Insulin resistance and hyperinsulinemia are frequently associated with a cluster of clinical and biochemical abnormalities that have been described with increasing detail and given a variety of names including deadly quartet, syndrome X, insulin resistance syndrome, metabolic syndrome, and cardiovascular dysmeta-bolic syndrome (9-13). Many prefer to call it insulin resistance syndrome because insulin resistance and the resulting hyperinsulinemia appear to be the underlying abnormalities from which the other features of the syndrome are derived (see Chap. 7). The hallmarks of insulin resistance syndrome are obesity, particularly central or intra-abdominal obesity, glucose intolerance, or type 2 diabetes mellitus, hypertension, a dyslipidemia characterized by elevated triglycerides, low HDL cholesterol and small dense LDL cholesterol, a hypercoagulable state characterized by alterations in both thrombosis and fibrinolysis and increased atherosclerosis manifesting as coronary artery disease, peripheral vascular dis- <j ease, or stroke (14-25). More recently, the polycystic ovary syndrome (PCOS) Ji has been added to the list of characteristic features of the insulin resistance syn- J
drome in women (25). From a clinical viewpoint, the syndrome should be sus-
& u pected in anyone who has a personal or a family history of obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, or premature cardiovascular disease. It should also be looked for in women with a history of gestational diabetes mellitus (GDM) or PCOS and members of various ethnic and racial groups that have increased risk for obesity and type 2 diabetes.
One of the most common manifestations of insulin resistance syndrome is the combination of obesity and type 2 diabetes mellitus. In the United States, approximately 80% of people with type 2 diabetes mellitus are overweight, defined as a body mass index (BMI) > 27 kg/m2, and the current rapid rate of increase in the prevalence of type 2 diabetes mellitus is closely linked to the increasing prevalence of obesity and physical inactivity in our society (26). It is estimated that there are now approximately 16 million people in the United States with type 2 diabetes mellitus, about 5 million of whom are undiagnosed, and another 10 million adults who have IGT and are at high risk for developing diabetes. The prevalence of type 2 diabetes mellitus is increasing at all ages from adolescence to the elderly, with the most rapid rates of increase being observed in the younger age groups. In addition to obesity and physical inactivity as risk factors for diabetes, genetic factors also clearly play an important role, making a detailed family history an important part of the assessment. It is now well established that various racial-ethnic groups are at increased risk of developing type 2 diabetes, including African Americans, Hispanic Americans, Native Americans, Asian Americans, and Pacific Islanders, all of whom have significantly higher rates of developing type 2 diabetes than the Caucasian population (27-30). As noted above, women who have a history of gestational diabetes (GDM) or who have polycystic ovary syndrome (PCOS) often have insulin resistance and are at increased risk for developing type 2 diabetes mellitus (25).
In addition to evaluating patients for their state of glucose homeostasis (see below), one should also look for the other manifestations of insulin resistance syndrome, including acanthosis nigricans, mild-to-moderate hypertension, dys-lipidemia, and evidence of premature atherosclerosis and cardiovascular disease.
A cluster of biochemical abnormalities is frequently associated with insulin resistance syndrome. These include a characteristic dyslipidemia consisting of elevated serum triglycerides and very-low-density lipoproteins (VLDL), a decrease in high-density-lipoprotein cholesterol (HDL-C), and a pattern of small, dense, low-density-lipoprotein (LDL) particles (31-34). Serum uric acid is often -o increased and, if measured, plasma FFA may be high. Fasting plasma glucose may be normal, intermediate (impaired fasting glucose), or in the diabetic range, but fasting insulin and C-peptide concentrations are usually elevated in relation to the degree of glycemia.
The insulin resistance syndrome is also associated with a hypercoagulable state characterized by a combination of procoagulant and antithrombolytic factors J
(35,36). Plasma fibrinogen is increased as is Von Willibrand factor (vWF) and a
& u plasminogen activity inhibitor 1 (PAI-1). Tissue plasminogen activator (tPA) is decreased and several studies have demonstrated impaired endothelial function and vascular reactivity in patients with insulin resistance syndrome (37,38).
While the mechanisms for the development of atherosclerosis in insulin resistance syndrome are complex and not yet fully understood, there is now substantial evidence that a chronic inflammatory process plays a significant role (39). Increases in endothelial cell-derived leukocyte adhesion molecules, such as intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), are increased as are proinflammatory cytokines such as interleuken-6 (IL-6), TNF-a, and the acute phase-reactant C-reactive protein (CRP) (40,41).
Another commonly observed abnormality in insulin resistance syndrome is elevated serum homocystine, which may reflect altered oxidative stress mechanisms that may contribute to accelerated atherosclerosis (42). Finally, a possible role of insulin itself, particularly its effects on cell growth and differentiation, continues to be examined. The potential benefit of measuring any of the above so-called ''nontraditional'' risk factors for coronary artery disease in evaluating a patient with insulin resistance syndrome is still unclear. Many of the biochemical markers of these processes are not readily available (or standardized) in clinical laboratories and more research is needed to determine how useful they will be in clinical practice. However, studies of endothelial dysfunction, altered coagulation and fibrinolysis, chronic inflammation, or oxidative stress are providing many new insights into the pathobiology of the vascular disease associated with insulin resistance and diabetes.
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