Metabolic syndrome: Definition, pathophysiology, and mechanisms

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Defining metabolic syndrome

Clinical findings most commonly associated with metabolic syndrome include insulin resistance, dyslipidemia (specifically high triglycerides, low levels of high-density lipoprotein [HDL], and small dense low-density lipoprotein [LDL]), central obesity, hypertension, impaired glucose tolerance or diabetes mellitus, and high rates of atherosclerotic disease. Recently, markers of inflammation and accelerated hemostasis/impaired fibrinolysis have been added to this list. Table I lists proposed

Measurements of insulin resistance

Insulin resistance, implying depressed cellular sensitivity to insulin, is a central feature of metabolic syndrome. Insulin sensitivity varies by organ, cell type, and metabolic pathway examined. Clinical measurement of insulin resistance generally focuses on whole-body glucose uptake in response to circulating insulin. The resulting measurement is an aggregate response of a complex homeostatic system. Not surprisingly, a variety of techniques have been proposed and used to measure insulin

Diagnostic criteria for metabolic syndrome

Several definitions and criteria have been proposed for the metabolic syndrome associated with insulin resistance. In 1998, the American Diabetes Association (ADA) issued a consensus statement identifying “glucose intolerance, central obesity, dyslipidemia (increased triglycerides, decreased HDL, increased small dense LDL), hypertension, increased prothrombotic and antifibrinolytic factors, and a predilection for atherosclerotic vascular disease” as components of the metabolic syndrome

Epidemiology and factor analysis

The prevalence of metabolic syndrome among US adults is approximately 22%, determined by applying NCEP criteria to the National Health and Nutrition Examination Survey III data set.2 Prevalence increased with age from 6.7% in the 20 to 29 y of age range to 43.5% in the 60 to 69 y of age range. Hispanics were affected more than either blacks or whites. When divided by sex, black women had greater prevalence than white women, whereas white men had greater prevalence than black men.

Isomaa et al,12

The next generation: Metabolic syndrome in children

Similar to the trend in adults, there is currently an alarming increase in the rate of obesity and type 2 diabetes mellitus in children in the United States.14., 15. Several studies have examined the interactions among fasting insulin, lipoproteins, blood pressure, and weight in children, pursuing the hypothesis that metabolic syndrome is a developmental disorder strongly influenced by risk factors in the first 2 decades of life.16., 17., 18.

Sinaiko et al17., 18. examined the relation among

Pathophysiology: Molecular mechanisms of insulin action and insulin resistance

Metabolic syndrome is associated with insulin resistance, but it is not a consequence of insulin resistance alone, nor is it a direct consequence of the lack of insulin action. This is most evident in patients with insulin receptor mutations or autoimmune antibodies to the insulin receptor; they may have 100-fold or greater elevations of circulating insulin or require similarly high doses of exogenous insulin to control diabetes. These patients exhibit a distinct syndrome with acanthosis

Pathophysiology: Dysfunctional energy storage and obesity

Some investigators regard insulin resistance as a mediating factor in metabolic syndrome, but not as the primary cause (Figure 2). These investigators consider dysfunctional energy storage to be the fundamental issue. In this theory, insulin resistance is thought to arise from abnormalities in the processing and storage of fatty acids and triglyceride, molecules that account for most of the body's energy utilization and storage. In most patients, the key abnormality is simply the presence of

Adipocytes as an endocrine organ

The adipocyte is now recognized as the source of multiple bioactive peptides. Increased adipocyte mass has been associated with increased expression of angiotensinogen, tumor necrosis factor-α (TNF-α), resistin, leptin, and PAI-1.32., 33., 34., 35. Adiponectin is a protein expressed by adipocytes. Circulating adiponectin concentrations are actually decreased in obesity, as well as in the type 2 diabetes mellitus.32 Angiotensinogen is linked with the development of hypertension in obesity, and

Glucose homeostasis

At a given level of obesity, an individual may have normal glucose tolerance, impaired glucose tolerance, or type 2 diabetes mellitus. The factors that determine the degree of impairment of glucose metabolism are insulin sensitivity and beta cell reserve capacity. Insulin sensitivity in normal individuals varies by approximately 3-fold.1 In insulin-resistant individuals, the pancreatic beta cells must secrete more insulin to maintain euglycemia. However, prolonged hyperfunction can lead to

Free fatty acid metabolism

In addition to its role in stimulating glucose uptake in peripheral cells, insulin also inhibits free fatty acid release from adipocytes. An early manifestation of insulin resistance is the inability to suppress lipolysis in fat tissue. The excessive plasma free fatty acids are transported to the liver and muscle, where they stimulate hepatic glucose production and inhibit insulin-stimulated glucose uptake, worsening hyperglycemia.28 Thiazolidinediones decrease free fatty acid concentrations

Dyslipidemia

The dyslipidemia of metabolic syndrome is characterized by elevated triglycerides (VLDL), low HDL, and small dense LDL, a triad that has been termed the atherogenic lipoprotein phenotype.37 In the Copenhagen Male Study, a prospective cardiovascular study of 5249 men, the combination of high triglyceride and low HDL concentrations was compared to high LDL concentrations as a risk factor for ischemic heart disease.38 Subjects were divided into 4 groups on the basis of lipid levels, and ischemic

Hypertension

Elevated blood pressure is included in most definitions of metabolic syndrome, but its relation to the syndrome is complex. Multivariate techniques such as factor analysis, reviewed earlier, show that hypertension tends to segregate independently of other variables in metabolic syndrome. Nevertheless, most experts agree that hypertension should remain one of the options in diagnostic criteria. Key points of the argument include the clear correlation between hypertension and body weight, the

Microalbuminuria

Microalbuminuria is defined as urinary albumin above the normal excretion rate and in the range of 30 to 300 mg per 24 h. Because the renal glomeruli contain vascular endothelial cells, as well as modified vascular smooth muscle cells known as mesangial cells (similar to cells in the vascular wall), the hypothesis has arisen that glomerular function (in particular, the function of excluding albumin rigorously from excreted urine) might mirror endothelial function and predict vascular disease.

Inflammation and coagulation

In recent years, markers of systemic inflammation and certain components of the hemostatic system have been found to predict atherosclerotic risk. Some of these factors are associated with insulin resistance or other components of metabolic syndrome. C-reactive protein, when measured by highly sensitive immunoassay, has emerged as a very strong atherosclerotic risk factor comparable in predictive power to the total/HDL cholesterol ratio.58 C-reactive protein was found to be independently

Summary and conclusions

Metabolic syndrome is a highly prevalent but underrecognized and undertreated condition. The concurrence of abdominal obesity, borderline hyperglycemia, atherogenic lipoprotein phenotype, and/or hypertension in a patient constitutes a system of linked pathogenesis and high atherogenicity. The complex pathogenetic links involve glucose and fat metabolism, insulin, and a variety of adipocyte-derived hormones and cytokines.

Current understanding can be summarized as follows: insulin resistance, a

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