Metabolic syndrome
Encyclopedia
Metabolic syndrome is a combination of medical
disorders that, when occurring together, increase the risk of developing cardiovascular disease
and diabetes
. It affects one in five people in the United States and prevalence increases with age. Some studies have shown the prevalence
in the USA to be an estimated 25% of the population.
Metabolic syndrome is also known as metabolic syndrome X, cardiometabolic syndrome, syndrome X, insulin resistance syndrome, Reaven's syndrome (named for Gerald Reaven
), and CHAOS (in Australia). A similar condition in overweight horses is referred to as equine metabolic syndrome
; it is unknown if they have the same etiology
.
and the revised National Cholesterol Education Program
. These are very similar and they identify individuals with a given set of symptoms as having metabolic syndrome. There are two differences, however: the IDF state that if BMI
> 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 < 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. These two definitions are much more similar than the original NCEP and WHO definitions.
The IDF consensus worldwide definition of the metabolic syndrome (2006)
Central obesity (defined as waist circumference# with ethnicity specific values)
AND any two of the following:
# If BMI is >30 kg/m², central obesity can be assumed and waist circumference does not need to be measured
criteria (1999) require presence of one of:
AND two of the following:
(hs-CRP
) 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 non-alcoholic fatty liver disease
in correlation with serum markers that indicated lipid and glucose metabolism.
The terms "metabolic syndrome," "insulin resistance syndrome," and "syndrome X" are now used specifically to define a constellation of abnormalities that is associated with increased risk for the development of type 2 diabetes and atherosclerotic vascular disease (e.g., heart disease and stroke).
is extremely complex and has been only partially elucidated. Most patients are older, obese, sedentary, and have a degree of insulin resistance
. Stress
can also be a contributing factor. The most important factors are:
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. A number of markers of systemic inflammation
, including C-reactive protein
, are often increased, as are fibrinogen
, interleukin 6
(IL–6), Tumor necrosis factor-alpha (TNFα), and others. Some have pointed to a variety of causes including increased uric acid
levels caused by dietary fructose
.
s (fat cell
s) of the visceral fat increase plasma
levels of TNFα and alter levels of a number of other substances (e.g., adiponectin
, resistin
, PAI-1). TNFα has been shown not only to cause the production of inflammatory cytokine
s but possibly to trigger cell signaling by interaction with a TNFα receptor
that may lead to insulin resistance . An experiment with rats that were fed a diet one-third of which was sucrose
has been proposed as a model for the development of metabolic syndrome. The sucrose first elevated blood levels of triglyceride
s, which induced visceral fat and ultimately resulted in insulin resistance. The progression from visceral fat to increased TNFα to insulin resistance has some parallels to human development of metabolic syndrome. The increase in adipose tissue also increases the number of immune cells present within, which play a role in inflammation. Chronic inflammation contributes to an increased risk of hypertension, artherosclerosis and diabetes.
can be an underlying cause of metabolic syndrome by upsetting the hormonal balance of the hypothalamic-pituitary-adrenal axis
(HPA-axis).
A dysfunctional HPA-axis causes high cortisol
levels to circulate which results in raising glucose
and insulin
levels which 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
. HPA-axis dysfunction may explain the reported risk indication of abdominal obesity
to cardiovascular disease
, type 2 diabetes and stroke
. Psychosocial
stress is also linked to heart disease
.
is a key feature of the syndrome, reflecting the fact that the syndrome's prevalence is driven by the strong relationship between waist
circumference
and increasing adiposity. However, despite the importance of obesity
, patients that are of normal weight may also be insulin-resistant
and have the syndrome.
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 computer
for less than one hour daily, those that carried out these behaviors for greater than four hours daily have a twofold increased risk
of metabolic syndrome.
(IGT
) have metabolic syndrome - . The presence of metabolic syndrome in these populations is associated with a higher prevalence of CVD than found in patients with type 2 diabetes or IGT without the syndrome. Hypoadiponectinemia has been shown to increase insulin resistance
, and is considered to be a risk factor
for developing metabolic syndrome.
