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Metabolic Syndrome Pathophysiology and Clinical PresentationMetabolic Institute of America, Tarzana, California, USA Correspondence: Yehuda Handelsman, M.D., F.A.C.P., F.A.C.E, Medical Director, Metabolic Institute of America, 18372 Clark St., Suite 212, Tarzana, CA 91356 USA; e-mail:yhandelsman{at}pacbell.net.
Metabolic syndrome is a relatively new definition, designed to help the health care practitioner to easily identify people at risk for the development of cardiovascular disease and diabetes. With the obesity epidemic, we are witnessing an epidemic of multiple-risk patients. Insulin resistance is the perceived pathophysiology of metabolic syndrome and defines its clinical presentation. Hypertension, dyslipedemia, polycystic ovarian syndrome, fatty liver disease, pre-diabetes, sleep and breathing disorder, certain cancers, and cognitive impairment are many of the presentations of the syndrome; patients with any of these conditions are at a high risk of developing cardiovascular disease and diabetes. The metabolic syndrome helps identify people at risk to allow early intervention for prevention. Lifestyle modification is the most important part of the management of people with the syndrome. Lately medications—though none approved by the U.S. Food and Drug Administration (FDA)—have been recommended by major medical societies when lifestyle modification is not enough or when it fails.
Key Words: metabolic syndrome • obesity • insulin resistance • pre-diabetes • hypertension • dyslipedemia • polycystic ovarian syndrome (PCOS) • nonalcoholic fatty liver disease (NAFLD) • sleep and breathing disorder • lifestyle modification • cardiovascular disease • diabetes
In recent years the medical and scientific communities have increased their attention to multiple-risk patients. Since the introduction, by Dr. Gerald Reaven in 1988, of syndrome X (Reaven 1988), now the insulin resistance syndrome (Einhorn et al. 2003), many names and definitions have evolved. The term "metabolic syndrome" has gained popularity and has been adopted by many organizations like the World Health Organization (WHO) (Alberti and Zimmet 1998), International Diabetes Federation (IDF) (IDF 2008), National Cholesterol Education Panel–Adult Treatment Panel III (NCEP–ATP III 2008), and the American Heart Association (AHA), to name but a few. Though multiple definitions exist, the concept of a clustering of risks leading to diabetes and cardiovascular disease (CVD) is well accepted. It is estimated that more than 47 million Americans have the syndrome, paralleling the global obesity epidemic (Ford et al. 2002). The main clinical feature of the syndrome is obesity; some groups focus simply on visceral obesity (Rexrode et al. 1998), measured by weight (Basal Metabolic Index [BMI]) or waist circumference, dysglycemia, elevated blood pressure, elevated triglyceride level, and reduced HDL cholesterol. Creating a simple clinical tool for the primary care physician, most organizations choose 3 out of the 5 risks to diagnose the patient with the syndrome (Grundy et al. 2005). Identifying the patient allows early intervention to prevent or delay the likely development of CVD or diabetes (Lorenzo et al. 2003). The underlying causes of the syndrome are genetic and environmental: overweight, obesity, and physical inactivity, which lead to insulin resistance, hyperinsulinemia, endothelial dysfunction, and inflammation (Ridker et al. 2003). There is alteration of fat cell function accompanied by secretion of multiple hormones and cytokines (Kahn and Flier 2000), culminating in the unhealthy accumulation of fat in tissues like muscles, specifically the heart muscle (Lan and Ravussin 2008). The metabolic syndrome appears in all ethnic groups affecting young and old, males and females. There are multiple clinical presentations: hypertension (Sironi et al. 2004), dyslipidemia (Reaven et al. 1993), nonalcoholic fatty liver disease (NAFLD) (Hanley et al. 2005), polycystic ovarian syndrome (PCOS) (Talbott et al. 2000), sleep and breathing disorders (Vgontzas et al. 1999), Alzheimer’s disease (Young et al. 2006), and cancers such as breast, prostate, and pancreas (Del Giudice et al. 1998). The unifying concept is that all these patients are at a high risk of developing diabetes and CVD (Lakka et al. 2002), and early intervention, primarily lifestyle modifications, may ultimately prevent these costly and deadly diseases.
Of all the definitions, the most popular today is that of the NCEP–ATP III, as modified by the AHA and the IDF. Both definitions include similar parameters, four of which are identical: (a) blood pressure (BP)
Until recently, lifestyle modification has been the only treatment recommended for the metabolic syndrome. As of today, the FDA has not approved any medications to treat the syndrome. Recently the American Association of Clinical Endocrinologists (AACE) published a recommendation on the management of people with pre-diabetes and metabolic syndrome (Garber et al. 2008). Untreated individuals with pre-diabetes are at increased risk for diabetes as well as for micro- and macrovascular complications. Treatment goals are to prevent deterioration in glucose levels and modify other risk factors, such as obesity, hypertension, and dyslipidemia. The same BP and lipid goals for pre-diabetes as for diabetes are suggested to prevent cardiovascular disease. Intensive lifestyle management is the cornerstone of all prevention efforts; pharmacotherapy targeted at glucose may be considered in high-risk patients after individual risk–benefit analysis. To achieve lipid control, medications from the "statin" family of drugs are recommended; for blood pressure, control medications from the angiotensin converting enzyme (ACE) and the angiotensin receptor blocker (ARB) families are suggested. Medications are also recommended should lifestyle modification fail to control progression in hyperglycemia and/or in high-risk patients, in other words, people who have the metabolic syndrome and impaired fasting glucose, or impaired glucose tolerance, or both. The recommended medications are metformin (Diabetes Prevention Program Research Group 2003), acarbose (Chiasson et al. 2002), and the glitazone class of drugs—both pioglitazone (DeFronzo 2008) and rosiglitazone (DREAM 2006)—with appropriate risk analysis.
In conclusion, the metabolic syndrome represents the clustering of several risk factors, a concept that is designed primarily to allow the physician to recognize people who are at a high risk of developing cardiovascular disease and diabetes. The term metabolic syndrome should not be misused as a disease unto itself. The syndrome is an important predictor of CVD and diabetes and allows early medical intervention. There is a great deal of evidence that insulin resistance underlies the pathogenesis of metabolic syndrome. The linked concepts of metabolic syndrome/insulin resistance syndrome have served a highly useful purpose by providing a simple construct to characterize many types of patients who clinicians see daily, and to help identify people at high risk. To prevent the development of diabetes and cardiovascular disease, management strategies are directed at obesity, blood pressure, dyslipidemia, and hyperglycemia. The recommended intervention is lifestyle modification; however, if and when it fails, medications—though not approved for use specifically for the syndrome by the FDA—are recommended by major medical societies like the AACE.
Dr. Handelsman received Grant/research support from Dahiichi-Sankyo, GSK, Sanofi-Aventis, and Takeda. Dr. Handelsman is a consultant for Amylin, BMS, Daiichi-Sankyo, GSK, Merck Medtronic, and Xoma. He is on the speakers bureau for AstraZeneca, BMS, Daiichi-Sankyo, GSK, Merck, Novartis, and Novo Nordisk.
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This version was published on January
1, 2009 Toxicologic Pathology, Vol. 37, No. 1,
18-20 (2009)
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Abstract
Introduction
130/85 mmHg; (b) triglycerides (TGL)