A man with marked central obesity, a hallmark of metabolic syndrome. His weight is 182 kg (400 lbs), height 185 cm (6 ft 1 in), and
body mass index (BMI) 53 (normal 18.5 to 25).
Metabolic syndrome is associated with the risk of developing
cardiovascular disease and
type 2 diabetes.[1] In the U.S., about 25% of the adult population has metabolic syndrome, a proportion increasing with age, particularly among racial and ethnic minorities.[2][3]
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.[4]
Neck circumference has been used as a surrogate simple and reliable index to indicate upper-body subcutaneous fat accumulation. Neck circumference of more than 40.25 cm (15.85 in) for men and more than 35.75 cm (14.07 in) for women are considered high-risk for metabolic syndrome. Persons with large neck circumferences have a more-than-double risk of metabolic syndrome.[7] In adults with overweight/obesity, clinically significant weight loss may protect against COVID-19[8] and neck circumference has been associated with the risk of being mechanically ventilated in COVID-19 patients, with a 26% increased risk for each centimeter increase in neck circumference.[9] Moreover, hospitalized COVID-19 patients with a "large neck phenotype" on admission had a more than double risk of death.[10]
Furthermore, metabolic syndrome is associated with a significantly increased risk of surgical complications across most types of surgery in a 2023 systematic review and meta-analysis of over 13 million individuals.[12]
Causes
The mechanisms of the complex pathways of metabolic syndrome are under investigation. The
pathophysiology is very complex and has been only partially elucidated. Most people affected by the condition are older, obese, sedentary, and have a degree of insulin resistance.
Stress can also be a contributing factor. The most important
risk factors are diet (particularly sugar-sweetened beverage consumption),[13] genetics,[14][15][16][17] aging, sedentary behavior[18] or low physical activity,[19][20] disrupted
chronobiology/sleep,[21] mood disorders/psychotropic medication use,[22][23] and excessive alcohol use.[24] The pathogenic role played in the syndrome by the excessive expansion of adipose tissue occurring under sustained
overeating, and its resulting
lipotoxicity was reviewed by
Vidal-Puig.[25]
There is debate regarding whether obesity or insulin resistance is the cause of the metabolic syndrome or if they are consequences of a more far-reaching metabolic derangement. Markers of systemic
inflammation, including
C-reactive protein, are often increased, as are
fibrinogen,
interleukin 6,
tumor necrosis factor-alpha (TNF-α), and others. Some have pointed to a variety of causes, including increased
uric acid levels caused by dietary
fructose.[26][27][28]
Research shows that Western diet habits are a factor in the development of metabolic syndrome, with high consumption of food that is not biochemically suited to humans.[29][page needed] Weight gain is associated with metabolic syndrome. Rather than total adiposity, the core clinical component of the syndrome is visceral and/or ectopic fat (i.e., fat in organs not designed for fat storage) whereas the principal metabolic abnormality is insulin resistance.[30] The continuous provision of energy via dietary
carbohydrate,
lipid, and
protein fuels, unmatched by physical activity/energy demand, creates a backlog of the products of
mitochondrial oxidation, a process associated with progressive mitochondrial dysfunction and insulin resistance.[citation needed]
Stress
Recent research indicates prolonged
chronic stress can contribute to metabolic syndrome by disrupting the hormonal balance of the
hypothalamic-pituitary-adrenal axis (HPA-axis).[31] A dysfunctional HPA-axis causes high
cortisol levels to circulate, which results in raising
glucose and
insulin levels, which in turn cause insulin-mediated effects on adipose tissue, ultimately promoting
visceral adiposity, insulin resistance, dyslipidemia and hypertension, with direct effects on the bone, causing "low turnover"
osteoporosis.[32] HPA-axis dysfunction may explain the reported risk indication of abdominal obesity to
cardiovascular disease (CVD), type 2 diabetes and
stroke.[33]Psychosocial stress is also linked to heart disease.[34]
Obesity
