Metabolic Syndrome

What is Metabolic Syndrome?

Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. It affects one in five people, and prevalence increases with age. Some studies estimate the prevalence in the USA to be up to 25% of the population.

Metabolic syndrome is also known as metabolic syndrome X, syndrome X, insulin resistance syndrome, Reaven's syndrome, and CHAOS (Australia). A similar condition in overweight horses is referred to as equine metabolic syndrome; it is unknown if they have the same etiology.

The exact mechanisms of the complex pathways of metabolic syndrome are not yet completely known. The pathophysiology 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:

  1. weight
  2. genetics
  3. stress
  4. aging
  5. sedentary lifestyle, 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, 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.

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 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 cytokines 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 the 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 TNFα to insulin resistance has some parallels to human development of metabolic syndrome.

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History of Metabolic Syndrome

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, atherosclerosis, gout and calculi.
  • Avogaro, Crepaldi and co-workers described six moderately obese patients with diabetes, hypercholesterolemia, and marked hypertriglyceridemia 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 obesity, diabetes mellitus, hyperlipoproteinemia, hyperuricemia, and Hepatic steatosis when describing the additive effects of risk factors on atherosclerosis.
  • The same year, Singer used the term for associations of obesity, gout, diabetes mellitus, and hypertension with hyperlipoprotenemia.
  • 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, hyperlipidemia and hypertriglyceridemia, and hypertension) 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 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.

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).

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Metabolic Syndrome Risk Factors

Stress

Prolonged stress 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. High cortisol levels (low levels may register due to HPA-axis 'burn out') can also cause loss of muscle bulk, accumulation of visceral fat and raised levels of clotting factor. All of these factors contribute to the damage of the endothelial lining of the artery wall which results in endothelial dysfunction or coronary artery disease which is then accelerated by further high levels of blood sugar, insulin, cortisol, and adrenaline. Raised levels of blood-clotting factors are also "directly and consistently associated with an increased risk of heart disease."

Overweight and Obesity

Central adiposity 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.

Sedentary lifestyle

Physical inactivity is a predictor of CVD events and related mortality. Many components of the 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 more less one hour daily, those that carried out these behaviors for greater than four hours daily have a twofold increased risk of the metabolic syndrome., and is considered to be a risk factor for developing metabolic syndrome.

Coronary Heart Disease

The approximate prevalence of the metabolic syndrome in patients with coronary heart disease (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 the revised National Cholesterol Education Program, respectively. The revised NCEP and IDF definitions of metabolic syndrome are very similar and it can be expected that they will identify many of the same individuals as having metabolic syndrome. The two differences are that IDF state 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, whereas, in the NCEP definition, metabolic syndrome can be diagnosed based on other criteria and 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 closer to each other than the original NCEP and WHO definitions.

IDF

International Diabetes Federation

  • central obesity: waist circumference ≥ 102 cm or 40 inches (male), ≥ 88 cm or 36 inches(female)
  • dyslipidaemia: TG ≥ 1.695 mmol/L (150 mg/dl)
  • dyslipidaemia: 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 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 — Equal to or greater than 40 inches (102 cm)
    • Women — Equal to or greater than 35 inches (88 cm)
    • Elevated triglycerides: Equal to or greater than 150 mg/dL
    • Reduced HDL (“good”) cholesterol:
      • Men — Less than 40 mg/dL
      • Women — Less than 50 mg/dL
      • 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 protein (hs-CRP) has been developed and used as a marker to predict coronary vascular diseases in metabolic syndrome, and it was recently used predictor for non-alcoholic fatty liver disease in correlation with serum markers that indicated lipid and glucose metabolism.

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Metabolic Syndrome 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 measures are effective in only a minority of people, primarily due to a lack of compliance with lifestyle and diet changes.

A 2007 study of 2,375 male subjects over 20 years suggested that daily intake of a pint of milk or equivalent dairy products more than halved the risk of metabolic syndrome. Other studies both support and dispute the authors' findings.

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Metabolic Syndrome Treatment

The first line treatment is change of lifestyle (i.e., caloric restriction and physical activity). However, drug treatment is frequently required. Generally, the individual disorders that comprise the metabolic syndrome are treated separately. Diuretics and ACE inhibitors 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 thiazolidinediones, 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.

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.

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