Atherosclerotic CVD

The risk for new-onset CHD in patients with the metabolic syndrome in the absence of diabetes has varied substantially from population to population but averages between about 1·5-fold and 3-fold higher (Eckel et al. Reference Eckel, Grundy and Zimmet2005). However, the population-attributable risk for the development of CHD over a follow-up period of 8 years in middle-aged men and women with the metabolic syndrome in the Framingham Offspring Study was found to be 34% and 16% respectively (Rutter et al. Reference Rutter, Meigs, Sullivan, D'Agostino and Wilson2005). Use of the Framingham risk scoring system for patients without diabetes but with the metabolic syndrome enhances the predictability of CHD. Elevations in C-reactive protein (CRP) also influence this risk, and more so in patients with the metabolic syndrome and type 2 diabetes (Rutter et al. Reference Rutter, Meigs, Sullivan, D'Agostino and Wilson2005).

Although the metabolic syndrome is a substantial predictor of CHD and atherosclerotic CVD in general (which includes CHD and stroke), there is a paucity of information about the specific risk of stroke and peripheral vascular disease. In the absence of diabetes and previous atherosclerotic CVD the relative risk of ischaemic stroke in Finnish men with the metabolic syndrome was found to be approximately 2·5 (Kurl et al. Reference Kurl, Laukkanen, Niskanen, Laaksonen, Sivenius, Nyyssonen and Salonen2006). In the Framingham Offspring Study both the metabolic syndrome and diabetes were found to predict ischaemic stroke, with the population-attributable risk being greater for patients with the metabolic syndrome than for patients with diabetes alone (19% v. 7%), particularly in women (27% v. 5%; Najarian et al. Reference Najarian, Sullivan, Kannel, Wilson, D'Agostino and Wolf2006).

Type 2 diabetes

Overall, the risk for type 2 diabetes in patients with the metabolic syndrome is 3-fold–5-fold higher (Eckel et al. Reference Eckel, Grundy and Zimmet2005). In an 8-year follow-up of middle-aged men and women in the Framingham Offspring Study the population-attributable risk for developing type 2 diabetes was found to be 62% and 47% respectively (Wilson et al. Reference Wilson, D'Agostino, Parise, Sullivan and Meigs2005). Clearly, patients with impaired fasting glucose or impaired glucose tolerance have a high risk for type 2 diabetes; a risk that may be independent of other components of the metabolic syndrome. However, in the Insulin Resistance Atherosclerosis Study (Hanley et al. Reference Hanley, Karter, Williams, Festa, D'Agostino, Wagenknecht and Haffner2005) the definitions of the International Diabetes Federation (Alberti et al. Reference Alberti, Zimmet and Shaw2005) and the National Cholesterol Education Program Adult Treatment Program III Committee (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001) were shown to predict type 2 diabetes equally well despite not requiring the use of oral glucose tolerance testing or measures of insulin resistance or microalbuminuria. The risk for new-onset type 2 diabetes may be as strong for the metabolic syndrome as for impaired glucose tolerance and may not require the presence of impaired fasting glucose as a predictor.

Insulin resistance

The most accepted and unifying hypothesis to describe the pathophysiology of the metabolic syndrome is insulin resistance (Eckel et al. Reference Eckel, Grundy and Zimmet2005). Insulin resistance has been most often defined using a glucocentric view, i.e. when a defect in insulin action results in fasting hyperinsulinaemia to maintain euglycaemia. Yet, even before fasting hyperinsulinaemia develops, postprandial hyperinsulinaemia exists. A series of biomarkers are available to assess the presence of insulin resistance, including fasting insulin, the homeostatic model assessment, pro-insulin and TAG:HDL-cholesterol, yet a number of limitations exist for each one. Although the modified intravenous tolerance test of Bergman (Boston et al. Reference Boston, Stefanovski, Moate, Sumner, Watanabe and Bergman2003) has proved useful in research settings, its practical application is lacking. The euglycaemic clamp continues to be the gold standard.