Central obesity is a key feature of the syndrome, as both a sign and a cause, in that the increasing adiposity often reflected in high
waist circumference may both result from and contribute to insulin resistance. However, despite the importance of obesity, affected people who are of normal weight may also be insulin-resistant and have the syndrome.[35]
Sedentary lifestyle
Physical inactivity is a predictor of CVD events and related
mortality. Many components of metabolic syndrome are associated with a
sedentary lifestyle, including increased adipose tissue (predominantly central); reduced HDL cholesterol; and a trend toward increased triglycerides, blood pressure, and glucose in the genetically susceptible. Compared with individuals who watched television or videos or used their computers for less than one hour daily, those who carried out these behaviors for greater than four hours daily have a twofold increased risk of metabolic syndrome.[35]
Aging
Metabolic syndrome affects 60% of the U.S. population older than age 50. With respect to that demographic, the percentage of women having the syndrome is higher than that of men. The age dependency of the syndrome's prevalence is seen in most populations around the world.[35]
The metabolic syndrome quintuples the risk of type 2 diabetes mellitus. Type 2 diabetes is considered a
complication of metabolic syndrome.[1] In people with impaired glucose tolerance or impaired fasting glucose, presence of metabolic syndrome doubles the risk of developing type 2 diabetes.[36] It is likely that prediabetes and metabolic syndrome denote the same disorder, defining it by the different sets of biological markers.[citation needed]
The presence of metabolic syndrome is associated with a higher prevalence of CVD than found in people with type 2 diabetes or
impaired glucose tolerance without the syndrome.[35]Hypoadiponectinemia has been shown to increase insulin resistance[37] and is considered to be a risk factor for developing metabolic syndrome.[38]
Coronary heart disease
The approximate prevalence of the metabolic syndrome in people with
coronary artery disease (CAD) is 50%, with a prevalence of 37% in people with premature coronary artery disease (age 45), particularly in women. With appropriate
cardiac rehabilitation and changes in lifestyle (e.g., nutrition, physical activity, weight reduction, and, in some cases, drugs), the prevalence of the syndrome can be reduced.[35]
There is research that associates comorbidity with rheumatic diseases. Both
psoriasis and
psoriatic arthritis have been found to be associated with metabolic syndrome.[39]
Chronic obstructive pulmonary disease
Metabolic syndrome is seen to be a comorbidity in up to 50 percent of those with
chronic obstructive pulmonary disease (COPD). It may pre-exist or may be a consequence of the lung pathology of COPD.[40]
Pathophysiology
It is common for there to be a development of
visceral fat, after which the
adipocytes (fat cells) of the visceral fat increase
plasma levels of
TNF-α and alter levels of other substances (e.g.,
adiponectin,
resistin, and
PAI-1). TNF-α has been shown to cause the production of inflammatory
cytokines and also possibly trigger cell signaling by interaction with a
TNF-α receptor that may lead to insulin resistance.[41] An experiment with rats fed a diet with 33%
sucrose has been proposed as a model for the development of metabolic syndrome. The sucrose first elevated blood levels of triglycerides, which induced visceral fat and ultimately resulted in insulin resistance. The progression from visceral fat to increased TNF-α to insulin resistance has some parallels to human development of metabolic syndrome. The increase in adipose tissue also increases the number of immune cells, which play a role in inflammation. Chronic inflammation contributes to an increased risk of hypertension, atherosclerosis and diabetes.[42]
The involvement of the
endocannabinoid system in the development of metabolic syndrome is indisputable.[43][44][45] Endocannabinoid overproduction may induce
reward system dysfunction[44] and cause
executive dysfunctions (e.g., impaired delay discounting), in turn perpetuating unhealthy behaviors.[medical citation needed] The brain is crucial in development of metabolic syndrome, modulating peripheral carbohydrate and lipid metabolism.[43][44]
As of 2023, the U.S.
