Magnesium physiology and pathogenic mechanisms that contribute to the development of the metabolic syndrome

ARTICLE

Auteur(s) : Rashad J Belin¹, Ka He²

¹Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL
²Departments of Nutrition and Epidemiology, Schools of Public Health and Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC

Metabolic syndrome

Epidemiology

Genetics and the MetS

Nutrition and the MetS

Data from several epidemiological studies have delineated a causal link between Mg²⁺ status and the MetS. A cross-sectional analysis demonstrated that a strong relation exists between low serum Mg²⁺ levels and prevalence of MetS and each of its components [47]. Furthermore, an inverse association between dietary Mg²⁺ intake and MetS prevalence was recently reported in over 11,000 middle-aged women within the Women’s Health Study [48]. Similar observations have been made in a smaller Italian study sample [49]. Recently, a small clinical trial consisting of 290 patients, revealed a strong correlation between serum [Mg²⁺], high plasma triglycerides, waist circumference, and microalbuminuria in patients with type II diabetes mellitus [50]. In a longitudinal analysis of 4 637 young adults within the Coronary Artery Risk Development in Young Adults (CARDIA) study, we found that Mg²⁺ intake was inversely related to incident MetS, each of its components, and fasting insulin levels [51]. The focus of this review is to provide an integrated analysis and discussion of the molecular and cellular mechanisms by which reduced Mg²⁺ intake and/or impaired Mg²⁺ status and consequent decrease in serum [Mg²⁺] and/or cellular [Mg²⁺] translates into pathogenesis of the MetS and its components.

Magnesium

Molecular and cellular physiology

Mg²⁺ homeostasis

By far, the kidney exerts the most predominant impact in controlling body Mg²⁺ status [63]. Absorption across the renal epithelial cell is accomplished via passive paracellular transport mediated, in part, by paracellin-1, a pore-building paracellular protein [64, 65]. Transcellular absorption is accomplished by secondary active mechanisms involving apical uptake through Mg²⁺ channels and basolateral export by the sodium-magnesium exchanger [63, 65]. Renal Mg²⁺ handling is tightly in sync with body Mg²⁺ status, as Mg²⁺ deficiency increases renal Mg²⁺reabsoprtion across all nephron segments [63]. Renal Mg²⁺ handling is also modified by loop diuretics such as furosemide and bumetanide, which disfavor Mg²⁺ reabsorption [66].

Both cellular and serum Mg²⁺ balance are regulated by hormones commonly altered in patients with MetS. Several studies have shown that insulin and glucose promote Mg²⁺ uptake into smooth muscle cells, erythrocytes, and platelets [67-69]. It has also been reported that α (phenylephrine) and β (norepinephrine, isoproteranol) adrenergic agonists prompt Mg²⁺ efflux from isolated hepatocytes [70]. Corica and coworkers have shown that subsequent to oral glucose loading plasma Mg²⁺ declines while erythrocyte and platelet Mg²⁺ increase in normotensive and hypertensive subjects [71]. In vascular smooth muscle cells from hypertensive animals, angiotensin II (AngII) and vasopressin were found to elicit increases in intracellular Mg²⁺, secondary to activation of the sodium-magnesium exchanger (NME) [72]. The NME removes one Mg²⁺ coupled to the secondary active uptake of 2 Na⁺[73] In an animal model of AngII dependent hypertension, interference with NME activity attenuated increases in systolic blood pressure [74]. Thus, it may be that alterations in cellular and tissue Mg²⁺ status commonly found in subjects with the MetS arise secondary to altered NME activity due to increased insulin and/or AngII signaling.

Deficiency

Magnesium and blood pressure

Alternatively, it may be that chronic deficiencies in Mg²⁺ by way of reduced intake promote the development of hypertension. Studies from the Dietary Approaches to Stop Hypertension (DASH) study demonstrate that a diet rich in fruit, vegetables, low-fat dairy products, fiber and minerals (calcium, potassium and magnesium) produces a potent antihypertensive effect [119]. A comprehensive review of 29 observational studies indicated that Mg²⁺ intake is inversely related to systolic and diastolic blood pressure and incident hypertension [120]. Recent prospective cohort data paint a convincing picture of insufficient intake of Mg²⁺ increasing the risk for increased systolic and diastolic blood pressure and hypertension. Joffres et al. reported that, of several nutrients, increased Mg²⁺ intake was the most strongly associated with blood pressure reduction in a large cohort of Japanese men within the Honolulu Heart Study [121]. These findings have also been paralleled in over 15 000 participants where lower Mg²⁺ intake and serum levels were associated with increased systolic and diastolic blood pressure and incident hypertension in the large, biracial Atherosclerosis Risk in Communities (ARIC) cohort [122, 123]. In the Women’s Health Study, subjects in the highest quintile of dietary Mg²⁺ intake displayed the lowest risk of developing incident hypertension [124]. Additionally, data from the Dietary Intervention Study in Children has shown that dietary intake of Mg²⁺ was strongly and inversely correlated with systolic and diastolic blood pressure in children between 8 and 11 years old [125]. Finally, the Belgian Interuniversity Research on Nutrition and Health Study indicates that Mg²⁺ intake is inversely related to systolic blood pressure in women [126].