A major contributor to the development of insulin resistance is circulating fatty acids. Albumin-bound NEFA are derived predominantly from TAG stores in adipose tissue. Historically, the cAMP-dependent enzyme hormone-sensitive lipase was considered to be the lipolytic enzyme; however, recent evidence from murine models indicates that adipose TAG lipase may be more important (Haemmerle et al. Reference Haemmerle, Lass, Zimmermann, Gorkiewicz, Meyer and Rozman2006). Lipoprotein lipase (LPL) also provides fatty acids but through the lipolysis of circulating TAG-rich lipoproteins (Eckel, Reference Eckel1989). Insulin is important to both anti-lipolysis and the stimulation of LPL in adipose tissue. Importantly, the most sensitive pathway of insulin action is the inhibition of lipolysis (Jensen et al. Reference Jensen, Caruso, Heiling and Miles1989). Paracrine regulation of lipolysis in adipose tissue may also be an important contributor to the circulating NEFA burden. One such paracrine affecter is the cytokines. With increasing adipose tissue mass, infiltration of monocyte-derived macrophages occurs and inflammatory cytokines are released. This local effect promotes additional impairment in the anti-lipolytic effect of insulin, creating more lipolysis (Suganami et al. Reference Suganami, Nishida and Ogawa2005).

In muscle excessive fatty acids decrease insulin sensitivity (Fig. 1(a)). Increased fatty acid availability results in the accumulation of intramyocellular fatty acyl-CoA, which then unfavourably modifies a number of downstream pathways including: insulin signalling; insulin-(in)dependent glucose transport and phosphorylation; insulin-stimulated glycogen synthesis; insulin-stimulated oxidative phosphorylation (ATP synthesis); accumulation of TAG; expression of PPARγ coactivator-1 and PPARγ coactivator-1-controlled genes involved in mitochondrial biogenesis and oxidative phosphorylation and potentially the initiation of inflammatory processes by activation of protein kinase C and NF-κB; expression of matrix metalloproteinases (for review, see Roden, Reference Roden2005). This effect of fatty acids on muscle insulin sensitivity is more attributable to SFA than unsaturated fatty acids (Storlien et al. Reference Storlien, Higgins, Thomas, Brown, Wang, Huang and Else2000; Lee et al. Reference Lee, Pinnamaneni, Eo, Cho, Pyo, Kim, Sinclair, Febbraio and Watt2006).

Fig. 1. Pathophysiology of the metabolic syndrome (insulin resistance and NEFA), (a) NEFA are released in abundance from an expanded adipose tissue mass. In the liver NEFA result in an increased production of glucose and TAG and secretion of VLDL. Associated lipid and lipoprotein abnormalities include reductions in HDL-cholesterol and an increased density of LDL. NEFA also reduce insulin sensitivity in muscle by inhibiting insulin-mediated glucose uptake. Associated defects include a reduction in glucose partitioning to glycogen and increased lipid accumulation in TAG. Increases in circulating glucose, and to some extent NEFA, increase pancreatic insulin secretion, resulting in hyperinsulinaemia. Hyperinsulinaemia may result in enhanced sodium reabsorption and increased sympathetic nervous system (SNS) activity and contribute to the hypertension, as might increased circulating levels of NEFA. (b) Superimposed and contributory to the insulin resistance produced by excessive NEFA is the paracrine and endocrine effect of the pro-inflammatory state. Produced by a variety of cells in adipose tissue, including adipocytes and monocyte-derived macrophages, the enhanced secretion of IL-6 and TNFα, among others, results in more insulin resistance and lipolysis of adipose tissue TAG stores to circulating NEFA. IL-6 and other cytokines also are increased in the circulation and may enhance hepatic glucose production, the production of VLDL by the liver and insulin resistance in muscle. Cytokines and NEFA also increase the production of fibrinogen and plasminogen activator inhibitor-1 (PAI-1) by the liver that complements the overproduction of PAI-1 by adipose tissue. This action results in a pro-thrombotic state. Higher circulating levels of cytokines also stimulate the hepatic production of C-reactive protein (CRP). Reductions in the production of the anti-inflammatory and insulin-sensitizing cytokine adiponectin are also associated with the metabolic syndrome and may contribute to the pathophysiology of the syndrome. , Increased; , reduced; , effects relatively reduced. (From Eckel et al. Reference Eckel, Grundy and Zimmet2005, with permission from Elsevier.)