National Cholesterol Education Program Adult Treatment Panel III (2001) continues to be the most widely-used clinical definition.[4] It requires at least three of the following:[48]
Central obesity: waist circumference ≥ 102 cm or 40 inches (male), ≥ 88 cm or 35 inches(female)
This definition recognizes that the risk associated with a particular waist measurement will differ in different populations. However, for international comparisons and to facilitate the etiology, the organizations agree that it is critical that a commonly agreed-upon set of criteria be used worldwide, with agreed-upon cut points for different ethnic groups and sexes. There are many people in the world of mixed ethnicity, and in those cases, pragmatic decisions will have to be made. Therefore, an international criterion of overweight may be more appropriate than ethnic specific criteria of abdominal obesity for an anthropometric component of this syndrome which results from an excess lipid storage in adipose tissue, skeletal muscle and liver.[49]
The report notes that previous definitions of the metabolic syndrome by the International Diabetes Federation[50] (IDF) and the revised
National Cholesterol Education Program (NCEP) are very similar, and they identify individuals with a given set of symptoms as having metabolic syndrome. There are two differences, however: the IDF definition states that if
body mass index (BMI) is greater than 30 kg/m2, central obesity can be assumed, and waist circumference does not need to be measured. However, this potentially excludes any subject without increased waist circumference if BMI is less than 30. Conversely, the NCEP definition indicates that metabolic syndrome can be diagnosed based on other criteria. Also, the IDF uses geography-specific cut points for waist circumference, while NCEP uses only one set of cut points for waist circumference regardless of geography.[citation needed]
WHO
The
World Health Organization (1999)[51] requires the presence of any one of diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance, AND two of the following:
Central obesity: waist:hip ratio > 0.90 (male); > 0.85 (female), or BMI > 30 kg/m2
Microalbuminuria: urinary albumin excretion ratio ≥ 20 µg/min or albumin:creatinine ratio ≥ 30 mg/g
EGIR
The
European Group for the Study of Insulin Resistance (1999) requires that subjects have insulin resistance (defined for purposes of clinical practivality as the top 25% of the fasting insulin values among nondiabetic individuals) AND two or more of the following:[52]
Central obesity: waist circumference ≥ 94 cm or 37 inches (male), ≥ 80 cm or 31.5 inches (female)
Dyslipidemia: TG ≥ 2.0 mmol/L (177 mg/dL) and/or HDL-C < 1.0 mmol/L (38.61 mg/dL) or treated for dyslipidemia
Blood pressure ≥ 140/90 mmHg or antihypertensive medication
Fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dL)
Cardiometabolic index
The Cardiometabolic index (CMI) is a tool used to calculate risk of type 2 diabetes, non-alcoholic fatty liver disease,[53] and metabolic issues. It is based on calculations from waist-to-height ratio and triglycerides-to-HDL cholesterol ratio.[54]
CMI can also be used for finding connections between cardiovascular disease and erectile dysfunction.[55] When following an anti inflammatory diet (low-glycemic carbohydrates, fruits, vegetables, fish, less red meat and processed foods) the markers may drop resulting in a significant reduction in body weight and adipose tissue.[56]
Other
High-sensitivity C-reactive protein has been developed and used as a marker to predict coronary vascular diseases in metabolic syndrome, and it was recently used as a predictor for nonalcoholic fatty liver disease (steatohepatitis) in correlation with serum markers that indicated lipid and glucose metabolism.[57] Fatty liver disease and steatohepatitis can be considered manifestations of metabolic syndrome, indicative of abnormal energy storage as fat in ectopic distribution.