Much evidence regarding the biological and functional impact of chronic dietary Mg²⁺ deficiency has been gleaned from work in animal models. These studies have shown that dietary restriction of Mg²⁺ results in: elevated blood pressure and development of hypertension, reduced arterial distensibility (increased stiffness), endothelial dysfunction, vascular remodeling (smooth muscle hypertrophy, increased intima-media thickness), increased sympathetic nervous system activity, and augmented responses to vasoconstrictor molecules (e.g. endothelin, AngII, phenyleprine, norepinephrine, and Ca²⁺) [102, 127-132]. In contrast, increases in Mg²⁺ status through supplementation in healthy animals, elicits vasodilation, increased blood flow, decreased vascular resistance, reduced arterial stiffness, increased capacitance of peripheral, coronary, renal, and cerebral arteries, and blunted agonist-elicited vasoconstriction [109, 133, 134].

Thus, while it appears that sufficient dietary intake of Mg²⁺ may lower blood pressure and prevent the development of hypertension through one of several mechanisms, data from interventional studies also illustrate that oral Mg²⁺ pharmacotherapy lowers blood pressure in subjects with and without established hypertension. In humans, oral Mg²⁺ pharmacotherapy was first shown to reduced blood pressure in patients with essential hypertension as early as 1925 [135]. Over the years, several clinical studies have shown that Mg²⁺ treatment reduces blood pressure in patients with established hypertension [136-139]. Mg²⁺ has also been used to treat pre-eclampsia, defined as hypertension in pregnant women after 20 weeks of gestation along with proteinuria and edema [140]. Taken together, although results from some clinical trials are slightly conflicting [141], a meta-analysis of 20 studies including over 1200 patients clearly indicates that Mg²⁺ supplementation does indeed elicit a dose-dependent decline in blood pressure in normal and hypertensive subjects [142].

The benefits of sufficient Mg²⁺ intake and/or oral Mg²⁺ pharmacotherapy are likely to lie, at least somewhat, in the normalization of Mg²⁺ levels in serum, erythrocytes, smooth muscle cells, and endothelial cells. In smooth muscle, a decline in [Mg²⁺] elicits a reciprocal increase in [Ca²⁺] which, in turn, prompts smooth muscle contraction, increased vessel tone and augmented blood pressure [143-147]. In the endothelial cell, the decline in [Mg²⁺] alters production of several vasoactive compounds including nitric oxide, prostaglandins, and endothelin-1 [131, 148-150]. In vitro studies indicate that Mg²⁺ deficiency results in decreased production of nitric oxide (NO) from endothelial cells along with a decreased vasodilatory response to acetylcholine and adenosine diphosphate, which could be restored by increasing [Mg²⁺] in the bathing solution [151]. Apparently, high [Mg²⁺] triggers production of NO by upregulating expression of endothelial nitric oxide synthase [131, 152]. NO is a potent vasodilator and not surprisingly a decline in its production has profound effects on arteriolar caliber, resistance, and blood pressure [153]. Mg²⁺ has also been shown to promote synthesis and release of endothelial and smooth muscle cell derived prostacyclin (prostaglandin I₂; PGI₂) which induces smooth muscle cell hyperpolarization by opening potassium channels, and thus, decreases smooth muscle cell contraction, arteriolar resistance, and, consequently, blood pressure [154-156]. In support of this tenet, Laurant et al., showed that, in the hypertensive DOCA-salt sensitive rat, increased Mg²⁺ intake results in decreased blood pressure as well as increased aortic concentration of PGI₂[157]. Furthermore, Mg²⁺ deficiency elicits profound effects on endothelin-1 homeostasis. Endothelin-1 is a potent vasoconstrictor peptide synthesized in and released from endothelial cells [158]. In experimental models of hypertension, Mg²⁺ supplementation decreased endothelin-1 expression, production, and vasoconstrictor effects, whereas Mg²⁺ depletion resulted in increases in endothelin-1 production and release [93, 97, 129, 159, 160].