In human subjects the infusion of a lipid emulsion with the simultaneous administration of intravenous heparin to release lipases and then lipoprotein-TAG fatty acids into the plasma compartment results in insulin resistance (Boden et al. Reference Boden, Cheung, Stein, Kresge and Mozzoli2002), which leads to defects in insulin action not only in skeletal muscle but also in the liver (Boden, Reference Boden2003). In the liver of high-fat-fed rats insulin resistance can be attributed to a defect in insulin-stimulated insulin receptor substrate-1 and insulin receptor substrate-2 tyrosine phosphorylation. These changes have been associated with activation of protein kinase C-ε and c-Jun N-terminal kinase-1 (Samuel et al. Reference Samuel, Liu, Qu, Elder, Bilz, Befroy, Romanelli and Shulman2004). Yet, while circulating fatty acids increase hepatic glucose production and diminish the inhibition of glucose production by insulin (Boden & Shulman, Reference Boden and Shulman2002), lipogenesis as a result of the stimulatory effects of fatty acids and insulin on sterol response element-binding protein-1c continues (Shimomura et al. Reference Shimomura, Bashmakov, Ikemoto, Horton, Brown and Goldstein1999). Very recent evidence has demonstrated that the pharmacological inhibition of the lipid biosynthetic enzymes acetyl-CoA carboxylase-1 and -2 increases fat oxidation and reduces hepatic steatosis and insulin resistance (Savage et al. Reference Savage, Choi, Samuel, Liu, Zhang and Wang2006).

More detailed studies in human subjects have examined the cellular and molecular basis of insulin resistance in more detail (Petersen et al. Reference Petersen, Befroy, Dufour, Dziura, Ariyan, Rothman, DiPietro, Cline and Shulman2003, Reference Petersen, Dufour, Befroy, Garcia and Shulman2004; Barbato et al. Reference Barbato, Cappuccio, Folkerd, Strazzullo, Sampson, Cook and Alberti2004), and in insulin-resistant subjects with obesity and/or type 2 diabetes and in the elderly a defect in mitochondrial oxidative phosphorylation has been identified. More recently, a common variant in mitochondrial DNA at bp 16189 (T→C transition) has been associated with the metabolic syndrome in Chinese adults (Weng et al. Reference Weng, Liou, Lin, Wei, Lee and Eng2005). Although the mitochondrial ribosomal RNA and transfer RNA are encoded by mitochondrial DNA in human subjects, all proteins involved in mitochondrial translation are encoded by nuclear genes. Moreover, increasingly nuclear genes associated with the metabolic syndrome are being recognized (Matsunaga & Muramatsu, Reference Matsunaga and Muramatsu2005).

Murine models of the metabolic syndrome are becoming more evident. In mice made deficient in the endoplasmic reticulum X-box-binding protein-1 hyperactivation of c-Jun N-terminal kinase increases serine phosphorylation of insulin receptor substrate-1 and insulin resistance (Ozcan et al. Reference Ozcan, Cao, Yilmaz, Lee, Iwakoshi, Ozdelen, Tuncman, Gorgun, Glimcher and Hotamisligil2004). Among other models addressing the mechanism of the metabolic syndrome in rodents are mice lacking the fatty acid-binding proteins aP2 and mal1. These mice exhibit a striking phenotype with strong protection from diet-induced obesity, insulin resistance, type 2 diabetes and fatty liver disease (Maeda et al. Reference Maeda, Cao, Kono, Gorgun, Furuhashi and Uysal2005).

A new report (Shuldiner & McLenithan, Reference Shuldiner and McLenithan2004) indicates that PPARγ coactivator-1α and -1β mRNA levels decrease with age in individuals with a genetic variant in PPARγ coactivator-1α, and that these decreases correlate with alterations in whole-body glucose and fatty acid oxidation. These data provide insights into how aging modifies genetic susceptibility to alterations in oxidative phosphorylation and type 2 diabetes.