(CHD
) is 50%, with a prevalence of 37% in patients 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.
) and acquired (e.g., HIV
-related lipodystrophy
in patients treated with highly active antiretroviral therapy) forms of lipodystrophy may give rise to severe insulin resistance
and many of metabolic syndrome's components.
, schizoaffective disorder
or bipolar disorder
may have a predisposition to metabolic syndrome that is exacerbated by sedentary lifestyle, poor dietary habits, possible limited access to care, and antipsychotic drug-induced adverse effects. It has been found that 32% and 51% of individuals with schizophrenia meet criteria for metabolic syndrome; the prevalence is higher in women than in men.
Associated diseases and signs are: hyperuricemia
, fatty liver
(especially in concurrent obesity
) progressing to non-alcoholic fatty liver disease
, polycystic ovarian syndrome (in women), and acanthosis nigricans
.
A 2007 study of 2,375 male subjects over 20 years suggested that daily intake of a pint (~568 ml) of milk or equivalent dairy products more than halved the risk of metabolic syndrome. Some subsequent studies support the authors' findings, while others dispute them.
s and ACE inhibitor
s may be used to treat hypertension
. Cholesterol drugs may be used to lower LDL cholesterol and triglyceride levels, if they are elevated, and to raise HDL levels if they are low. Use of drugs that decrease insulin resistance
, e.g., metformin
and thiazolidinedione
s, is controversial; this treatment is not approved by the U.S. Food and Drug Administration.
A 2003 study indicated that cardiovascular exercise was therapeutic in approximately 31% of cases. The most probable benefit was to triglyceride levels, with 43% showing improvement; but fasting plasma glucose and insulin resistance of 91% of test subjects did not improve.
Many other studies have supported the value of increased physical activity and restricted caloric intake (exercise and diet) to treat metabolic syndrome.
Restricting the overall dietary carbohydrate intake is more effective in reducing the most common symptoms of metabolic syndrome than the more commonly prescribed reduction in dietary fat intake.
These concerns have led to the American Diabetes Association
and the European Association for the Study of Diabetes
to issue a joint statement identifying eight major concerns on the clinical utility of the metabolic syndrome.
It is not contested that cardiovascular risk factors tend to cluster together, but what is contested is the assertion that the metabolic syndrome is anything more than the sum of its constituent parts.
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
disorders that, when occurring together, increase the risk of developing cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
and diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
. It affects one in five people in the United States and prevalence increases with age. Some studies have shown the prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
in the USA to be an estimated 25% of the population.
Metabolic syndrome is also known as metabolic syndrome X, cardiometabolic syndrome, syndrome X, insulin resistance syndrome, Reaven's syndrome (named for Gerald Reaven
Gerald Reaven
Gerald M. "Jerry" Reaven is an American endocrinologist and professor emeritus in medicine at the Stanford University School of Medicine in Stanford, California, United States.Reaven's work on insulin resistance and diabetes with John W...
), and CHAOS (in Australia). A similar condition in overweight horses is referred to as equine metabolic syndrome
Equine metabolic syndrome
Also known as Peripheral Cushings Disease and Equine Syndrome X.It is an illness affecting Equidae .This is an area of much new research and is increasingly believed to have a major role in conditions such as laminitis...
; it is unknown if they have the same etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
.
Definitions and diagnosis
Presently there are a couple of sets of defining criteria for metabolic syndrome set out by two different sources -- the International Diabetes FederationInternational Diabetes Federation
The International Diabetes Federation is a worldwide alliance of some 200 diabetes associations in more than 160 countries, who have come together to enhance the lives of people with diabetes everywhere. For over 50 years, IDF has been at the vanguard of global diabetes advocacy...
and the revised National Cholesterol Education Program
National Cholesterol Education Program
The National Cholesterol Education Program is a program managed by the National Heart, Lung and Blood Institute, a division of the National Institutes of Health. Its goal is to reduce increased cardiovascular disease rates due to hypercholesterolemia in the United States of America...
