Submitted by: sdemir   Date: 2010-06-04 07:06
The Metabolic Syndrome
Marc-Andre Cornier, Dana Dabelea, Teri L. Hernandez, Rachel C. Lindstrom, Amy J. Steig, Nicole R. Stob, Rachael E. Van Pelt, Hong Wang and Robert H. Eckel

The "metabolic syndrome" (MetS) is a clustering of components that reflect overnutrition, sedentary lifestyles, and resultant excess adiposity. The MetS includes the clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities including the prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, and reproductive disorders. Because the MetS is a cluster of different conditions, and not a single disease, the development of multiple concurrent definitions has resulted. The prevalence of the MetS is increasing to epidemic proportions not only in the United States and the remainder of the urbanized world but also in developing nations. Most studies show that the MetS is associated with an approximate doubling of cardiovascular disease risk and a 5-fold increased risk for incident type 2 diabetes mellitus. Although it is unclear whether there is a unifying pathophysiological mechanism resulting in the MetS, abdominal adiposity and insulin resistance appear to be central to the MetS and its individual components. Lifestyle modification and weight loss should, therefore, be at the core of treating or preventing the MetS and its components. In addition, there is a general consensus that other cardiac risk factors should be aggressively managed in individuals with the MetS. Finally, in 2008 the MetS is an evolving concept that continues to be data driven and evidence based with revisions forthcoming.

I. Introduction

II. Definitions
A. Brief history: nomenclature of the metabolic syndrome
B. Diverging definitions: a syndrome rooted in controversy

III. Epidemiology
A. Prevalence estimates according to definition
B. Prevalence estimates by sex
C. Prevalence estimates by race/ethnicity
D. Prevalence estimates by age
E. Prevalence estimates by socioeconomic status, tobacco, alcohol, and level of education
F. Changes in prevalence following intervention

IV. Pathophysiology
A. Insulin resistance: a conceptual prologue
B. Obesity as a "driving force" in the prevalence of insulin resistance
C. Insulin resistance in adipose tissue
D. Insulin resistance in the liver
E. Insulin resistance in muscle
F. Hypertension and insulin resistance
G. Other contributors to insulin resistance (nocturnal FFA flux: sympathetic nervous system)
H. Proinflammatory molecules, ER stress, and their roles in insulin resistance and the metabolic syndrome
I. Animal models of the metabolic syndrome
J. Genetic determinants of the metabolic syndrome in humans

V. Risks of the Metabolic Syndrome
A. Cardiovascular disease
B. Type 2 diabetes mellitus

VI. Associated Conditions
A. Nonalcoholic fatty liver disease
B. Polycystic ovarian syndrome
C. Obstructive sleep apnea
E. Lipodystrophy
F. Microvascular disease

VII. Therapeutics
A. Lifestyle modification
B. Pharmaceutical therapy
C. Bariatric surgery

VIII. Unanswered Questions

IX. Summary and Conclusions

Pathophysiology of the Metabolic Syndrome and insulin resistance. A, FFA are released in abundance from an expanded adipose tissue mass. In the liver, FFA result in increased production of glucose and triglycerides and secretion of VLDL. Associated lipid/lipoprotein abnormalities include reductions in HDL-C and increased density of LDL. FFA also reduce insulin sensitivity in muscle by inhibiting insulin-mediated glucose uptake. Associated defects include a reduction in glucose partitioning to glycogen and increased lipid accumulation. Elevated circulating glucose and to some extent FFA increase pancreatic insulin secretion, resulting in hyperinsulinemia. Hyperinsulinemia may result in enhanced sodium reabsorption and increased sympathetic nervous system activity and may contribute to hypertension, as might increased levels of FFA. B, Superimposed and contributory to the insulin resistance produced by excessive FFA is the paracrine and endocrine effect of the proinflammatory state. Produced by a variety of cells in adipose tissue, including adipocytes and monocyte-derived macrophages, the enhanced secretion of IL-6 and TNF- among others results in more insulin resistance and lipolysis of adipose tissue triglyceride stores, resulting in increased circulating FFA. IL-6 and other cytokines also are increased in the circulation and may enhance hepatic glucose production, the production of VLDL by the liver, and insulin resistance in muscle. Cytokines and FFA also increase the production of fibrinogen and PAI-1 by the liver, complementing the overproduction of PAI-1 by adipose tissue. This results in a prothrombotic state. Reductions in the production of the antiinflammatory and insulin-sensitizing cytokine adiponectin are also associated with the metabolic syndrome and insulin resistance. [Reproduced from R.H. Eckel et al.: Lancet 365:1415–1428, 2005 (113 ) with permission from Elsevier.]

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