Oxidative stress has also been viewed as a cellular mechanism for insulin resistance. One enzyme that initiates base excision repair of ring-fragmented purines and some pyrimidines is neil1. In the absence of oxidative stress neil1-knock-out (neil1−/−) and heterozygotic (neil1+/−) mice develop severe obesity, dyslipidaemia and hepatic steatosis with more modest hyperinsulinaemia (Vartanian et al. Reference Vartanian, Lowell, Minko, Wood, Ceci, George, Ballinger, Corless, McCullough and Lloyd2006).

Thus, with time more basic mechanisms of insulin resistance are being discovered. Presumably, these biochemical changes in insulin-mediated signalling pathways result in decreases in insulin-mediated glucose transport and metabolism in the metabolic syndrome as well.

Obesity and increased waist circumference

Although the first description of the metabolic syndrome occurred in the early 20th century (Kylin, Reference Kylin1923), the worldwide obesity epidemic has been the most important driving force for the much more recent recognition of the syndrome. Despite the importance of obesity in the model, it is relevant to remember that patients who are normal weight may also be insulin resistant (Ruderman et al. Reference Ruderman, Chisholm, Pi-Sunyer and Schneider1998).

For the International Diabetes Federation (Alberti et al. Reference Alberti, Zimmet and Shaw2005) definition of the metabolic syndrome the waist circumference as defined must be increased (Table 1). It is important to distinguish between a large waist circumference that is a result of increases in subcutaneous adipose tissue from that in which the visceral depot is expanded. This distinction can be made using computerized tomography or MRI (Lee et al. Reference Lee, Janssen and Ross2004). With increases in intra-abdominal or visceral adipose tissue a higher rate of flux of adipose tissue-derived NEFA to the liver would be expected, whereas increases in abdominal subcutaneous fat would release lipolysis products into the systemic circulation and avoid more direct effects on hepatic metabolism, i.e. glucose production, lipid synthesis, lipoprotein secretion and the secretion of pro-thrombotic proteins such as fibrinogen and plasminogen activator inhibitor-1 (Aubert et al. Reference Aubert, Frere, Aillaud, Morange, Juhan-Vague and Alessi2003).

Despite these potential differences in mechanisms related to excessive abdominal adipose tissue distribution, the clinical diagnosis of the metabolic syndrome does not distinguish between increases in subcutaneous and visceral fat. Yet, perhaps by a mechanism related to NEFA flux and metabolism, the predominance of visceral v. subcutaneous adipose tissue with increasing waist circumference in Asians and Asian Indians (Bajaj & Banerji, Reference Bajaj and Banerji2004) renders the relative prevalence of the syndrome higher than that in African-American men in whom subcutaneous fat predominates (Tanaka et al. Reference Tanaka, Horimai and Katsukawa2003). However, there is evidence that the elevated postprandial NEFA release in upper-body obese women originates from the non-splanchnic upper body fat, and not from the visceral depot (Guo et al. Reference Guo, Hensrud, Johnson and Jensen1999). These results suggest that visceral fat may be a marker for, but not the source of, excess postprandial fatty acids in obesity.

The amount of epicardial fat assessed by echocardiography could be a simple and practical tool for cardiovascular risk stratification in clinical practice and research (Iacobellis et al. Reference Iacobellis, Corradi and Sharma2005). Epicardial fat is a metabolically-active organ that generates various bioactive molecules, some of which might markedly affect cardiac function. This small ‘visceral fat’ depot is now recognized as a rich source of NEFA and a number of bioactive molecules, such as inflammatory cytokines and adiponectin. Presently, validation and more clinical significance are needed.

