Author(s): Authors Lam DW, LeRoith D
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Excerpt The metabolic syndrome (MetS) is a compilation of risk factors that predispose individuals to the development of type 2 diabetes (T2DM) and cardiovascular disease (CVD) first described in 1988 by Reaven. Since then multiple definitions of the syndrome have been proposed, the most recent being the Harmonized Definition where 3 of the 5 risk factors are present: enlarged waist circumference with population-specific and country-specific criteria; triglycerides ≥ 150 mg/dL, HDL-c < 40 mg/dL in men and < 50 mg/dL in women, systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg and fasting glucose > 100 mg/dL, with the inclusion of patients taking medication to manage hypertriglyceridemia, low HDL-c, hypertension and hyperglycemia. In the years since its definition, there have been mixed results from studies examining MetS’ comparative ability in predicting CVD and T2DM over traditional risk models. Despite this, it continues to be used both in clinical practice as well as the research arena. Insulin resistance is thought to play a paramount role in connecting the different components of MetS and adding to the syndrome's development. Insulin resistance has been demonstrated to alter glucose and lipid metabolism. In addition, elevated free fatty acids, a pro-inflammatory state, increased oxidative stress, and alterations in adipokine profile have all been described in animal models as well as patients with MetS. T2DM, dyslipidemia, non-acoholic fatty liver disease, polycystic ovarian syndrome, obstructive sleep apnea, sexual dysfunction, and cancer are among the disease states associated with MetS. The association is not surprising given commonalities pathophysiologic pathways thought to be essential in their genesis. Ultimately, as a clinical tool, MetS should heighten attention and focus treatment on its components in an effort to reduce risk of CVD and other sequelae of MetS. Lifestyle modifications including increased physical activity and dietary changes are considered a paramount component of treatment for with strong evidence in its efficacy of treating individual components. Beyond lifestyle modifications, further treatment lies in treatment specifically for obesity, dyslipidemia, hypertension and impaired glucose tolerance in which there have been advances. For in depth review of all related aspects of endocrinology, visit www.endotext.org. BACKGROUND The metabolic syndrome (MetS) is a compilation of risk factors that predispose individuals to the development of type 2 diabetes (T2DM) and cardiovascular disease (CVD). Reaven (1) first described MetS in his 1988 Banting lecture as “Syndrome X. ” Reaven suggested that insulin resistance clustered together with glucose intolerance, dyslipidemia and hypertension to increase the risk of cardiovascular disease. The initial definition of metabolic syndrome included impaired glucose tolerance (IGT), hyperinsulinemia, elevated triglycerides (TG) and reduced high-density lipoprotein cholesterol (HDL-c). Hyperuricemia, microvascular angina and elevated plasminogen activator inhibitor 1 (PAI-1) were later proposed as possible additional components of the same syndrome (1,2). Obesity was not included as part of Syndrome X as Reaven believed that insulin resistance, not obesity, was the common denominator. Reaven noted that all of the elements of Syndrome X could occur in non-obese individuals, and while he acknowledged that obesity could lead to a decrease in insulin mediated glucose uptake, he stressed that obesity was only one of the environmental factors that affect insulin sensitivity (3,4). The World Health Organization (WHO) produced the first formalized definition of the MetS in 1998. The working definition included impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or diabetes mellitus and/or insulin resistance (as measured using a hyperinsulinemic euglycemic clamp study) together with two or more additional components. Additional components included hypertension (defined as a blood pressure ≥160/90 mm Hg), raised plasma triglycerides (≥150 mg/dl) and/or low HDL-cholesterol (<35 mg/dl for men and <39 mg/dl for women), central obesity (defined either as body mass index (BMI) > 30 kg/m2 or waist to hip ratio>0.90 for males and >0.85 for females) and microalbuminuria (5). Critics questioned the practicality of this definition given the need for a hyperinsulinemic clamp study. Others argued that measuring waist circumference was superior in terms of convenience to the waist to hip ratio with similar correlations to obesity. Additionally, there was a question about the value of including microalbuminuria in the definition as there was insufficient evidence of a connection with insulin resistance (5). These critiques led to the first revision of the definition of the syndrome in 1999 by the European Group for the Study of Insulin Resistance (EGIR). They renamed the syndrome the “insulin resistance syndrome” (IRS) as it included non-metabolic features. They excluded patients with diabetes because of the difficulty of measuring insulin resistance in these individuals. The need for hyperinsulinemic clamp studies was obviated by defining insulin resistance as a fasting insulin level above the 75th percentile for the population. Additional criteria (elements associated with increased risk of coronary artery disease by the Second Joint Task Force of European and other Societies on Coronary Prevention) were also included, namely obesity (defined as waist circumference ≥ 94 cm (37 inches) for men and ≥ 80 cm (32 inches) for women), hypertension (now defined as a blood pressure ≥140/90 mm Hg) and dyslipidemia (with triglycerides ≥ 180 mg/dl or HDL-c ≤ 39). Additionally, microalbuminuria was omitted from the definition (6). The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) recognized that these multiple metabolic elements were cardiovascular risk factors and renamed the constellation of these metabolic risk factors as “The Metabolic Syndrome” (7). The criteria included any three of the following: obesity (defined as waist circumference ≥ 102 cm (40 inches) in males and ≥ 88 cm (35 inches) in females (based on the 1998 National Institutes of Health (NIH) obesity clinical guidelines), hypertension (defined as blood pressure ≥ 130/85 mm Hg based on the Joint National Committee guidelines), fasting glucose > 110 mg/dL, triglycerides ≥ 150 mg/dL and HDL-c < 40 mg/dL. Additionally, in this report MetS was recognized as a secondary target of risk reduction therapy after the primary target of LDL cholesterol (7). In 2003, the American Association of Clinical Endocrinologists (AACE) modified the ATP III criteria and restored the condition to the name “Insulin Resistance Syndrome,” again highlighting the central role of insulin resistance in the pathogenesis of the syndrome (8). This definition did not rely on strict diagnostic criteria. The components of the syndrome included some degree of glucose intolerance (but not overt diabetes), abnormal uric acid metabolism, dyslipidemia, hemodynamic changes (including hypertension), prothrombotic factors, markers of inflammation and endothelial dysfunction. The AACE position statement also identified factors that increased the likelihood of developing the insulin resistance syndrome, including a diagnosis of CVD, hypertension, polycystic ovarian syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD) or acanthosis nigricans, a family history of T2DM, hypertension or CVD, a personal history of gestational diabetes (GDM) or glucose intolerance, non-Caucasian ethnicity, a sedentary lifestyle, overweight/obesity (defined as BMI > 25 kg/m2 or waist circumference > 40 inches in men and > 35 inches in women) and age > 40 years (8). The International Diabetes Federation (IDF) aimed to create a straightforward, clinically useful definition to identify individuals in any country worldwide at high risk of CVD and diabetes and to allow for comparative epidemiologic studies. This resulted in the IDF consensus definition of MetS in 2005 (9). Central obesity, as defined as BMI> 30 kg/m2 or if ≤ 30 kg/m2 by ethnic specific waist circumference measurements) was a requisite for the syndrome. Additionally, the definition required the presence of two of the following four elements: triglycerides ≥ 150 mg/dL, HDL-c < 40 mg/dL in men or < 50 mg/dL in women, systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg, fasting glucose > 100 mg/dL ( based on the 2003 ADA definition of IFG) (10) including diabetes and those with a prior diagnosis of or treatment of any of these conditions (9). In 2005, the American Heart Association (AHA)/ National Heart, Lung and Blood Institute (NHLBI) also suggested criteria for diagnosis of the metabolic syndrome. Their revised definition of the metabolic syndrome was based on the ATP III criteria and required three of any of the five following criteria: elevated waist circumference ( ≥ 102 cm (40 inches) in males and ≥ 88 cm (35 inches) in females) , triglycerides ≥ 150 mg/dL and HDL-c < 40 mg/dL in men and < 50 mg/dL in women, elevated blood pressure ≥ 130/85 mm Hg and elevated fasting glucose > 100 mg/dL (11). As suggested by the IDF, ethnic-specific waist circumferences were taken into account when using this definition. Additionally, impaired fasting glucose was defined as >100, which was also consistent with the IDF guidelines. Despite the efforts by the IDF and AHA/NHBLI to provide a more unified definition for practitioners and researchers alike, all of these conflicting definitions led to confusion on how to identify patients with MetS and inconsistencies that proved difficult when trying to compare different epidemiologic research studies. Copyright © 2000-2016, MDText.com, Inc.
This article was published in Metabolic Syndrome
and referenced in Journal of Diabetes & Metabolism