. These are very similar and they identify individuals with a given set of symptoms as having metabolic syndrome. There are two differences, however: the IDF state that if BMI
Body mass index
The body mass index , or Quetelet index, is a heuristic proxy for human body fat based on an individual's weight and height. BMI does not actually measure the percentage of body fat. It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing...
> 30 kg/m2, central obesity
Central obesity
Abdominal obesity, colloquially known as belly fat or clinically as central obesity, is the accumulation of abdominal fat resulting in an increase in waist size...
can be assumed, and waist circumference does not need to be measured. However, this potentially excludes any subject without increased waist circumference if BMI < 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. These two definitions are much more similar than the original NCEP and WHO definitions.
IDF
International Diabetes FederationInternational Diabetes Federation
The International Diabetes Federation is a worldwide alliance of some 200 diabetes associations in more than 160 countries, who have come together to enhance the lives of people with diabetes everywhere. For over 50 years, IDF has been at the vanguard of global diabetes advocacy...
The IDF consensus worldwide definition of the metabolic syndrome (2006)
Central obesity (defined as waist circumference# with ethnicity specific values)
AND any two of the following:
- Raised triglycerides: > 150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality.
- Reduced HDL cholesterol: < 40 mg/dL (1.03 mmol/L) in males, < 50 mg/dL (1.29 mmol/L) in females, or specific treatment for this lipid abnormality
- Raised blood pressure: systolic BP > 130 or diastolic BP >85 mm Hg, or treatment of previously diagnosed hypertension.
- Raised fasting plasma glucose :(FPG)>100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes. If FPG >5.6 mmol/L or 100 mg/dL, OGTT Glucose tolerance testGlucose tolerance testA glucose tolerance test is a medical test in which glucose is given and blood samples taken afterward to determine how quickly it is cleared from the blood. The test is usually used to test for diabetes, insulin resistance, and sometimes reactive hypoglycemia and acromegaly, or rarer disorders of...
is strongly recommended but is not necessary to define presence of the Syndrome.
# If BMI is >30 kg/m², central obesity can be assumed and waist circumference does not need to be measured
WHO
The World Health OrganizationWorld Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
criteria (1999) require presence of one of:
- Diabetes mellitus,
- Impaired glucose tolerance,
- Impaired fasting glucose or
- Insulin resistanceInsulin resistanceInsulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
;
AND two of the following:
- Blood pressure: ≥ 140/90 mmHg
- DyslipidemiaDyslipidemiaDyslipidemia or dyslipidaemia is an abnormal amount of lipids in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. The prolonged elevation of insulin levels can lead to dyslipidemia...
: triglycerides (TG): ≥ 1.695 mmol/L and high-density lipoproteinLipoproteinA lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
cholesterol (HDL-C) ≤ 0.9 mmol/L (male), ≤ 1.0 mmol/L (female) - Central obesity: waist:hip ratio > 0.90 (male); > 0.85 (female), or body mass index > 30 kg/m2
- MicroalbuminuriaMicroalbuminuriaMicroalbuminuria occurs when the kidney leaks small amounts of albumin into the urine, in other words, when there is an abnormally high permeability for albumin in the renal glomerulus.-Diagnosis:...