Murine examples of the impact of body fat distribution on insulin resistance and the metabolic syndrome include mice with over-expression of 11-hydroxysteroid dehydrogenase 1 that have elevated intra-adipose corticosterone levels but normal circulating corticosterone levels (Masuzaki et al. Reference Masuzaki, Paterson, Shinyama, Morton, Mullins, Seckl and Flier2001). These mice exhibit central obesity, hypertension, impaired glucose tolerance and hypertriacylglycerolaemia. Conversely, mice that fail to express 11-hydroxysteroid dehydrogenase 1 are resistant to the development of metabolic syndrome (Kotelevtsev et al. Reference Kotelevtsev, Holmes, Burchell, Houston, Schmoll, Jamieson, Best, Brown, Edwards, Seckl and Mullins1997).

More recent studies have shown that the ectopic expression of very low levels of uncoupling protein 1 in epididymal fat reverses both insulin and leptin resistance. Uncoupling protein 1 expression in epididymal fat improves glucose tolerance and decreases food intake in both diet-induced and genetically-obese mouse models (Yamada et al. Reference Yamada, Katagiri, Ishigaki, Ogihara, Imai and Uno2006). Moreover, in wild-type mice local-nerve dissection in the epididymis or pharmacological afferent blockade blunts the decrease in food intake, suggesting that afferent-nerve signals from intra-abdominal adipose tissue regulate food intake.

In the setting of partial or complete lipoatrophy insulin resistance and the metabolic syndrome typically co-exist (Garg & Misra, Reference Garg and Misra2004). Evidence from these less-common disorders does support a genetic basis of the syndrome, including single-gene defects in PPAR-λ, lamin A/C, 1-acylglycerol-3-phosphate, O-acyltransferase, seipin (Hegele, Reference Hegele2003), the β-2 adrenergic receptor (Dallongeville et al. Reference Dallongeville, Helbecque, Cottel, Amouyel and Meirhaeghe2003) and adiponectin (Fumeron et al. Reference Fumeron, Aubert, Siddiq, Betoulle, Pean and Hadjadj2004).

Dyslipidaemia

With increased NEFA flux to the liver, increased production of apoB-containing TAG-rich VLDL occurs (Lewis et al. Reference Lewis, Uffelman, Szeto, Weller and Steiner1995). The effect of insulin on this process is somewhat complex. In the setting of insulin resistance the increased flux of NEFA to the liver increases hepatic TAG synthesis; however, under physiological conditions insulin inhibits rather than increases the secretion of VLDL into the systemic circulation (Lewis & Steiner, Reference Lewis and Steiner1996). This inhibitory effect in part is an effect of insulin on the degradation of apoB (Taghibiglou et al. Reference Taghibiglou, Rashid-Kolvear, Van Iderstine, Le Tien, Fantus, Lewis and Adeli2002). Yet, insulin is also lipogenic, increasing the transcription and enzyme activity of many genes that relate to TAG biosynthesis (Foufelle & Ferre, Reference Foufelle and Ferre2002). Not completely addressed is whether or not this pathway remains operational in the setting of systemic insulin resistance.

In addition, insulin resistance may also reduce the level of LPL in peripheral tissues, i.e. in adipose tissue more than in muscle (Eckel et al. Reference Eckel, Yost and Jensen1995). This alteration in LPL, however, appears to contribute less to the hypertriacylglycerolaemia. However, mutations in the LPL gene affect LPL expression and are associated with both dyslipidaemia and insulin resistance (Holzl et al. Reference Holzl, Iglseder, Sandhofer, Malaimare, Lang, Paulweber and Sandhofer2002; Ma et al. Reference Ma, Thomas, Ng, Critchley, Chan and Tomlinson2003; Goodarzi et al. Reference Goodarzi, Guo, Taylor, Quinones, Saad, Yang, Hsueh and Rotter2004). Recent evidence even suggests that levels of LPL mass in pre-heparin plasma may be a quantitative indicator of whole-body insulin resistance (Miyashita & Shirai, Reference Miyashita and Shirai2005).