There is now substantial evidence that Mg²⁺ controls activation of both the renin-angiotensin-aldosterone system (RAAS) in health and disease. Aberrant activation of the RAAS has been associated with hypertension, insulin resistance, diabetes mellitus, along with increased oxidative stress, reduced NO bioavailability, and increased synthesis of pro-inflammatory cytokines; several common MetS phenomena [161]. Serum and cellular [Mg²⁺] has been reported to relate inversely to renin, aldosterone, epinephrine, and norepinephrine in patients with hypertension [113, 162]. For example, in hypertensive subjects with high plasma renin activity, serum [Mg²⁺] was much lower than that in normotensive patients [163]. Additionally, others indicate that, at the adrenal cortex, Mg²⁺ supplementation decreases AngII stimulated production and release of aldosterone from zona glomerulosa cells of normotensive subjects [164]. In Mg²⁺ deficient animals, others have reported increased plasma renin activity and circulating levels of corticosterone and aldosterone [128, 165]. Finally, in vitro studies in isolated umbilical arteries revealed that exclusion of Mg²⁺ from the bathing medium results in increased contractile response to AngII, serotonin, and prostaglandin F2α [166].

Mg²⁺ also controls activity of the sympathetic nervous system. Shimosawa and coworkers noted that high [Mg²⁺] interferes with the release of norepinephrine in perfused mesenteric arteries by blocking N-type Ca²⁺ channels at nerve endings, which counteracts increases in blood pressure [167]. Rats fed a Mg²⁺ deficient diet manifest increases in catecholamine excretion and renal sympathetic activity coincident with increases in blood pressure [132]. In chronically hypertensive animals, Mg²⁺ supplementation has also been shown to attenuate anti-diuretic hormone and norepinephrine induced vasoconstriction of vascular smooth muscle along with vascular remodeling [129]. In vitro studies have shown that increasing Mg²⁺ in the bathing solution promotes relaxation of norepinephrine-precontracted aorta isolated from hypertensive rats [98]. Finally, in cultured mesenteric and aortic smooth muscle cells isolated from hypertensive rats, Touyz et al. illustrated that Mg²⁺ blunted vasopression dependent increases in smooth muscle Ca²⁺ and consequent contraction [168].

Recent studies have expanded our understanding of the precise molecular details involved in Mg²⁺-dependent control of endothelial cell function, smooth muscle cell contractility, and blood pressure. In work with experimental models of hypertension, Northcott and Watts found that a decline in Mg²⁺ triggered activation of phosphatidylinositol-3-kinase (PI3-K), which increased both smooth muscle contraction and the contractile response to the vasoconstrictor phenylephrine, all of which were ablated by PI3-K inhibition [101]. Other studies, in cultured carotid and cerebral smooth muscle cells, revealed that Mg²⁺ deficiency induces smooth muscle contraction through activation of PI3-K as well as protein kinase C (PKC) α and βII [144-147]. Of note, inhibitors of both PI3-K and PKC decreased contraction of smooth muscle cells [147]. Investigators went on to illustrate that chronic Mg²⁺ depletion of aortic and cerebral smooth muscle cells activates transcription of early response genes (c-fos, c-jun), increases DNA synthesis, and increases protein expression of NF-κB; responses which were ablated by nonspecific PKC inhibition [90]. NF-κB is a multifunctional transcription factor of various genes linked to inflammation [169]. Finally, low Mg²⁺ has also been shown to promote smooth muscle cell contraction through activation of mitogen activated protein kinases and tyrosine kinases [144-146]. In summary, there is considerable experimental, clinical, and epidemiologic data that chronically reduced Mg²⁺ status causes endothelial dysfunction, enhanced smooth muscle contractility, increased responsiveness to vasoconstrictor agonists, and, as result, high blood pressure.

