Etiopathogenesis of Metabolic Syndrome
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by: Andre Garcia
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Etiopathogenesis of “Metabolic Syndrome” (a.k.a. “Syndrome X”/”Reaven’s Syndrome”/”CHAOS”) - a concise and updated review
This syndrome corresponds to the association of disorders which will increase the risk of cardiovascular disease and Type 2 Diabetes Mellitus. In some studies, the prevalence in the USA is calculated as being up to 25% of the population.
To understand the etiologic and pathophysiologic roots of this serious pathologic condition, our attention must be focused on:
*) Insulin resistance
The most accepted hypothesis to describe the pathophysiology of the metabolic syndrome is insulin resistance; thus it is also known as the insulin resistance syndrome. Insulin resistance means a defect in insulin action which results in hyperinsulinemia, required as an attempt to maintain euglycemia.
An important contributor to the development of insulin resistance is an excess of circulating free fatty acids (FFA), released from an expanded adipose tissue mass (overweight or obesity). FFA decrease insulin sensitivity in muscle by inhibiting insulin-mediated glucose uptake. Increased level of circulating glucose increases pancreatic insulin secretion resulting in hyperinsulinemia. In the liver, FFA increase the production of glucose, triglycerides and secretion of very low density lipoproteins (VLDL). This leads to the reduction in glucose conversion to glycogen and incremented accumulation of triglycerides (TG). Insulin is an important anti-lipolytic hormone. When insulin resistance occurs, the higher rate lipolysis of stored triacylglycerol molecules in adipose tissue generates more fatty acids, which could further inhibit the anti-lipolytic effect of insulin, creating additional lipolysis (a “vicious cycle” thereby occurs).
*)Obesity and increased waist circumference
Obesity, particularly the abdominal/central/visceral/"apple-shaped" obesity, usually plays a key etiopathogenic role in Metabolic Syndrome. Male gender is more susceptible to this high-risk adipose distribution (testosterone versus estrogens seems to be an important influence).
Nevertheless, patients with normal weight (and/or women) can also be insulin resistant. The so called “metabolically obese” patients, are those which despite being normal-weight or near-normal-weight persons; have an increased amount of (“hidden”) visceral adipose tissue; probably because of genetic/hereditary/familiar causation.
According to some credible theories, when visceral adipose tissue mass is increased, there is an higher flux rate of adipose tissue-derived free fatty acids reaching the liver through the splanchnic circulation; contrasting with increases in abdominal subcutaneous fat, which could release lipolysis products into the systemic circulation and so avoid more direct and noxious effects on hepatic metabolism.
*) Dyslipidemia
In general, with increases in free fatty acid flux to the liver, increased production of very low-density lipoproteins (VLDL) occurs. Under physiological conditions, insulin inhibits the secretion of VLDL into the systemic circulation. When insulin resistance occurs, the increased flux of free fatty acids to the liver increases hepatic triglyceride synthesis. Hence, hypertriglyceridemia is an excellent reflection of the insulin resistant condition and is one of the most important criteria for the Metabolic Syndrome diagnosis.
The other main lipoprotein disturbance, in the Metabolic Syndrome, is a decrease in HDL-cholesterol levels (the “good” cholesterol). This reduction is a consequence of changes in HDL composition and metabolism. When hypertriglyceridemia is present, a decrease in the cholesterol content of HDL results from decreases in the cholesteryl ester content of the lipoprotein core with variable increases in triglyceride. In addition to HDL, the composition of LDL is also modified in a similar way. In fact, with fasting serum triglycerides > 2.0 mmol/L, almost all patients have a predominance of small dense LDL. This change in LDL composition is attributable to relative depletion of unesterified and esterified cholesterol, and phospholipids, with either no change or an increase in LDL triglyceride. In some studies, this alteration in LDL composition is an independent risk factor for cardiovascular disease.
*) Glucose intolerance
The defects of insulin action in glucose metabolism include failure to suppress gluconeogenesis in the liver, and to mediate glucose uptake in insulin sensitive tissues (muscle and adipose tissue). To compensate for defects in insulin action, insulin secretion must be increased to sustain euglycemia. When this compensation becomes exhausted and fails, defects in insulin secretion predominate and hyperglycemia occurs. Although free fatty acids can stimulate insulin secretion, prolonged exposure to excessive concentrations of FFA results in falls in insulin secretion (due to a lipotoxic effect).
*) Hypertension
The relation between insulin resistance and hypertension is well established. Several different mechanisms seems to contribute.
First, insulin has vasodilator effect when given intravenously to people of normal weight, with secondary effects on sodium reabsorption in the kidney. When persistent insulin resistance goes on, the vasodilatory effect of insulin can be lost, but the renal effect on sodium reabsorption tends to be preserved.
Fatty acids, themselves, can mediate relative vasoconstriction.
Hyperinsulinemia may result in increased sympathetic nervous system (SNS) activity and contribute to the development of hypertension.
*) Other pathologic signs
Many other abnormalities can occur in patients with Metabolic Syndrome; such as: increases in apo-B and apo-C-III, uric acid, prothrombotic factors (fibrinogen, plasminogen activator inhibitor 1), serum viscosity, asymmetric di-methyl-arginine, homocysteine, white blood cell count, pro-inflammatory cytokines; and also the presence of microalbuminuria; non-alcoholic fatty liver disease; obstructive sleep apnea; and polycystic ovarian disease (all this abnormalities have some significant degree of association with insulin resistance, although they are not the most important features, at all, in the majority of patients with Metabolic Syndrome).
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