The other major lipoprotein disturbance in the metabolic syndrome is a reduction in HDL-cholesterol. This reduction is a consequence of changes in HDL composition and metabolism. In the presence of hypertriacylglycerolaemia a decrease in the cholesterol content of HDL is a consequence of decreases in the cholesteryl ester content of the lipoprotein core, with variable increases in TAG making the particle small and dense, a function in part of cholesteryl ester transfer protein (Murakami et al. Reference Murakami, Michelagnoli, Longhi, Gianfranceschi, Pazzucconi, Calabresi, Sirtori and Franceschini1995). Although HDL typically possess many features that appear to contribute to the association between increased HDL-cholesterol and protection from atherosclerosis, HDL may be modified to become pro-inflammatory (Ansell et al. Reference Ansell, Watson, Fogelman, Navab and Fonarow2005). The ability of HDL to inhibit or paradoxically to enhance vascular inflammation, lipid oxidation, plaque growth and thrombosis reflects changes in specific enzyme and protein components, e.g. increases in serum amyloid A, an acute-phase reactant and pro-inflammatory molecule (Kontush & Chapman, Reference Kontush and Chapman2006). This change in lipoprotein composition also results in an increased clearance of HDL from the circulation (Brinton et al. Reference Brinton, Eisenberg and Breslow1991; Chan et al. Reference Chan, Barrett and Watts2006). Thus, reductions in plasma levels of apoA-1 (a reflection of HDL particle number) are seen.

The relationship between these changes in HDL and insulin resistance is probably indirect, occurring in concert with the changes in TAG-rich lipoprotein metabolism. Although small dense HDL particles are typically better lipid acceptors, the formation of HDL that are small and dense in the setting of the dyslipidaemia of the metabolic syndrome may attenuate anti-atherogenic properties (Kontush & Chapman, Reference Kontush and Chapman2006). Thus, low circulating levels of HDL-cholesterol might, therefore, be associated with small HDL particles of abnormal structure and composition with defective functionality.

In addition to HDL, LDL are also modified in composition in a similar way. In fact, with fasting serum TAG of >2·0 mm almost all patients have a predominance of small dense LDL (de Graaf et al. Reference de Graaf, Hendriks, Demacker and Stalenhoef1993; Manzato et al. Reference Manzato, Zambon, Zambon, Cortella, Sartore and Crepaldi1993). This change in LDL composition is attributable to relative depletion of non-esterified cholesterol, esterified cholesterol and phospholipid with either no change or an increase in LDL-TAG (Halle et al. Reference Halle, Berg, Baumstark, Konig, Huonker and Keul1999; Kwiterovich, Reference Kwiterovich2002). Small dense LDL may be more atherogenic because they are more toxic to the endothelium, more able to transit through the endothelial basement membrane, more likely to adhere to arterial wall glycosaminoglycans, have increased susceptibility to oxidation and/or are more selectively bound to scavenger receptors on monocyte-derived macrophages (Packard, Reference Packard1996; Krauss, Reference Krauss1995). However, the direct relationship between small dense LDL and the natural history of atherosclerotic CVD is not entirely accepted (Lada & Rudel, Reference Lada and Rudel2004; Jungner et al. Reference Jungner, Sniderman, Furberg, Aastveit, Holme and Walldius2006). In some studies this alteration in LDL composition is an independent risk factor for CVD (Zambon et al. Reference Zambon, Hokanson, Brown and Brunzell1999). Recently, the effects of gemfibrozil on NMR-measured LDL and HDL particle subclasses, not reflected by conventional lipoprotein-cholesterol measures, has helped to explain the beneficial effect of the fibrate in patients with low HDL-cholesterol and CHD. However, most often the association between particle composition and atherosclerotic CVD events is not independent, but related to the concomitant changes in other lipoproteins and other risk factors (Sacks & Campos, Reference Sacks and Campos2003). It is possible that when circulating levels of LDL-cholesterol are lower, measurements of LDL particle number may ultimately prove to be more useful.

Glucose intolerance

The defects in insulin action in glucose metabolism include deficiencies in the ability of the hormone to suppress glucose production by the liver and kidney and mediate glucose uptake and metabolism in insulin-sensitive tissues, i.e. muscle and adipose tissue. The relationship between impaired fasting glucose or glucose tolerance and insulin resistance is well supported by human studies (Abdul-Ghani et al. Reference Abdul-Ghani, Tripathy and DeFronzo2006). To compensate for defects in insulin action insulin secretion and/or clearance must be modified to sustain euglycaemia. On failure of this compensation defects in insulin secretion rather than insulin clearance predominate.

