with a significantly increased risk of surgical complications across most types of surgery in a 2023 systematic review and meta-analysis of >13 million individuals.<ref>Template:Cite journal</ref>

Causes

The mechanisms underlying metabolic syndrome are under investigation and only partially elucidated. Most affected people are older, obese, sedentary, and have some degree of insulin resistance. Stress can also contribute. Important risk factors include diet (particularly sugar-sweetened beverages),<ref name="PMID20693348">Template:Cite journal</ref> genetics,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Groop2000">Template:Cite journal</ref><ref name="Bouchard1995">Template:Cite journal</ref> aging, sedentary behaviour<ref name="PMID22514690">Template:Cite journal</ref> or low physical activity,<ref name="katzmaryk">Template:Cite journal</ref><ref>Template:Cite journal</ref> disrupted chronobiology/sleep,<ref name="PMID23890470">Template:Cite journal</ref> mood disorders and some medications,<ref name="PMID24262678">Template:Cite journal</ref><ref name="PMID23361837">Template:Cite journal</ref> and excessive alcohol use.<ref name="PMID24315622">Template:Cite journal</ref> The pathogenic role of excessive adipose expansion under sustained overeating and resulting lipotoxicity has also been proposed.<ref>Template:Cite journal</ref>

Markers of systemic inflammation including C-reactive protein, fibrinogen, interleukin 6, and tumor necrosis factor-alpha (TNF-α) are often increased. Some research has focused on increased uric acid levels from dietary fructose.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Modern "Western diet" patterns with high intake of energy-dense processed foods are a factor in the development of metabolic syndrome.<ref name="PMID22351884">Template:Cite journal</ref> Rather than total adiposity, the core clinical component is visceral/ectopic fat, and the principal metabolic abnormality is insulin resistance.<ref>Template:Cite journal</ref> A chronic energy surplus unmatched by activity may lead to mitochondrial dysfunction and insulin resistance.<ref>Template:Cite journal</ref>

Stress

Prolonged chronic stress may contribute to metabolic syndrome via dysregulation of the hypothalamic–pituitary–adrenal axis.<ref name="Gohill">Template:Cite journal</ref> Elevated cortisol can raise glucose and insulin levels, promoting visceral adiposity, insulin resistance, dyslipidaemia, and hypertension, and has effects on bone turnover.<ref name="tsigos">Template:Cite journal</ref><ref name="rosmond">Template:Cite journal</ref><ref name="brunner">Template:Cite journal</ref>

Pathophysiology

It is common for there to be a development of visceral fat, after which adipocytes increase plasma levels of TNF-α and alter levels of other adipokines (e.g., adiponectin, resistin, PAI-1). TNF-α can induce inflammatory cytokines and may trigger insulin resistance.<ref>Template:Cite journal</ref> Rat models with high-sucrose diets have shown progression from hypertriglyceridaemia to visceral fat accumulation and insulin resistance. Increased adipose tissue elevates immune cells and chronic inflammation, contributing to hypertension, atherosclerosis and diabetes.<ref>Whitney, Ellie; Ralfes, R. Sharon. 2011. Understanding Nutrition. Wadsworth Cengage Learning: Belmont, CA.</ref><ref>Template:Cite journal</ref>

The endocannabinoid system may contribute to metabolic dysregulation.<ref name="ECS - metabolic disorders" /><ref name="ECS - MS" /><ref name="AA and endocannabinoids" /> Overproduction can alter reward circuitry and executive function, perpetuating unhealthy behaviours.Template:Medical citation needed The brain modulates peripheral carbohydrate and lipid metabolism.<ref name="ECS - metabolic disorders">Template:Cite book</ref><ref name="ECS - MS">Template:Cite journal</ref> Overfeeding with sucrose/fructose, particularly with high-fat intake, can induce features of metabolic syndrome in animals.<ref>Template:Cite journal</ref> Arachidonic acid–derived mediators (eicosanoids; 2-arachidonoylglycerol; anandamide) may link lipid oversupply and inflammation.<ref name="FAAH">Template:Cite journal</ref><ref name="AA and endocannabinoids">Template:Cite journal</ref>

Diagnosis

NCEP

As of 2023, the U.S. National Cholesterol Education Program Adult Treatment Panel III (2001) remains widely used.<ref name="Anagnostis2023" /> It requires at least three of the following:<ref>Template:Cite journal</ref>