: 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 insulin resistance defined as the top 25% of the fasting insulin values among non-diabetic individuals AND two or more of the following:- central obesity: waist circumference ≥ 94 cm (male), ≥ 80 cm (female)
- dyslipidemia: TG ≥ 2.0 mmol/L and/or HDL-C < 1.0 mmol/L or treated for dyslipidemia
- hypertension: blood pressure ≥ 140/90 mmHg or antihypertensive medication
- fasting plasma glucose ≥ 6.1 mmol/L
NCEP
The US National Cholesterol Education Program Adult Treatment Panel III (2001) requires at least three of the following:- central obesity: waist circumference ≥ 102 cm or 40 inches (male), ≥ 88 cm or 36 inches(female)
- dyslipidemia: TG ≥ 1.7 mmol/L (150 mg/dl)
- dyslipidemia: HDL-C < 40 mg/dL (male), < 50 mg/dL (female)
- blood pressure ≥ 130/85 mmHg
- fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dl)
American Heart Association/Updated NCEP
There is confusion as to whether, in 2004, the AHA/NHLBI intended to create another set of guidelines or simply update the NCEP ATP III definition. According to Scott Grundy, University of Texas Southwestern Medical School, Dallas, Texas, the intent was just to update the NCEP ATP III definition and not create a new definition.:- Elevated waist circumference:
- Men — greater than 40 inches (102 cm)
- Women — greater than 35 inches (88 cm)
- Elevated triglycerides: Equal to or greater than 150 mg/dL (1.7 mmol/L)
- Reduced HDL (“good”) cholesterol:
- Men — Less than 40 mg/dL (1.03 mmol/L)
- Women — Less than 50 mg/dL (1.29 mmol/L)
- Elevated blood pressure: Equal to or greater than 130/85 mm Hg or use of medication for hypertension
- Elevated fasting glucose: Equal to or greater than 100 mg/dL (5.6 mmol/L) or use of medication for hyperglycemia
Other
High-sensitivity C-reactive proteinC-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
(hs-CRP
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
) 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 non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease is one cause of a fatty liver, occurring when fat is deposited in the liver not due to excessive alcohol use. It is related to insulin resistance and the metabolic syndrome and may respond to treatments originally developed for other insulin-resistant states...
in correlation with serum markers that indicated lipid and glucose metabolism.
History
The term "metabolic syndrome" dates back to at least the late 1950s, but came into common usage in the late 1970s to describe various associations of risk factors with diabetes that had been noted as early as the 1920s.- The Marseilles physician Dr. Jean Vague, in 1947, observed that upper body obesity appeared to predispose to diabetes, atherosclerosisAtherosclerosisAtherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, goutGoutGout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
and calculiCalculus (medicine)A calculus is a stone that forms in an organ or duct of the body. Formation of calculi is known as lithiasis...
. - Avogadro, Crepaldi and co-workers described six moderately obese patients with diabetes, hypercholesterolemiaHypercholesterolemiaHypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
, and marked hypertriglyceridemiaHypertriglyceridemiaIn medicine, hypertriglyceridemia denotes high blood levels of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia . It can also lead to pancreatitis in excessive concentrations In medicine,...
all of which improved when the patients were put on a hypocaloric, low-carbohydrate diet. - In 1977, Haller used the term "metabolic syndrome" for associations of obesityObesityObesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, diabetes mellitusDiabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, hyperlipoproteinemia, hyperuricemiaHyperuricemiaHyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
, and hepatic steatosis when describing the additive effects of risk factors on atherosclerosisAtherosclerosisAtherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
. - The same year, Singer used the term for associations of obesity, goutGoutGout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
, diabetes mellitus, and hypertensionHypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
with hyperlipoproteinemia. - In 1977 and 1978, Gerald B. Phillips developed the concept that risk factors for myocardial infarctionMyocardial infarctionMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
concur to form a "constellation of abnormalities" (i.e., glucose intolerance, hyperinsulinemiaHyperinsulinemiaHyperinsulinemia, or hyperinsulinaemiais a condition which there is excess levels of insulin circulating in the blood than expected relative to the level of glucose. While it is often mistaken for diabetes or hypoglycaemia, hyperinsulinemia can result from a variety of metabolic diseases and...
, hypercholesterolemiaHypercholesterolemiaHypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
, hypertriglyceridemiaHypertriglyceridemiaIn medicine, hypertriglyceridemia denotes high blood levels of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia . It can also lead to pancreatitis in excessive concentrations In medicine,...
