What causes metabolic syndrome?

Updated: Mar 30, 2020
  • Author: Stanley S Wang, JD, MD, MPH; Chief Editor: Yasmine S Ali, MD, MSCI, FACC, FACP  more...
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The underlying etiology for metabolic syndrome remains unclear. [20] However, known risk factors for metabolic syndrome include family history, poor diet, and inadequate exercise. Two forces that have spread metabolic syndrome globally are the increased availability and consumption of high calorie-low fiber fast food as well as decreased physical activity engendered by sedentary lifestyles and mechanized transportation. [21]  Contributing factors and mechanisms appear to include the following [20] :

  • Insulin resistance
  • Pancreatic beta-cell dysfunction
  • Cellular dysfunction by protein kinases and phoshatases
  • Suppression of insulin receptor substrate-1 and 2 (IRS1/IRS2) gene expression and function
  • Obesity and lipid toxicity
  • Oxidative stress and glucose toxicity
  • Chronic inflammation
  • Dysrupted circadian rhythm
  • Genetics and epigenetics
  • Gut microbial imbalance
  • Dietary effects

Metabolic syndrome is thought to be caused by adipose tissue dysfunction and insulin resistance. Dysfunctional adipose tissue also plays an important role in the pathogenesis of obesity-related insulin resistance. [22] Both adipose cell enlargement and infiltration of macrophages into adipose tissue result in the release of proinflammatory cytokines and promote insulin resistance. [23]

Insulin resistance appears to be the primary mediator of metabolic syndrome. [24] Insulin promotes glucose uptake in muscle, fat, and liver cells and can influence lipolysis and the production of glucose by hepatocytes.

Additional contributors to insulin resistance include abnormalities in insulin secretion and insulin receptor signaling, impaired glucose disposal, and proinflammatory cytokines. These abnormalities, in turn, may result from obesity with related increases in free fatty acid levels and changes in insulin distribution (insulin accumulates in fat).

The distribution of adipose tissue appears to affect its role in metabolic syndrome. Fat that is visceral or intra-abdominal correlates with inflammation, whereas subcutaneous fat does not. There are a number of potential explanations for this, including experimental observations that omental fat is more resistant to insulin and may result in a higher concentration of toxic free fatty acids in the portal circulation. [25]

Abdominal fat is known to produce potentially harmful levels of cytokines, such as tumor necrosis factor, adiponectin, leptin, resistin, and plasminogen activator inhibitor. [26]

Psychological characteristics, including anger, depression, and hostility, may be linked to increased risk for metabolic syndrome. [27] However, psychological disorders, especially anxiety, may represent comorbidity or a complication of metabolic syndrome. [28]  Further study is warranted.

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