| Authors | Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R. | |
| Title | Metabolic
syndrome: a comprehensive perspective based on interactions between obesity,
diabetes, and inflammation |
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| Full source | Circulation. 2005 Mar 22;111(11):1448-54. | |
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 Per scorrere le diapositive |
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| Introduction | The
original description of the metabolic syndrome by Reaven consisted of obesity,
insulin resistance, hypertension, impaired glucose tolerance or diabetes,
hyperinsulinemia and dyslipidemia characterized by elevated triglyceride,
and low HDL concentrations. All of the features described above are risk
factors for atherosclerosis, and thus, metabolic syndrome constituted a
significant risk for coronary heart disease. The features of obesity/overweight
and insulin resistance also provided a significant risk for developing type
2 diabetes. The risks for coronary heart disease and diabetes with metabolic
syndrome are greater than those for simple obesity alone, and therefore,
an understanding of the pathogenesis and through it, a rational approach
to its therapy are of prime importance. As our understanding of the action of insulin evolves to comprehensively include the recent discoveries, we can better see that insulin resistance is the basis of most if not all of the features of this syndrome. The original conceptualization of this syndrome was on the basis of resistance to the metabolic actions of insulin. Thus, hyperinsulinemia, glucose intolerance, type 2 diabetes, hypertriglyceridemia, and low HDL concentrations could be accounted for by resistance to the actions of insulin on carbohydrate and lipid metabolism. Although the features described above would to some extent explain the atherogenesis, Reaven has maintained that hyperinsulinemia itself contributes to atherogenicity, and thus, insulin is atherogenic, leading to the coronary heart disease and cerebrovascular disease associated with this syndrome. Obesity probably leads to hypertension through (1) increased vascular tone created by a reduced bioavailability of NO because of increased oxidative stress, (2) increased asymmetric dimethylarginine (ADMA) concentrations, (3) increased sympathetic tone, and (4) increased expression of angiotensinogen by adipose tissue leading to an activation of the renin-angiotensin system. The last of these factors requires further critical investigation. Metabolic syndrome is characterized by a low HDL in association with an elevated triglyceride concentration. This is believed to be a result of an increased triglyceride load in the HDL particle that is acted on by hepatic lipase, which hydrolyzes the triglyceride. The loss of the triglyceride results in a small HDL particle that is filtered by the kidney, resulting in a decrease in apolipoprotein (apo) A and HDL concentrations. Apart from an increase in the loss of apoA, there are data demonstrating that insulin may promote apoA gene transcription. Therefore, insulin resistance states may be associated with diminished apoA biosynthesis. An increase in plasma free fatty acid (FFA) concentrations plays a key role in the pathogenesis of insulin resistance through specific actions that block insulin signal transduction. An increase in plasma FFA concentrations in normal subjects to levels comparable to those in the obese also results in the induction of oxidative stress, inflammation, and subnormal vascular reactivity, in addition to causing insulin resistance. Because resistance to insulin also results in the relative nonsuppression of adipocyte hormone–sensitive lipase, there is further enhancement of lipolysis and increase in FFA concentration. Thus, there occurs a vicious circle of lipolysis, increased FFA, insulin resistance, and inflammation. Several new features have been added to the syndrome over time. These include elevated plasminogen activator inhibitor-1 (PAI-1) concentrations and now, elevated C-reactive protein (CRP) concentrations. These features were added on the basis that they were frequently found in association with the metabolic syndrome, and there has hitherto been no rational explanation as to why they actually occur. These features are probably related to both insulin resistance and obesity. The relationship of inflammation to obesity and insulin resistance needs to be explained. |
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