• Central obesity: waist circumference ≥102 cm (40 in) men; ≥88 cm (35 in) women
• Dyslipidaemia: TG ≥1.7 mmol/L (150 mg/dL)
• Dyslipidaemia: HDL-C <40 mg/dL (men), <50 mg/dL (women)
• Blood pressure ≥130/85 mmHg (or treated for hypertension)
• Fasting plasma glucose ≥6.1 mmol/L (110 mg/dL)

2009 Interim Joint Statement

The International Diabetes Federation Task Force and partner organisations harmonised criteria in 2009.<ref name="PMID19805654">Template:Cite journal</ref> Diagnosis is three or more of:

• Elevated waist circumference (population- and country-specific)
• Triglycerides ≥150 mg/dL (1.7 mmol/L)
• Reduced HDL-C (≤40 mg/dL (1.0 mmol/L) men; ≤50 mg/dL (1.3 mmol/L) women)
• Elevated blood pressure (systolic ≥130 and/or diastolic ≥85 mmHg)
• Fasting glucose ≥100 mg/dL (5.55 mmol/L)<ref name="PMID19805654" />

This statement recognises population differences in waist risk thresholds and encourages common criteria with agreed cut points for international comparisons.<ref name="PMID19805654" />

The prior IDF and revised NCEP definitions are similar, but differ on assumptions when body mass index ≥30 kg/m² and on geography-specific waist cut points.Template:Citation needed

WHO

The World Health Organization (1999)<ref>Template:Cite web</ref> requires one of diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance and two of:

• Blood pressure ≥140/90 mmHg
• Dyslipidemia: TG ≥1.695 mmol/L and HDL-C ≤0.9 mmol/L (men), ≤1.0 mmol/L (women)
• Central obesity: waist:hip ratio >0.90 (men); >0.85 (women), or BMI >30 kg/m²
• Microalbuminuria: urinary albumin excretion ≥20 μg/min or albumin:creatinine ≥30 mg/g

EGIR

The European Group for the Study of Insulin Resistance (1999) requires insulin resistance (top 25% fasting insulin among nondiabetic individuals) and two or more of:<ref name="BalkauCharlesEGIR">Template:Cite journal</ref>

• Central obesity: waist ≥94 cm (37 in) men; ≥80 cm (31.5 in) women
• Dyslipidaemia: TG ≥2.0 mmol/L (177 mg/dL) and/or HDL-C <1.0 mmol/L (38.61 mg/dL) or treated for dyslipidaemia
• Blood pressure ≥140/90 mmHg or antihypertensive medication
• Fasting plasma glucose ≥6.1 mmol/L (110 mg/dL)

Cardiometabolic index

The Cardiometabolic Index (CMI) estimates risk of type 2 diabetes, non-alcoholic fatty liver disease, and metabolic issues from waist-to-height ratio and triglycerides-to-HDL-C ratio.<ref name="Pluta Dudzińska Lubkowska 2022 p=624">Template:Cite journal</ref> CMI has also been explored alongside cardiovascular disease and erectile dysfunction.<ref name="Chen Shi Huang Li 2019 p=108585">Template:Cite journal</ref> Anti-inflammatory dietary patterns may improve related markers.<ref name="Bagheri Zolghadri Stanek 2022 p=3985">Template:Cite journal</ref>

Other

High-sensitivity C-reactive protein is used to predict cardiovascular risk in metabolic syndrome and may predict nonalcoholic fatty liver disease.<ref name="pmid19271113">Template:Cite journal</ref> Reproductive disorders (such as polycystic ovary syndrome in women of reproductive age) and erectile dysfunction or decreased total testosterone in men have also been associated.<ref name="PMID20870782">Template:Cite journal</ref>

Prevention

Prevention of metabolic syndrome centres on improving modifiable lifestyle factors that contribute to excess visceral fat, insulin resistance, and cardiometabolic risk. Even modest, sustained changes in activity and diet have been shown to improve multiple components of the syndrome.<ref name=ADA2024/><ref name=Peterseim2024/>