Insulin resistance in pancreatic islet β-cells implies that the signals that generate glucose-dependent insulin secretion have been adversely modified, and fatty acids are prime candidates. Although NEFA can stimulate insulin secretion, increasing and prolonged exposure to excessive levels results in decreases in insulin secretion (Lee et al. Reference Lee, Hirose, Ohneda, Johnson, McGarry and Unger1994). The mechanism for this alteration has been attributed to lipotoxicity through a number of potential different mechanisms (Shimabukuro et al. Reference Shimabukuro, Zhou, Levi and Unger1998; Yaney & Corkey, Reference Yaney and Corkey2003; Boucher et al. Reference Boucher, Lu, Burgess, Telemaque-Potts, Jensen, Mulder, Wang, Unger, Sherry and Newgard2004; Joseph et al. Reference Joseph, Koshkin, Saleh, Sivitz, Zhang, Lowell, Chan and Wheeler2004).

Insulin also feeds back on its own secretion. The importance of this feedback relates to experiments in rodents in which the insulin receptor is tissue-specifically deleted. When the insulin receptor is deleted in skeletal muscle hyperglycaemia does not result (Bruning et al. Reference Bruning, Michael, Winnay, Hayashi, Horsch, Accili, Goodyear and Kahn1998); however, the β-cell-specific knock-out of the insulin receptor produces progressive glucose intolerance and diabetes (Kulkarni et al. Reference Kulkarni, Bruning, Winnay, Postic, Magnuson and Kahn1999). In human subjects with genetic predispositions to develop diabetes the presumed stress of the insulin-resistant environment on β-cell function produces glucose intolerance and ultimately the higher risk of diabetes.

Hypertension

The relationship between insulin resistance and hypertension is well established (Ferrannini et al. Reference Ferrannini, Buzzigoli, Bonadonna, Giorico, Oleggini, Graziadei, Pedrinelli, Brandi and Bevilacqua1987), and relates to several different mechanisms. Insulin is a vasodilator when given intravenously to normal-weight subjects (Steinberg et al. Reference Steinberg, Brechtel, Johnson, Fineberg and Baron1994), with secondary effects on Na re-absorption in the kidney (DeFronzo et al. Reference DeFronzo, Cooke, Andres, Faloona and Davis1975). Of interest, Na re-absorption is increased in Caucasians but not in Africans or Asians with the metabolic syndrome (Barbato et al. Reference Barbato, Cappuccio, Folkerd, Strazzullo, Sampson, Cook and Alberti2004). In insulin-resistant subjects the vasodilatory effect of insulin may be lost (Tooke & Hannemann, Reference Tooke and Hannemann2000), but the renal effect on Na re-absorption preserved (Kuroda et al. Reference Kuroda, Uzu, Fujii, Nishimura, Nakamura, Inenaga and Kimura1999). Insulin also increases the activity of the sympathetic nervous system (Anderson et al. Reference Anderson, Hoffman, Balon, Sinkey and Mark1991), an effect that may also be preserved in the setting of the insulin resistance (Egan, Reference Egan2003). In addition, fatty acids themselves can produce vasoconstriction (Tripathy et al. Reference Tripathy, Mohanty, Dhindsa, Syed, Ghanim, Aljada and Dandona2003).

