Introduction

The insulin resistance syndrome (IRS), also known as the metabolic syndrome, is a "cluster" of cardiovascular (CV) risk factors that are frequently, but not always, associated with obesity. This grouping of risk factors has been known by several other synonyms including Syndrome X, deadly quartet, and cardiometabolic syndrome. Because insulin resistance describes the underlying pathophysiologic basis of the "syndrome," it is the term used for this chapter. Reaven first drew attention to the association of insulin resistance and obesity, type 2 diabetes, high plasma triglycerides and low plasma HDL cholesterol (HDL) and hypertension (1). Since its original description there has been much experimental, clinical, and epidemiological data to support the association of this syndrome with cardiovascular disease (CVD) (2)2. Additionally, other "nontraditional" CV risk factors have been frequently included in the description of the syndrome. These include inflammation, abnormal fibrinolysis, and endothelial dysfunction and microalbuminuria (3-5). Figure 1 summarizes the relationship of these risk factors and their link with CVD. It remains unclear to what extent the components of this syndrome develop independently of each other or spring from "common soil" genetic abnormalities (6). In either case, the frequency of these coexisting abnormalities are increasing at an alarming rate, paralleling the obesity and diabetes epidemics. This is now a major clinical and public health problem—NHANES 1999-2000 estimates the prevalence of metabolic syndrome at 26.7% of US adults (7). The IRS is present in approximately 80% of persons with an established diagnosis of type 2 diabetes (8,9).

Historically, research studies have used complex experimental techniques to quantify insulin sensitivity/resistance (Table 1). Epidemiological studies utilize hyperinsulinemia to define insulin resistance. Since plasma insulin concentrations are a reflection of both ambient glucose and pancreatic P cell function (which decreases even before the onset of type 2 diabetes), it is a poor marker of insulin resistance. Furthermore, lack of standardization of the insulin assay makes interpretation of plasma insulin concentration difficult. Therefore, in order to provide a clinically useful framework, several groups have defined and updated criteria for diagnosis of the metabolic syndrome. The World Health Organization (WHO), the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and the International Diabetes Federation (IDF) have set forth measurements and values of individual components as shown (see Table 2 and NCEP ATP III at www.nhlbi.nih.gov/guidelines/ cholesterol/atp_iii.htm). Subjects identified using these clinical definitions have been shown to be at increased risk of CVD. Recently, there has been much controversy regarding the use of the term the metabolic syndrome and its diagnostic criteria (10-12). Several organizations have suggested that the term not be used until further research is done. Is metabolic syndrome the same as the IRS.

Insulin resistance in the context of type 2 diabetes is discussed elsewhere in this book. In this chapter we will discuss (1) the relationship of the syndrome, and its components to CVD and its associated risk factors; (2) the pathophysiology of the syndrome; and (3) its clinical evaluation and treatment.

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