, and hypertensionHypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
) that is 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. - In 1988, in his Banting lectureBanting LecturesThe Banting Lectures a yearly series of research presentations given by an expert in diabetes. The name of the lecture series refers to Frederick Banting, who was a seminal scientist, doctor and Nobel laureate for the co-discovery of insulin...
, Gerald M. Reaven proposed insulin resistanceInsulin resistanceInsulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
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.
The terms "metabolic syndrome," "insulin resistance syndrome," and "syndrome X" are now used specifically to define a constellation of abnormalities that is associated with increased risk for the development of type 2 diabetes and atherosclerotic vascular disease (e.g., heart disease and stroke).
Etiology
The exact mechanisms of the complex pathways of metabolic syndrome are not yet completely known. The pathophysiologyPathophysiology
Pathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
is extremely complex and has been only partially elucidated. Most patients are older, obese, sedentary, and have a degree of insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
. Stress
Stress (biology)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
can also be a contributing factor. The most important factors are:
- weight
- genetics
- endocrine disorders, such as polycystic ovary syndromePolycystic ovary syndromePolycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....
in women of reproductive age. - aging
- sedentary lifestyleSedentary lifestyleSedentary lifestyle is a medical term used to denote a type of lifestyle with no or irregular physical activity. A person who lives a sedentary lifestyle may colloquially be known as a couch potato. It is commonly found in both the developed and developing world...
, i.e., low physical activity and excess caloric intake.
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. A number of markers of systemic inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, including C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
, are often increased, as are fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
, interleukin 6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
(IL–6), Tumor necrosis factor-alpha (TNFα), and others. Some have pointed to a variety of causes including increased uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
levels caused by dietary fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
.
Pathophysiology
It is common for there to be a development of visceral fat, after which the adipocyteAdipocyte
However, in some reports and textbooks, the number of fat cell increased in childhood and adolescence. The total number is constant in both obese and lean adult...
s (fat cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s) of the visceral fat increase plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
levels of TNFα and alter levels of a number of other substances (e.g., adiponectin
Adiponectin
Adiponectin is a protein which in humans is encoded by the ADIPOQ gene.- Structure :...
, resistin
Resistin
Resistin also known as adipose tissue-specific secretory factor or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein is a cysteine-rich protein that in humans is encoded by the RETN gene....
, PAI-1). TNFα has been shown not only to cause the production of inflammatory cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s but possibly to trigger cell signaling by interaction with a TNFα receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
that may lead to insulin resistance . An experiment with rats that were fed a diet one-third of which was sucrose
Sucrose
Sucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...
has been proposed as a model for the development of metabolic syndrome. The sucrose first elevated blood levels of triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s, which induced visceral fat and ultimately resulted in insulin resistance. The progression from visceral fat to increased TNFα to insulin resistance has some parallels to human development of metabolic syndrome. The increase in adipose tissue also increases the number of immune cells present within, which play a role in inflammation. Chronic inflammation contributes to an increased risk of hypertension, artherosclerosis and diabetes.
Stress
Recent research indicates that prolonged stressStress (biology)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
can be an underlying cause of metabolic syndrome by upsetting the hormonal balance of the hypothalamic-pituitary-adrenal axis
Hypothalamic-pituitary-adrenal axis
The hypothalamic-pituitary-adrenal axis , also known as thelimbic-hypothalamic-pituitary-adrenal axis and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland ,...
(HPA-axis).
