Until the 1960s, the prevailing belief was that an absolute insulin deficiency was the primary metabolic defect in type 2 DM. This belief persisted despite studies performed as early as the 1930s that indicated that resistance to insulin-mediated stimulation of glucose clearance was present in subjects with type 2 DM (1, 2, 3, 4, 5). The availability of the insulin immunoassay, developed by Yalow and Berson in 1960, established that most patients with DM had higher plasma insulin levels than healthy subjects (6). This new ability to measure both plasma glucose and insulin concentration allowed the development of oral glucose tolerance testing (7) and the glucose clamp techniques (8). Various glucose clamp techniques exist; however, the most commonly performed is probably the euglycemic hyperinsulinemic clamp. In this protocol, a constant infusion of insulin is administered to the subject to cause hyperinsulinemia, and the rate of glucose infusion (glucose disposal) necessary to maintain euglycemia is determined. Concomitant infusion of stable isotope-labeled tracers of amino acids, glucose, and fatty acids (FAs) during clamps may be performed to allow for calculation of glucose production, amino acid deposition, VLDL-TG synthesis, and lipolysis, among other metabolic measures (9, 10, 11, 12, 13). These methods have proved critical in dissecting the complex relationships between organ-specific IR and insulin secretion.

Subsequent studies showed that most subjects with type 2 DM had resistance to insulin action in adipose tissue (inhibition of lipolysis), liver (inhibition of glucose production), and skeletal muscle (stimulation of glucose disposal) (14, 15, 16). Curiously, insulin-mediated stimulation of amino acid deposition may be normal in subjects with DM, but it is impaired in subjects with other forms of IR, such as that of the human immunodeficiency virus (HIV)- associated MS (17). It is widely believed in the United States that IR almost always precedes the development of DM. This paradigm is supported by studies that have shown that IR is seen at an early age in first-degree relatives of people with type 2 DM (18), and IR indicates an increased risk of development of DM (19, 20, 21, 22, 23).

The relationship between IR and insulin secretion is complex. In general, IR causes increased insulin secretion and reduced hepatic insulin clearance, resulting in systemic hyperinsulinemia. Although a focus is often placed on insulin as a regulator of blood glucose, insulin plays a key role in the regulation of lipid and protein metabolism, in addition to cellular growth and development. Seminal studies by Hollenbeck and Reaven and Yeni-Komshian
et al (24, 25) systematically examined IR in nondiabetic individuals. Insulin-mediated glucose uptake was found to vary by up to eightfold in healthy subjects.

These and subsequent studies showed that more insulin-resistant subjects had greater plasma insulin concentration, VLDL-TG, and plasma glucose during the oral glucose tolerance test than did insulin-sensitive subjects, findings supporting the relationship between IR and MS (26). During his Banting lecture, Reaven proposed that DM was not the only adverse outcome associated with hyperinsulinemia, but that elevated insulin concentrations could activate metabolic pathways and result in dyslipidemia and HTN (27). He termed this collection of metabolic disturbances syndrome X. Subsequently, several articles described the associations among IR, dyslipidemia, HTN, elevated waist circumference (WC), and the risk of CVD and DM (28, 29, 30, 31, 32).

The first formal definition of MS was by the World Health Organization (WHO) in 1998 (Table 62.1) (33). This initial definition focused on IR as the main contributor to the syndrome and required the presence of IR in addition to two of the following: obesity, HTN, high TG, low HDL-C, or microalbuminuria. In 2001, the report of the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program also noted the relationship between IR and known CVD risk factors (Table 62.2) (34). The committee suggested that these lipid and nonlipid abnormalities were all metabolically related and used the term metabolic syndrome. In contrast to the WHO, this definition did not require the presence of IR, but rather a focus was placed on abdominal obesity, thus suggesting an additional risk posed by abdominal fat.

Since these initial definitions, MS has entered the clinical vernacular and is used to define a clinical state associated with an increased risk for the development of CVD and DM. Reaven himself did not propose syndrome X for use as a diagnostic entity but rather to provide a framework for understanding the complex relationships among abdominal obesity, IR, and the adverse consequences of hyperinsulinemia. The rest of this chapter describes the components of MS, a critical appraisal of the role of IR as the pathogenic factor for MS, and the utility of MS in clinical practice.