Although the metabolic syndrome per se is not central to the focus of this review, we must give brief consideration to this major public health concern. The prevalence of the metabolic syndrome as defined by the NCEP-ATP III report is about 23% in the American population and rises to about 43% of elderly people in the USA, while higher prevalence rates can be observed in various ethnic groups around the world (Ford et al., 2002). This syndrome associates obesity, excessive blood pressure, high plasma glucose with disturbances of lipid homeostasis (high plasma triglycerides and low HDL cholesterol).
Numerous epidemiological studies have pointed out the role played by both environmental factors (e.g. lack of physical exercise, smoking) and nutritional factors (calorically dense, low-fibre and high-fat diets) (Zhu et al., 2004). On the other hand, some recent clues that heredity plays an important role came from the discovery of certain rare but major mutations associated with severe forms of glucose impairment (Yki-Jarvinen, 1997). The role played by genetic factors has also been highlighted by several epidemiological studies. It has been shown, for example, that impairment of insulin action could be inherited in the offspring of diabetic probands (Vauhkonen et al., 1998). Similarly, when the various determinants of glucose homeostasis are analysed in different populations, only the resistance of glucose intake, which is directly linked to impaired function of insulin, correlates with genetic background (Ferrannini et al., 2003).
It has long been thought that obesity precedes the metabolic syndrome, but it is now known that this syndrome can be observed in lean subjects, even if its prevalence increases in a graded fashion as body weight increases (St-Onge et al., 2004). Recent findings about the endocrine (but also paracrine and autocrine) function of adipocytes have renewed interest in the topic. Indeed, it has been demonstrated that fat cells are able to secrete pro-inflammatory and insulin resistance-inducing cytokines (TNF-alpha, resistin), as well as molecules acting in concert to facilitate glucose uptake (adiponectin) or the central control of satiety (leptin) (Lafontan, 2005).
The main feature of the metabolic syndrome is an association between dysfunction of energy storage (adipocyte physiology) and insulin resistance in a dramatic vicious circle (Miranda et al., 2005). Insulin resistance results in a decreased translocation of the GLUT4 glucose transporter to the plasma membrane of adipocytes. This would induce a relative glucose deprivation, thus contributing to an adipocyte stress response and secretion of inflammatory and anti-insulinic compounds such as TNF-alpha. Dysfunction of energy storage (overflow) leads to day-long elevated plasma free fatty acid levels and accumulation of triglycerides in muscle and liver, which in turn hinders glucose utilization, thus contributing to the overall insulin resistance. In plasma, beside disturbances of fasting insulin and glucose levels, the main quantitative abnormalities are decreased HDL cholesterol levels and increased VLDL and IDL triglyceride-rich lipoproteins, an abnormality that is exacerbated in the postprandial period (Chen et al., l993; Mekki et al., l999).
Another important feature of the metabolic syndrome is explained through the particular pathways of insulin action. This hormone, which is also a growth factor, displays pleiotrophic and tissue-specific effects, so that, within the same cell, metabolic pathways may differ in their response to insulin (Saltiel and Kahn, 200l). This observation supports the hypothesis that fat cell, muscle or liver dysfunctions, as observed in the metabolic syndrome, may be due to a decrease in insulin action for some of them, but in others to the consequence of hyperinsulinaemia.
The extracellular binding of insulin to the insulin receptor induces a conformational change that results in the activation of tyrosine kinase in the intracellular domain of the receptor, which induces the phosphorylation of specific substrates. These substrates are also able to be phosphorylated on seryl residues, which generally counteracts activating effects of the tyrosine phosphorylation (Bouzakri et al., 2003). Two main signalling cascades are initiated, the first through the activation of an insulin-receptor substrate (IRS) that leads to the activation of phosphatidylinositol 3-kinase PI(3)K kinase, and the synthesis of phosphatidyl-3-phosphate. This compound activates several distinct pathways, one of them resulting in the activation of the protein kinase Akt/PKB, which in turn seems to activate several other regulatory proteins; the activities of some of them have been shown to be associated with obesity (Manning, 2004). Downstream of the IRS-PI(3)K pathway lies the insulinmediated expression of SREBP-lc isoform, which plays an important role in regulation of lipid synthesis in liver, muscle and adipose tissue (Shimano, 2002).
The second signalling cascade activates the MAP kinase pathway and induces mitogenic and pro-inflammatory effects (Muller-Wieland et al., 200l). The tyrosyl residues of the insulin receptor can also be dephosphorylated by protein tyrosine phosphatases (PTP) and null mice for the PTP lB isoform has been shown to display improved insulin sensitivity and resistance to diet induced obesity (Elchebly et al., l999). In the metabolic syndrome, pathways leading to the activation of the PI(3)K are blocked while those inducing the MAP kinases pathways remain open and will be hyper-activated by the raised insulin levels that characterize the metabolic syndrome (Cusi et al., 2000). Therefore, some of the features of the metabolic syndrome are due to a relative hyperinsulinaemia, while others are the consequence of insulin resistance.
Accordingly, candidate genes for predisposition to the metabolic syndrome are those involved in the fat cell metabolism, including secreted adipokines, or the insulin signalling pathway acting in liver, muscle or fat cells. Some of them have already been described above, those associated with dyslipidaemia (Laakso, 2004), such as hepatic lipase (Ordovas et al., 2002), CETP (Weitgasser et al., 2004), LPL (Holzl et al., 2002) and apolipoprotein E (Kesaniemi et al., 1992). PPAR gamma, a nuclear receptor that is involved in adipocyte differentiation and is a fatty acid-sensitive gene, will be described below (Baratta et al., 2003). Some others are more specifically linked to insulin resistance. For example, the transmembrane glycoprotein PC-1 has been shown to inhibit in vitro insulin-induced tyrosine kinase activity of the insulin receptor. As a matter of fact, a polymorphism of the PC-1 protein, p.Lys121Gln has been correlated with clinical insulin resistance and a high plasma leptin level independently of obesity (Frittitta et al., 2001; Gonzalez Sanchez et al., 2002). But owing to variability in nutritional intake this correlation has been questioned in other studies. Interestingly, a recent study showed that, among individuals homozygous for the p12P variant in the PPAR gamma gene, those bearing the Q allelic variant display significantly higher fasting plasma glucose level and lower insulin sensitivity than p121 K carriers (Baratta et al., 2003). Another example is provided by the p.Gly972Arg polymorphism in the IRS-1 gene that causes carriers of the R variant to have a significantly reduced insulin sensitivity when compared with carriers of the G allelic variant (McGettrick et al., 2005). This insulin resistance is accompanied with several features of the metabolic syndrome, such as increased total triglyceridaemia, decreased plasma HDL or elevated blood pressure. Finally, recent studies have shown that SREBF-1 gene polymorphisms could be associated with obesity and insulin resistance (Laudes et al., 2004; Eberle et al., 2004).
However, despite the growing interest in the metabolic syndrome, relatively few studies have been focused on the influence of insulin resistance on lipid and lipoprotein response to dietary intervention. Most studies indicate that in patients with metabolic syndrome, responsiveness to dietary intervention is less marked than in lean and insulin-sensitive subjects (Beynen and Katan, 1985; Knopp et al., 1997, 2000). A recent study has also shown that insulin-resistant subjects present a decreased cholesterol absorption (Knopp et al., 2003). These findings are supportive of studies suggesting a role for insulin in the postprandial accumulation of intestinally derived lipoproteins (Harbis et al., 2001, 2004).
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