A dysfunctional HPA-axis causes high cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
levels to circulate which results in raising glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
and insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
levels which cause insulin-mediated effects on adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
, ultimately promoting visceral adiposity, insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
, dyslipidemia
Dyslipidemia
Dyslipidemia or dyslipidaemia is an abnormal amount of lipids in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. The prolonged elevation of insulin levels can lead to dyslipidemia...
and hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
with direct effects on the bone, causing “low turnover” osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. HPA-axis dysfunction may explain the reported risk indication of abdominal obesity
Abdominal obesity
Abdominal obesity, colloquially known as belly fat or clinically as central obesity, is the accumulation of abdominal fat resulting in an increase in waist size...
to cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, type 2 diabetes and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
. Psychosocial
Psychosocial
For a concept to be psychosocial means it relates to one's psychological development in, and interaction with, a social environment. The individual needs not be fully aware of this relationship with his or her environment. It was first commonly used by psychologist Erik Erikson in his stages of...
stress is also linked to heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
.
Overweight and obesity
Central adiposityCentral obesity
Abdominal obesity, colloquially known as belly fat or clinically as central obesity, is the accumulation of abdominal fat resulting in an increase in waist size...
is a key feature of the syndrome, reflecting the fact that the syndrome's prevalence is driven by the strong relationship between waist
Waist
The waist is the part of the abdomen between the rib cage and hips. On proportionate people, the waist is the narrowest part of the torso....
circumference
Circumference
The circumference is the distance around a closed curve. Circumference is a special perimeter.-Circumference of a circle:The circumference of a circle is the length around it....
and increasing adiposity. However, despite the importance of obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, patients that are of normal weight may also be insulin-resistant
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
and have the syndrome.
Sedentary lifestyle
Physical inactivitySedentary lifestyle
Sedentary lifestyle is a medical term used to denote a type of lifestyle with no or irregular physical activity. A person who lives a sedentary lifestyle may colloquially be known as a couch potato. It is commonly found in both the developed and developing world...
is a predictor of CVD
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
events and related mortality
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
. Many components of metabolic syndrome are associated with a sedentary lifestyle
Sedentary lifestyle
Sedentary lifestyle is a medical term used to denote a type of lifestyle with no or irregular physical activity. A person who lives a sedentary lifestyle may colloquially be known as a couch potato. It is commonly found in both the developed and developing world...
, including increased adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
(predominantly central
Central obesity
Abdominal obesity, colloquially known as belly fat or clinically as central obesity, is the accumulation of abdominal fat resulting in an increase in waist size...
); reduced HDL cholesterol; and a trend toward increased triglycerides, blood pressure
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, and glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
in the genetically susceptible. Compared with individuals who watched television
Television
Television is a telecommunication medium for transmitting and receiving moving images that can be monochrome or colored, with accompanying sound...
or videos
Videotape
A videotape is a recording of images and sounds on to magnetic tape as opposed to film stock or random access digital media. Videotapes are also used for storing scientific or medical data, such as the data produced by an electrocardiogram...
or used their computer
Computer
A computer is a programmable machine designed to sequentially and automatically carry out a sequence of arithmetic or logical operations. The particular sequence of operations can be changed readily, allowing the computer to solve more than one kind of problem...
for less than one hour daily, those that carried out these behaviors for greater than four hours daily have a twofold increased risk
Risk
Risk is the potential that a chosen action or activity will lead to a loss . The notion implies that a choice having an influence on the outcome exists . Potential losses themselves may also be called "risks"...
of metabolic syndrome.
Aging
Metabolic syndrome affects 44% 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.Diabetes mellitus
It is estimated that the large majority (~75%, or just above 40 million) of patients with type 2 diabetes or impaired glucose toleranceImpaired glucose tolerance
Impaired glucose tolerance is a pre-diabetic state of dysglycemia that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years...
(IGT
Impaired glucose tolerance
Impaired glucose tolerance is a pre-diabetic state of dysglycemia that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years...
) have metabolic syndrome - . The presence of metabolic syndrome in these populations is associated with a higher prevalence of CVD than found in patients with type 2 diabetes or IGT without the syndrome. Hypoadiponectinemia has been shown to increase insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
, and is considered to be a risk factor
Risk factor
In epidemiology, a risk factor is a variable associated with an increased risk of disease or infection. Sometimes, determinant is also used, being a variable associated with either increased or decreased risk.-Correlation vs causation:...
for developing metabolic syndrome.