Reproductive disorders (such as polycystic ovary syndrome in women of reproductive age), and erectile dysfunction or decreased total testosterone (low testosterone-binding globulin) in men can be attributed to metabolic syndrome.[58]
Prevention
Various strategies have been proposed to prevent the development of metabolic syndrome. These include increased
physical activity (such as walking 30 minutes every day),[59] and a healthy, reduced calorie diet.[60] Many studies support the value of a healthy lifestyle as above. However, one study stated these potentially beneficial measures are effective in only a minority of people, primarily because of a lack of compliance with lifestyle and diet changes.[19] The
International Obesity Taskforce states that interventions on a sociopolitical level are required to reduce development of the metabolic syndrome in populations.[61]
The
Caerphilly Heart Disease Study followed 2,375 male subjects over 20 years and suggested the daily intake of an Imperial
pint (~568 mL) of milk or equivalent dairy products more than halved the risk of metabolic syndrome.[62] Some subsequent studies support the authors' findings, while others dispute them.[63] A systematic review of four
randomized controlled trials said that, in the short term, a
paleolithic nutritional pattern improved three of five measurable components of the metabolic syndrome in participants with at least one of the components.[64]
Management
Medications
Generally, the individual disorders that compose the metabolic syndrome are treated separately.[65]Diuretics and
ACE inhibitors may be used to treat hypertension. Various cholesterol medications may be useful if LDL cholesterol, triglycerides, and/or HDL cholesterol is abnormal.[citation needed]
Diet
Dietary
carbohydrate restriction reduces blood glucose levels, contributes to weight loss, and reduces the use of several medications that may be prescribed for metabolic syndrome.[66]
Approximately 20–25 percent of the world's adult population has the cluster of risk factors that is metabolic syndrome.[50] In 2000, approximately 32% of U.S. adults had metabolic syndrome.[67][68] In more recent years that figure has climbed to 34%.[68][69]
In young children, there is no consensus on how to measure metabolic syndrome since age-specific cut points and reference values that would indicate "high risk" have not been well established.[70] A continuous cardiometabolic risk summary score is often used for children instead of a dichotomous measure of metabolic syndrome.[71]
Other conditions[72] and specific microbiome diversity[73] seems to be associated with metabolic syndrome, with certain-degree of gender-specificity.[74]
History
In 1921, Joslin first reported the association of diabetes with hypertension and hyperuricemia.[75]
In 1923, Kylin reported additional studies on the above triad.[76]
In 1947, Vague observed that upper body obesity appeared to predispose to
diabetes,
atherosclerosis,
gout and
calculi.[77]
In the late 1950s, the term metabolic syndrome was first used.
In 1967, Avogadro, Crepaldi and coworkers described six moderately obese people with diabetes,
hypercholesterolemia, and marked
hypertriglyceridemia, all of which improved when the affected people were put on a hypocaloric, low-carbohydrate diet.[78]
In 1977, Haller used the term metabolic syndrome for associations of obesity, diabetes mellitus,
hyperlipoproteinemia,
hyperuricemia, and
hepatic steatosis when describing the additive effects of risk factors on atherosclerosis.[79]
The same year, Singer used the term for associations of obesity, gout, diabetes mellitus, and hypertension with hyperlipoproteinemia.[80]
In 1977 and 1978, Gerald B. Phillips developed the concept that risk factors for
myocardial infarction concur to form a "constellation of abnormalities" (i.e.,
glucose intolerance,
hyperinsulinemia,
hypercholesterolemia,
hypertriglyceridemia, and hypertension) associated not only with heart disease, but also with aging, obesity and other clinical states. He suggested there must be an underlying linking factor, the identification of which could lead to the prevention of cardiovascular disease; he hypothesized that this factor was
sex hormones.[81][82]
In 1988, in his
Banting lecture,
Gerald M. Reaven proposed insulin resistance as the underlying factor and named the constellation of abnormalities syndrome X. Reaven did not include abdominal obesity, which has also been hypothesized as the underlying factor, as part of the condition.[83]
^Bouchard C (May 1995). "Genetics and the metabolic syndrome". International Journal of Obesity and Related Metabolic Disorders. 19 (Suppl 1): S52–59.
PMID7550538.
^He D, Xi B, Xue J, Huai P, Zhang M, Li J (June 2014). "Association between leisure time physical activity and metabolic syndrome: a meta-analysis of prospective cohort studies". Endocrine. 46 (2): 231–40.
doi:
10.1007/s12020-013-0110-0.
PMID24287790.
S2CID5271746.
