No specific etiology is known to account for the metabolic syndrome, nevertheless, subjects with the syndrome exhibit a variety of metabolic abnormalities associated with the individual components of the syndrome. Most notable are obesity and insulin dysregulation, which are the most frequently occurring metabolic syndrome components (Ervin, 2009). Multiple metabolic abnormalities could additively or synergistically influence the progression of CVD and diabetes.
Insulin resistance may be characterized by impaired glucose tolerance and elevated fasting glucose due to reduced insulin action. In the insulin-sensitive state, insulin not only affects glucose metabolism but also suppresses adipose tissue lipolysis. In overweight or obese individuals, increased adiposity results in elevated circulating free fatty acids (FFA) due to higher rates of triglyceride lipolysis, mediated primarily by the inability of insulin to suppress triglyceride lipolysis through the action of hormone sensitive lipase and reduced expression of adipose triglyceride lipase (Jocken et al, 2007).
Increased circulating FFA has been hypothesized to lead to tissue-specific lipotoxicity (Kusminski et al, 2009; Unger, 2003). Elevated FFA levels inhibit insulin-stimulated skeletal muscle glucose uptake and increase hepatic glucose production (Boden, 1999), thus contributing to peripheral insulin resistance. Further, the increase in FFA levels promotes increased hepatic triglyceride synthesis and storage, and the excess triglycerides are secreted as very low-density lipoproteins (VLDL) (Lewis, 1997), which lead to an increased production of LDL. Elevated plasma triglycerides are inversely correlated with HDL-C levels (Austin, 1989), which is thought to occur by the action of cholesteryl ester transfer protein (Sandhofer et al, 2006). This leads to smaller, triglyceride-rich HDL particles with higher catabolic rate due to increased renal clearance, which results in reduced HDL levels (Ji et al, 2006). In similar fashion, elevated triglyceride levels lead to formation of atherogenic small, dense LDL particles which are more slowly cleared by the LDL receptor and thus tend to accumulate (Kwiterovich, Jr., 2002). Therefore, increased adiposity through increased FFA flux, and compounded by insulin resistance, contributes to the dyslipidemia associated with metabolic syndrome. In muscle, increased FFA levels inhibit insulin-mediated glucose transport activity (McGarry, 2002), affecting peripheral glucose uptake (contributing to IGT) and eventually leading to hyperglycemia. Additionally, excess FFA levels result in an increase of myocyte triglyceride levels that have been shown to directly affect insulin resistance in the muscle (Krssak et al, 1999). Increased levels of FFA have also been shown to mediate vasoconstriction and activate the sympathetic nervous system (SNS), potentially contributing to hypertension and atherogenesis (Grekin et al, 1995; Tripathy et al, 2003). The consequences of increased adiposity can influence many of the metabolic syndrome components directly and contribute to, or exacerbate, the insulin-resistant state.
The SNS plays an important role in both etiology and pathogenesis of the metabolic syndrome and has been linked to an increased risk of CVD. Accumulating evidence suggests that human obesity is characterized by increased SNS activity and decreased cardiac vagal activity, which could contribute to the adverse consequences of the metabolic syndrome (Garruti et al, 2008; Straznicky et al, 2008; Tentolouris et al, 2008). Schneiderman and Skyler (1996) proposed a pathway for atherogenesis that is based on an interactive relation among insulin resistance, hyperinsulinemia, and sympathetic tone. According to this notion, social and emotional factors can interact with insulin-sensitive metabolic variables to promote the development of cardiovascular disease. Several studies have now shown that activation of the sympa-thoadrenal system inhibits glucose uptake by peripheral tissue and increases hepatic glucose uptake, thus directly impacting insulin resistance and hyperglycemia (Nonogaki, 2000). In hypertension, increased SNS activity may lead to CVD through modifications of heart rate, cardiac output, and renal sodium retention (Grassi, 2006). As mentioned above, stimulation of P-adrenergic receptors increases circulating FFA levels through increased adipose tissue triglyceride lipolysis, which contributes to the dyslipi-demia associated with metabolic syndrome and to insulin resistance. Together, these observations suggest a direct role for SNS dysfunction in adverse outcomes associated with the metabolic syndrome. Still undetermined is whether sympathetic dysfunction is involved in the development of, or is a consequence of, the metabolic syndrome.
The metabolic syndrome condition has been described as a proinflammatory state characterized by an excessive release of inflammatory cytokines, accompanied by increased oxi-dant stress (Cornier et al, 2008). It has been reported that in subjects with the metabolic syndrome, plasma and tissue levels of inflammatory molecules are elevated, including C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), interleukin (IL)-6, IL-1P, IL-18, and resistin (Espinola-Klein et al, 2008; Kowalska et al, 2008; Reilly et al, 2007; You et al, 2008). Increased adiposity contributes directly to cytokine levels by at least two mechanisms. The first involves increased numbers of adipose tissue resident macrophages, and the second direct cytokine production by the adipocytes (Weisberg et al, 2003; Xu et al, 2003). The adipocyte-derived cytokines can subsequently affect insulin action in other tissues and within the adipocyte (Kennedy et al, 2009). IL-6 is produced by both adipose tissue and skeletal muscle, has been shown to be associated with BMI and fasting insulin, and is elevated in subjects with type 2 diabetes (Ruge et al, 2009). IL-6 has been shown to affect insulin action by interfering with insulin receptor signaling, thus contributing to insulin resistance. Elevations of circulating cytokines, particularly TNF-a, can directly cause beta-cell dysfunction contributing to IGT, hyperlipidemia, and diabetes (LeRoith, 2002). Adiponectin, a cytokine released by adipose tissue, acts to sensitize tissues to insulin action and is reduced in individuals with the metabolic syndrome (Hung et al, 2008). Hepatic CRP production is induced by peripheral IL-6 (and other cytokines) and may serve as a relatively stable marker of inflammation and has been shown to be an independent predictor of CVD (Ridker et al, 2003). Population studies have shown that subjects with the metabolic syndrome and elevated CRP have increased risk of CVD relative to subjects with the syndrome and lower CRP levels.
Inflammation, oxidative stress, and dys-lipidemia are all factors shown to promote CVD. Inflammatory cytokines induce endothe-lial dysfunction through expression of endothe-lial cell surface adhesion molecules, which leads to macrophage infiltration of the vessel wall and initiation of atherogenesis (Libby, 2006). Elevated plasma LDL results in increased transcytosis of LDL through the vessel wall. Intravascular oxidative stress leads to modification of LDL to an oxidized form readily taken up by macrophages and leading to formation of foam cells and fatty streaks, which are the earliest histologic manifestations of atherosclerosis (Ross, 1986). Decreased plasma HDL levels diminishe both the anti-inflammatory and the anti-oxidant properties attributed to this lipopro-tein (Movva and Rader, 2008). Additionally, oxidant stress inhibits nitric oxide production, which impairs vascular reactivity, further contributing to CVD.
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