Regular physical activity is strongly supported by clinical and public-health organizations. Guidelines from the American Heart Association recommend at least 150 minutes per week of moderate-intensity aerobic activity, or 75 minutes of vigorous activity, with additional muscle-strengthening exercises on two or more days per week.<ref name=AHA2024/> Walking—even in shorter bouts that accumulate to 30 minutes per day—is associated with measurable improvements in blood pressure, insulin sensitivity, and waist circumference.<ref name=Peterseim2024/>

Dietary patterns emphasizing whole foods appear beneficial. Evidence from observational studies and randomized trials supports Mediterranean-style eating, which is associated with reduced central adiposity and improved lipid and glycaemic measures.<ref name=Dominguez2023/> Calorie reduction, improved diet quality, and lowering intake of refined carbohydrates also contribute to improved metabolic parameters.<ref name=Feinman2015/> Time-restricted eating (a form of intermittent fasting) has shown preliminary benefits in reducing waist circumference and fasting glucose in adults with metabolic syndrome, though long-term effects remain under investigation.<ref name=Manoogian2024/>

Other behavioural factors influence prevention outcomes. Adequate sleep duration and quality have been linked to lower cardiometabolic risk, with insufficient sleep associated with higher rates of hypertension, obesity, and dysregulated glucose metabolism.<ref name=Eshera2023/> Reducing alcohol intake may also be protective, as heavy use can worsen hepatic and metabolic outcomes in people with underlying metabolic risk.<ref name=Hagstrom2024/>

Although individual-level changes are effective for many people, adherence varies widely in real-world settings.<ref name=Feinman2015/> Public-health bodies—including the International Obesity Taskforce—argue that sustained prevention requires population-level interventions, such as improved access to healthy foods, urban design that supports physical activity, and policies addressing socioeconomic drivers of obesity.<ref name="idf.org" />

Management

Management focuses on reducing cardiovascular and metabolic risk through lifestyle modification, pharmacologic therapy, and, in selected cases, surgery.<ref name=Peterseim2024/> Because metabolic syndrome represents a cluster of interrelated conditions, treatment typically targets each component individually rather than the syndrome as a single entity.<ref name=Swarup2024/>

Diet and meal timing

A Mediterranean-style eating pattern—emphasising vegetables, fruits, whole grains, legumes, nuts, and unsaturated fats—is associated with improvements in blood pressure, lipids, insulin sensitivity, and cardiovascular risk.<ref name=Dominguez2023/> Reduced-carbohydrate approaches may lower glucose and promote weight loss in insulin-resistant individuals.<ref name=Feinman2015/> Evidence on meal timing suggests time-restricted eating or avoidance of late-night meals can modestly improve glycaemic and lipid markers, though long-term data are limited.<ref name=Manoogian2024/> Guidance recommends tailoring dietary advice to personal preference, culture, and access to improve adherence.<ref name=Peterseim2024/>

Follow-up and equity considerations

Ongoing follow-up includes monitoring waist circumference, body weight, blood pressure, lipids, and fasting glucose or HbA1c.<ref name=Peterseim2024/> Recent guidance emphasises equitable care through culturally appropriate counselling, affordable medication access, and community-based support.<ref name=Giangregorio2024/>

Medications and therapies

Treatment of individual risk factors follows established cardiovascular and diabetes guidelines.<ref name=Swarup2024/>

• Blood pressure: First-line agents include thiazide-type diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers. Selection depends on comorbid conditions and tolerance.<ref name=Swarup2024/>
• Dyslipidaemia: Statins remain first-line therapy for lowering low-density lipoprotein cholesterol (LDL-C). Fibrates or omega-3 fatty acids may be added for persistent severe hypertriglyceridaemia.<ref name=Grundy2005/>
• Glucose control: Lifestyle intervention is the foundation of therapy. When medications are required, glucose-lowering agents with demonstrated cardiovascular and renal benefits—such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors—are preferred for individuals with type 2 diabetes or elevated cardiovascular risk.<ref name=ADA2024/>
• Obesity management: Pharmacotherapies such as semaglutide and tirzepatide produce clinically significant weight loss and improvements in blood pressure, lipids, and glycaemic control. Randomized controlled trials have reported reduced major adverse cardiovascular events in adults with overweight or obesity and established cardiovascular disease.<ref name=Wilding2021/><ref name=Frias2022/>