^Xi B, He D, Zhang M, Xue J, Zhou D (August 2014). "Short sleep duration predicts risk of metabolic syndrome: a systematic review and meta-analysis". Sleep Medicine Reviews. 18 (4): 293–97.
doi:
10.1016/j.smrv.2013.06.001.
PMID23890470.
^Vancampfort D, Vansteelandt K, Correll CU, Mitchell AJ, De Herdt A, Sienaert P, Probst M, De Hert M (March 2013). "Metabolic syndrome and metabolic abnormalities in bipolar disorder: a meta-analysis of prevalence rates and moderators". The American Journal of Psychiatry. 170 (3): 265–74.
doi:
10.1176/appi.ajp.2012.12050620.
PMID23361837.
^Sun K, Ren M, Liu D, Wang C, Yang C, Yan L (August 2014). "Alcohol consumption and risk of metabolic syndrome: a meta-analysis of prospective studies". Clinical Nutrition. 33 (4): 596–602.
doi:
10.1016/j.clnu.2013.10.003.
PMID24315622.
^Vidal-Puig A (2013). "Adipose tissue expandability, lipotoxicity and the metabolic syndrome". Endocrinologia y Nutricion. 60 (Suppl 1): 39–43.
doi:
10.1016/s1575-0922(13)70026-3.
PMID24490226.
^Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ (March 2006). "A causal role for uric acid in fructose-induced metabolic syndrome". American Journal of Physiology. Renal Physiology. 290 (3): F625–31.
doi:
10.1152/ajprenal.00140.2005.
PMID16234313.
^Gohil BC, Rosenblum LA, Coplan JD, Kral JG (July 2001). "Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of obesity". CNS Spectrums. 6 (7): 581–86, 589.
doi:
10.1017/s1092852900002121.
PMID15573024.
S2CID22734016.
^Lara-Castro C, Fu Y, Chung BH, Garvey WT (June 2007). "Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease". Current Opinion in Lipidology. 18 (3): 263–70.
doi:
10.1097/MOL.0b013e32814a645f.
PMID17495599.
S2CID20799218.
^Renaldi O, Pramono B, Sinorita H, Purnomo LB, Asdie RH, Asdie AH (January 2009). "Hypoadiponectinemia: a risk factor for metabolic syndrome". Acta Medica Indonesiana. 41 (1): 20–24.
PMID19258676.
^Whitney, Ellie and Ralfes, R. Sharon. 2011. Understanding Nutrition.
Wadsworth Cengage Learning: Belmont, CA
^
abGatta-Cherifi B, Cota D (2015). "Endocannabinoids and Metabolic Disorders". Endocannabinoids. Handbook of Experimental Pharmacology. Vol. 231. pp. 367–91.
doi:
10.1007/978-3-319-20825-1_13.
ISBN978-3-319-20824-4.
PMID26408168. The endocannabinoid system (ECS) is known to exert regulatory control on essentially every aspect related to the search for, and the intake, metabolism and storage of calories, and consequently it represents a potential pharmacotherapeutic target for obesity, diabetes and eating disorders. ... recent research in animals and humans has provided new knowledge on the mechanisms of actions of the ECS in the regulation of eating behavior, energy balance, and metabolism. In this review, we discuss these recent advances and how they may allow targeting the ECS in a more specific and selective manner for the future development of therapies against obesity, metabolic syndrome, and eating disorders.
^
abcVemuri VK, Janero DR,
Makriyannis A (March 2008).
"Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome". Physiology & Behavior. 93 (4–5): 671–86.
doi:
10.1016/j.physbeh.2007.11.012.
PMC3681125.
PMID18155257. The etiology of many appetitive disorders is characterized by a pathogenic component of reward-supported craving, be it for substances of abuse (including alcohol and nicotine) or food. Such maladies affect large numbers of people as prevalent socioeconomic and healthcare burdens. Yet in most instances drugs for their safe and effective pharmacotherapeutic management are lacking despite the attendant medical needs, collateral adverse physical and psychological effects, and enormous global market potential. The endocannabinoid signaling system plays a critical role in motivational homeostasis as a conduit for reward stimuli and a positive modulator of brain reward circuits. Endocannabinoid-system hyperactivity through CB1 receptor transmission is considered contributory to a range of appetitive disorders and, hence, is a major focus of contemporary pharmaceutical research.
