Small dense LDL Glyconeogenesis Protein catabolism Protein synthesis Hyperuricemia

Source: From Dandona, P. et al., Circulation 111, 1448, 2005.

The original conceptualization of this syndrome was based on 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. While the features described above explain the atherogenesis to some extent, Reaven maintained that hyperinsulinemia contributed to atherogenicity and thus insulin is atherogenic, leading to CHD and cerebrovascular disease associated with this syndrome. However, as our understanding of the action of insulin evolves to comprehensively include recent discoveries,7 we can better see that insulin resistance is the basis of most if not all the features of this syndrome.

Obesity probably leads to hypertension through (1) increased vascular tone created by a reduced bioavailability of nitric oxide (NO) due to increased oxidative stress,8 (2) increased asymmetric dimethyl arginine (ADMA) concentrations,9 (3) increased sympathetic tone,10 and (4) increased expression of angiotensinogen by adipose tissue leading to an activation of the renin-angiotensin system.11 The last factor requires further critical investigation.

Metabolic syndrome is characterized by low HDL in association with an elevated triglyceride concentration. This is believed to be due to an increased triglyceride load in HDL particles that are acted upon by hepatic lipase that hydrolyzes the triglyceride. The loss of the triglyceride results in a small HDL particle filtered by the kidney, resulting in decreases in apolipoprotein A (apo A) and HDL concentrations. Apart from an increase in the loss of apo A, data demonstrate that insulin may promote apo A gene transcription.12 Therefore, insulin-resistant states may be associated with diminished apo A biosynthesis.13

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. Increases of plasma FFA concentrations in normal subjects to levels comparable to those in the obese also resulted in the induction of oxidative stress, inflammation, and subnormal vascular reactivity along with insulin resistance.14 Because resistance to insulin also results in the relative non-suppression of adipocyte hormone-sensitive lipase, there is further enhancement of lipolysis and an increase in FFA concentration, leading to a vicious cycle 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 elevated C-reactive protein (CRP) concentrations. These features were added on the basis that they were found frequently in association with metabolic syndrome and no rational explanation indicated why they actually occurred. These features are probably related to both insulin resistance and obesity. The relationship of inflammation to obesity and insulin resistance still needs to be explained.15

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