The spontaneous-hypertensive rat is a widely-studied model of hypertension that exhibits metabolic abnormalities that share features with the human metabolic syndrome. Genetic-linkage studies have revealed a defective CD36 gene encoding a membrane fatty acid transporter and hyperinsulinaemia in the spontaneous-hypertensive rat. However, there is no unifying mechanism that can explain these phenotypes as a consequence of a defective CD36 gene (Tanaka et al. Reference Tanaka, Sohmiya, Kono, Terasaki, Horie, Ohkaru, Muramatsu, Takai, Miyazaki and Kitaura2006). Of interest, the hearts of CD36-defective spontaneous-hypertensive rats exhibit uncoupling of glucose oxidation from its uptake and enhanced protein O-linked N-acetylglucosaminylation, suggesting increased glucose shunt through the hexose monophosphate pathway. Thiamine repletion in the CD36-defective spontaneous-hypertensive rat results in correction of the uncoupling of glucose oxidation to glucose uptake, reduced protein O-linked N-acetylglucosaminylation and the expression of mRNA involved in the hexose monophosphate shunt, renin–angiotensin system and adipokines in epididymal adipose tissue, and reduced hypertension and hyperinsulinaemia.

Subjects with CD36 mutations have also been identified (Yamashita et al. Reference Yamashita, Hirano, Kuwasako, Janabi, Toyama, Ishigami and Sakai2006). In addition to mild hypertension and dyslipidaemia, whole-body insulin-mediated body glucose uptake is reduced in CD36-deficient patients, indicating the presence of insulin resistance. The frequency of CD36 deficiency is also higher in patients with CHD than in control subjects.

Yet, despite the plethora of potential mechanisms by which insulin resistance might cause hypertension, with the current level of understanding insulin resistance appears to contribute only moderately to the increased prevalence of hypertension in the metabolic syndrome (Hanley et al. Reference Hanley, Karter, Festa, D'Agostino, Wagenknecht, Savage, Tracy, Saad and Haffner2002).

Other manifestations

Insulin resistance is accompanied by many other alterations that are not included in the diagnostic criteria for the metabolic syndrome (Table 2). Increases in apoB and apoC-III, uric acid, pro-thrombotic factors (fibrinogen, plasminogen activator inhibitor-1), serum viscosity, asymmetric dimethylarginine, homocysteine, leucocyte count, pro-inflammatory cytokines, the presence of microalbuminuria, non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis, polycystic ovarian disease, obstructive sleep apnea and cholesterol gallstones and a decrease in adiponectin are all associated with insulin resistance.

Table 2. Other alterations that accompany insulin resistance that are not included in the diagnostic criteria for the metabolic syndrome

↑, Increased; ↓, decreased.

Cigarette smoking (Eliasson et al. Reference Eliasson, Attvall, Taskinen and Smith1994) and a sedentary lifestyle (Lakka et al. Reference Lakka, Laaksonen, Lakka, Mannikko, Niskanen, Rauramaa and Salonen2003) can also produce many of the major criteria of the syndrome and beyond. Increases in apoB, apoC-III (Onat et al. Reference Onat, Hergenc, Sansoy, Fobker, Ceyhan, Toprak and Assmann2003) and non-alcoholic steatohepatitis (Medina et al. Reference Medina, Fernandez-Salazar, Garcia-Buey and Moreno-Otero2004) are tied to the effects of fatty acids on VLDL production by the liver, and in the case of apoB and apoC-III provide evidence of an increased number of pro-atherogenic particles in the circulation. Hyperuricaemia reflects defects in insulin action on the renal tubular re-absorption of uric acid (Facchini et al. Reference Facchini, Chen, Hollenbeck and Reaven1991), whereas the increase in asymmetric dimethylarginine, an endogenous inhibitor of NO synthase, relates to endothelial dysfunction (Egan, Reference Egan2003). An extended form of endothelial pathophysiology in insulin-resistant states could be microalbuminuria (Rowley et al. Reference Rowley, O'Dea and Best2003). Insulin resistance is also associated with gall bladder disease (Nervi et al. Reference Nervi, Miquel, Alvarez, Ferreccio, Garcia-Zattera, Gonzalez, Perez-Ayuso, Rigotti and Villarroel2006). Bile is typically more lithogenic when it contains a higher cholesterol:bile acids and phospholipids. The primary reason for lithogenic bile in obese patients is an increase in total body cholesterol synthesis, possibly secondary to the overload of tissues with fatty acids that are precursors for cholesterol synthesis (Grundy, Reference Grundy2004).