Physical activity and weight reduction

Weight loss of ~7–10% over 6–12 months improves BP, lipids, and insulin sensitivity.<ref name=Peterseim2024/> Public-health guidance advises ≥150 min/week moderate aerobic activity (or 75 min vigorous) plus muscle-strengthening ≥2 days/week.<ref name=AHA2024>Template:Cite web</ref>

Sleep, tobacco, and alcohol

Inadequate/irregular sleep and untreated obstructive sleep apnoea increase metabolic and CV risk.<ref name=Eshera2023/> Smoking increases insulin resistance and CV risk; cessation reduces adverse outcomes.<ref name=Swarup2024/> High alcohol intake raises BP, TGs, and hepatic steatosis; moderation is advised.<ref name=Hagstrom2024/>

Surgery

Metabolic (bariatric) surgery is considered when lifestyle and pharmacotherapy are insufficient. Surgery is associated with durable weight loss and partial or complete remission of type 2 diabetes, hypertension, and dyslipidaemia.<ref name=Mirghani2023/> Guidelines endorse surgery for BMI ≥35 kg/m², or ≥30 kg/m² with metabolic complications.<ref name=Angrisani2023/>

Epidemiology

Template:Main Approximately 20–25% of the world's adults have metabolic syndrome.<ref name="idf.org" /> In 2000, ~32% of U.S. adults met criteria;<ref name="Ford ES">Template:Cite journal</ref><ref name="Ford ES et al">Template:Cite journal</ref> more recent estimates are ~34%.<ref name="Ford ES et al" /><ref>Template:Cite journal</ref>

In young children, there is no consensus on measurement; age-specific cut points are not well established.<ref name="Metabolic syndrome in children">Template:Cite journal</ref> Continuous risk scores are often used instead.<ref name="Continuous measure for metabolic syndrome in children">Template:Cite journal</ref> Microbiome composition and some conditions have been associated with metabolic syndrome, sometimes with gender-specific patterns.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

History

In 1921, Joslin reported the association of diabetes with hypertension and hyperuricaemia.<ref>Template:Cite journal</ref> In 1923, Kylin expanded on this triad.<ref>Template:Cite journal</ref> In 1947, Vague observed that upper-body obesity predisposed to diabetes, atherosclerosis, gout and calculi.<ref>Template:Cite journal</ref> The term metabolic syndrome began appearing in the late 1950s. In 1967, Avogaro, Crepaldi and coworkers described moderately obese people with diabetes, hypercholesterolemia, and marked hypertriglyceridemia that improved on hypocaloric, low-carbohydrate diets.<ref>Template:Cite journal</ref> In 1977, Haller used the term for associations of obesity, diabetes mellitus, hyperlipoproteinemia, hyperuricemia, and hepatic steatosis.<ref>Template:Cite journal</ref> The same year, Singer used it for associations of obesity, gout, diabetes, and hypertension with hyperlipoproteinemia.<ref>Template:Cite journal</ref> In 1977–1978, Gerald B. Phillips proposed a "constellation of abnormalities" (glucose intolerance, hyperinsulinemia, hypercholesterolemia, hypertriglyceridemia, hypertension) and hypothesised sex hormones as a linking factor.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In 1988, Gerald M. Reaven's Banting lecture proposed insulin resistance as the underlying factor and coined syndrome X.<ref>Template:Cite journal</ref>

See also

• Metabolic disorder
• Portal-visceral hypothesis

References

<references> <ref name=ADA2024>Template:Cite journal</ref> <ref name=Angrisani2023>Template:Cite journal</ref> <ref name=Dominguez2023>Template:Cite journal</ref> <ref name=Eshera2023>Template:Cite journal</ref> <ref name=Feinman2015>Template:Cite journal</ref> <ref name=Frias2022>Template:Cite journal</ref> <ref name=Giangregorio2024>Template:Cite journal</ref> <ref name=Grundy2005>Template:Cite journal</ref> <ref name=Hagstrom2024>Template:Cite journal</ref> <ref name="idf.org">Template:Cite web</ref> <ref name=Manoogian2024>Template:Cite journal</ref> <ref name=Mirghani2023>Template:Cite journal</ref> <ref name=Peterseim2024>Template:Cite journal</ref> <ref name=Swarup2024>Template:Cite book</ref> <ref name=Wilding2021>Template:Cite journal</ref> </references>