Coronary heart disease
The approximate prevalence of the metabolic syndrome in patients with coronary heart diseaseCoronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
(CHD
Coronary disease
Coronary disease refers to the failure of coronary circulation to supply adequate circulation to cardiac muscle and surrounding tissue. It is already the most common form of disease affecting the heart and an important cause of premature death in Europe, the Baltic states, Russia, North and South...
) is 50%, with a prevalence of 37% in patients with premature coronary artery disease ( age 45), particularly in women. With appropriate cardiac rehabilitation
Cardiopulmonary rehabilitation
Cardiac Rehabilitation is a branch of rehabilitation medicine dealing with optimizing physical function in patients with cardiac disease. CR services are generally provided in an outpatient setting as comprehensive, long-term programs involving medical evaluation, prescribed exercise, cardiac...
and changes in lifestyle (e.g., nutrition
Nutrition
Nutrition is the provision, to cells and organisms, of the materials necessary to support life. Many common health problems can be prevented or alleviated with a healthy diet....
, physical activity, weight
Weight
In science and engineering, the weight of an object is the force on the object due to gravity. Its magnitude , often denoted by an italic letter W, is the product of the mass m of the object and the magnitude of the local gravitational acceleration g; thus:...
reduction, and, in some cases, drugs
DRUGS
Destroy Rebuild Until God Shows are an American post-hardcore band formed in 2010. They released their debut self-titled album on February 22, 2011.- Formation :...
), the prevalence of the syndrome can be reduced.
Lipodystrophy
Lipodystrophic disorders in general are associated with metabolic syndrome. Both genetic (e.g., Berardinelli-Seip congenital lipodystrophy, Dunnigan familial partial lipodystrophyDunnigan familial partial lipodystrophy
Dunnigan-type familial partial lipodystrophy, abbreviated as , is a rare monogenic form of insulin resistance characterized by loss of subcutaneous fat from the extremities, trunk, and gluteal region...
) and acquired (e.g., HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-related lipodystrophy
Lipodystrophy
Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy is used when describing the loss of fat from one area...
in patients treated with highly active antiretroviral therapy) forms of lipodystrophy may give rise to severe insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
and many of metabolic syndrome's components.
Schizophrenia and other psychiatric illnesses
Patients with schizophreniaSchizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, schizoaffective disorder
Schizoaffective disorder
Schizoaffective disorder is a psychiatric diagnosis that describes a mental disorder characterized by recurring episodes of elevated or depressed mood, or of simultaneously elevated and depressed mood, that alternate with, or occur together with, distortions in perception.Schizoaffective disorder...
or bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
may have a predisposition to metabolic syndrome that is exacerbated by sedentary lifestyle, poor dietary habits, possible limited access to care, and antipsychotic drug-induced adverse effects. It has been found that 32% and 51% of individuals with schizophrenia meet criteria for metabolic syndrome; the prevalence is higher in women than in men.
Rheumatic diseases
There are new findings regarding the comorbidity associated with rheumatic diseases. Both psoriasis and psoriatic arthritis have been found to be associated with metabolic syndrome.Signs and symptoms
Symptoms and features are:- Fasting hyperglycemiaHyperglycemiaHyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
— diabetes mellitus type 2Diabetes mellitus type 2Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
or impaired fasting glucose, impaired glucose toleranceImpaired glucose toleranceImpaired glucose tolerance is a pre-diabetic state of dysglycemia that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years...
, or insulin resistanceInsulin resistanceInsulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types... - High blood pressure
- Central obesityCentral obesityAbdominal obesity, colloquially known as belly fat or clinically as central obesity, is the accumulation of abdominal fat resulting in an increase in waist size...