^
abcdTurcotte C, Chouinard F, Lefebvre JS, Flamand N (June 2015). "Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites". Journal of Leukocyte Biology. 97 (6): 1049–70.
doi:
10.1189/jlb.3RU0115-021R.
PMID25877930.
S2CID206999921.
^Fukuchi S, Hamaguchi K, Seike M, Himeno K, Sakata T, Yoshimatsu H (June 2004). "Role of fatty acid composition in the development of metabolic disorders in sucrose-induced obese rats". Experimental Biology and Medicine. 229 (6): 486–93.
doi:
10.1177/153537020422900606.
PMID15169967.
S2CID20966659.
^Expert Panel On Detection, Evaluation (May 2001). "Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults". JAMA. 285 (19): 2486–97.
doi:
10.1001/jama.285.19.2486.
PMID11368702.
^Balkau B, Charles MA (May 1999). "Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR)". Diabet Med. 16 (5): 442–3.
doi:
10.1046/j.1464-5491.1999.00059.x.
PMID10342346.
^Kogiso T, Moriyoshi Y, Shimizu S, Nagahara H, Shiratori K (2009). "High-sensitivity C-reactive protein as a serum predictor of nonalcoholic fatty liver disease based on the Akaike Information Criterion scoring system in the general Japanese population". Journal of Gastroenterology. 44 (4): 313–21.
doi:
10.1007/s00535-009-0002-5.
PMID19271113.
S2CID1193178.
^Lakka TA, Laaksonen DE (February 2007). "Physical activity in prevention and treatment of the metabolic syndrome". Applied Physiology, Nutrition, and Metabolism. 32 (1): 76–88.
doi:
10.1139/h06-113.
PMID17332786.
^Feldeisen SE, Tucker KL (February 2007). "Nutritional strategies in the prevention and treatment of metabolic syndrome". Applied Physiology, Nutrition, and Metabolism. 32 (1): 46–60.
doi:
10.1139/h06-101.
PMID17332784.
^James PT, Rigby N, Leach R (February 2004). "The obesity epidemic, metabolic syndrome and future prevention strategies". European Journal of Cardiovascular Prevention and Rehabilitation. 11 (1): 3–8.
doi:
10.1097/01.hjr.0000114707.27531.48.
PMID15167200.
S2CID36797932.
^Kylin E (1923). "[Studies of the hypertension-hyperglycemia-hyperuricemia syndrome]". Zentralbl Inn Med (in German). 44: 105–127.
^Vague J (1947). "La diffférenciacion sexuelle, facteur déterminant des formes de l'obésité". Presse Med. 30: 339–340.
^Avogaro P, Crepaldi G, Enzi G, Tiengo A (1967). "Associazione di iperlipemia, diabete mellito e obesita' di medio grado" [Association of hyperlipemia, diabetes mellitus and middle-degree obesity]. Acta Diabetologica Latina (in Italian). 4 (4): 572–90.
doi:
10.1007/BF01544100.
S2CID25839940.
^Haller H (April 1977). "[Epidermiology and associated risk factors of hyperlipoproteinemia]". Zeitschrift für Sie Gesamte Innere Medizin und Ihre Grenzgebiete. 32 (8): 124–28.
PMID883354.
^Singer P (May 1977). "[Diagnosis of primary hyperlipoproteinemias]". Zeitschrift für die Gesamte Innere Medizin und Ihre Grenzgebiete. 32 (9): 129–33.
PMID906591.
^Phillips GB (July 1978). "Sex hormones, risk factors and cardiovascular disease". The American Journal of Medicine. 65 (1): 7–11.
doi:
10.1016/0002-9343(78)90685-X.
PMID356599.