(also known as visceral, male-pattern or apple-shaped adiposity), overweight with fat deposits mainly around the waist - Decreased HDLHigh density lipoproteinHigh-density lipoprotein is one of the five major groups of lipoproteins, which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...
cholesterol - Elevated triglycerideTriglycerideA triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s
Associated diseases and signs are: hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
, fatty liver
Fatty liver
Fatty liver, also known as fatty liver disease , is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells via the process of steatosis...
(especially in concurrent obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
) progressing to non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease is one cause of a fatty liver, occurring when fat is deposited in the liver not due to excessive alcohol use. It is related to insulin resistance and the metabolic syndrome and may respond to treatments originally developed for other insulin-resistant states...
, polycystic ovarian syndrome (in women), and acanthosis nigricans
Acanthosis nigricans
Acanthosis nigricans is a brown to black, poorly defined, velvety hyperpigmentation of the skin. It is usually found in body folds, such as the posterior and lateral folds of the neck, the axilla, groin, umbilicus, forehead, and other areas.-Causes:...
.
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), and a healthy, reduced calorie diet. There are many studies that support the value of a healthy lifestyle as above. However, one study stated that these potentially beneficial measures are effective in only a minority of people, primarily due to a lack of compliance with lifestyle and diet changes. The International Obesity Taskforce states that interventions on a sociopolitical level are required to reduce development of the metabolic syndrome in populations.A 2007 study of 2,375 male subjects over 20 years suggested that daily intake of a pint (~568 ml) of milk or equivalent dairy products more than halved the risk of metabolic syndrome. Some subsequent studies support the authors' findings, while others dispute them.
Therapy
The first line treatment is change of lifestyle (e.g., Dietary Guidelines for Americans and physical activity). However, if in three to six months of efforts at remedying risk factors prove insufficient, then drug treatment is frequently required. Generally, the individual disorders that comprise the metabolic syndrome are treated separately. DiureticDiuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
s and ACE inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
s may be used to treat hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
. Cholesterol drugs may be used to lower LDL cholesterol and triglyceride levels, if they are elevated, and to raise HDL levels if they are low. Use of drugs that decrease insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
, e.g., metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
and thiazolidinedione
Thiazolidinedione
The thiazolidinediones , also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.- Mechanism of action :...
s, is controversial; this treatment is not approved by the U.S. Food and Drug Administration.
A 2003 study indicated that cardiovascular exercise was therapeutic in approximately 31% of cases. The most probable benefit was to triglyceride levels, with 43% showing improvement; but fasting plasma glucose and insulin resistance of 91% of test subjects did not improve.
Many other studies have supported the value of increased physical activity and restricted caloric intake (exercise and diet) to treat metabolic syndrome.
Restricting the overall dietary carbohydrate intake is more effective in reducing the most common symptoms of metabolic syndrome than the more commonly prescribed reduction in dietary fat intake.
Controversy
The clinical value of using "metabolic syndrome" as a diagnosis has recently come under fire. It is asserted that different sets of conflicting and incomplete diagnostic criteria are in existence, and that when confounding factors such as obesity are accounted for, diagnosis of the metabolic syndrome has a negligible association with the risk of heart disease.These concerns have led to the American Diabetes Association
American Diabetes Association
The American Diabetes Association is a United States-based association working to fight the consequences of diabetes, and to help those affected by diabetes...
and the European Association for the Study of Diabetes
European Association for the Study of Diabetes
The European Association for the Study of Diabetes is an scientific association founded in Montecatini, Italy in 1965 with Dr. Joseph Hoet as Founding President...
to issue a joint statement identifying eight major concerns on the clinical utility of the metabolic syndrome.
It is not contested that cardiovascular risk factors tend to cluster together, but what is contested is the assertion that the metabolic syndrome is anything more than the sum of its constituent parts.
External links
- Metabolic Syndrome X at the Stanford University Pharmacogenomic Knowledge Base