Magnesium, glucose intolerance, insulin resistance and diabetes mellitus

Clinical trials have delineated a convincing benefit of oral Mg²⁺ pharmacotherapy in improving insulin sensitivity (indexed by HOMA-IR analysis), glucose homeostasis (fasting glucose, glucose uptake, oxidative glucose metabolism), and hemoglobin A1c levels in patients suffering with diabetes mellitus [184, 185]. Moreover, a recent meta-analysis of 9 randomized double-blind controlled studies of 370 patients indicated that oral Mg²⁺ supplementation for a period of 12 weeks significantly lowered fasting serum glucose levels in type II diabetic patients [186]. These salutary effects appear to be due, in part, to improved insulin elicited glucose uptake as Mg²⁺ is essential for optimal coupling and signaling through the insulin receptor. Indeed, glycolytic flux is strongly determined and dependent upon cellular Mg²⁺ status [187]. For example, in animal models, Mg²⁺ deficiency results in increased serum glucose, decreased glucose utilization, blunted glucose-elicited β-cell insulin release, reduced insulin sensitivity, decreased phosphorylation of the β-subunit of the insulin receptor, concomitant with decreased tyrosine kinase activity [188, 189]. In vitro studies utilizing myocardial purified insulin receptors have shown that Mg²⁺ stimulates the insulin receptor tyrosine kinase in both insulin-dependent and independent fashions [190]. Moreover, there is lucid evidence that prolonged increases in cellular [Ca²⁺], arising secondary to a decline in [Mg²⁺], blunt insulin sensitivity. Specifically, it appears that increased [Ca²⁺] causes a decline in the ability of insulin to activate phosphoserine phosphatase-1, which promotes insulin-triggered glucose influx and storage by removing phosphates from GLUT-4, glycogen phosphorylase, and glycogen synthase [191]. Others postulate that enhanced cellular Ca²⁺ activates protein kinase C isozymes, which increase protein phosphorylation and decrease insulin sensitivity [192]. In addition to modulating insulin sensitivity and responsiveness in skeletal muscle and adipose tissue, there is some evidence that Mg²⁺ may also regulate pancreatic β-cell function [193, 194]. Taken together decreased Mg²⁺ status results in: decreased tyrosine kinase activity, increased intracellular [Ca²⁺], decreased activation of phosphoserine phosphatase-1, and increased protein kinase C activity, all of which conspire to decrease insulin sensitivity, glucose uptake and utilization, and glycolytic flux.

Magnesium, atherogenic dyslipidemia and ischemic cardiomyopathy

The antiatherogenic effects of Mg²⁺ appear to involve, at least partially, modification of several enzymes intricately linked with lipid metabolism and turnover including: lipoprotein lipase, HMG CoA reductase, and lecithin acyltransferase. Lipoprotein lipase is an enzyme normally docked on endothelial cells which hydrolyzes lipids in lipoproteins, like those found in chylomicrons and very low density lipoproteins (VLDL), into three fatty acids and one glycerol molecule [216]. Rodents fed a Mg²⁺-deficient diet display increased serum triglycerides and reduced HDL-cholesterol secondary to reduced serum activity of lipoprotein lipase [217]. Mg²⁺ is also an essential short-term modulator of HMG-CoA reductase, which catalyzes the rate-limiting step in cholesterol synthesis. Indeed, in in vitro studies, increasing the [Mg²⁺] in the bathing solution attenuates HMG-CoA reductase activity [218]. In this capacity, Mg²⁺ functions as a “physiological statin”. Lecithin acyltransferase (LCAT) is involved in reverse cholesterol uptake and, in so doing, facilitates cholesterol uptake from tissues into HDL-cholesterol [219]. LCAT activity is markedly reduced in patients with an acute MI and coronary artery disease coincident with increased LDL-cholesterol, triglycerides, and reduced HDL-cholesterol [219]. LCAT activity also has been reported to be altered by changes in Mg²⁺ homeostasis [220, 221]. Nozue et al. suggest that there is a direct relation between ionized Mg²⁺, serum LCAT activity, and HDL-cholesterol levels in children [222]. Furthermore, in Mg²⁺ deficient rats, other investigators observed decreased LCAT activity along with reduced HDL-cholesterol and hyperlipidemia [84, 220]. Similarly, Δ-6 desaturase activity and expression was found to be decreased in hepatic microsomes isolated from Mg²⁺ deficient animals [223]. Δ-6 desaturase is an enzyme important in the conversion of essential ω-3 and ω-6 fatty acids to prostaglandins, which execute vasodilatory, anti-platelet aggregating, and antiatherogenic effects [223, 224]. Besides modulating catalytic activity of multiple enzymes involved in lipid metabolism, Mg²⁺ also regulates LDL-cholesterol uptake and oxidation. In animal models of Mg²⁺ depletion, LDL-cholesterol particles were more susceptible to oxidative damage [225, 226]. At the cellular level, exposure of endothelial and smooth muscle cells to low Mg²⁺ results in increased LDL transport and uptake, increased LDL oxidation, along with smooth muscle cell proliferation and intimal invasion; all of which are key features of the atherogenic process [210, 226-229]. Low Mg²⁺ increases IL-1 and IL-6 along with (vascular cell adhesion molecule (VCAM) which is important for binding of leukocytes to the vascular endothelium and formation of atherosclerotic lesions [230]. Mg²⁺ deficiency has also been associated with structural changes in the vascular wall such as thinner aorta, altered expression of collagen and elastin, and changes in protein levels of matrix metalloproteinases 2 and 9 and thereby contribute to vascular smooth muscle remodeling and coronary artery disease [231]. Mechanistically, it appears that Mg²⁺ decreases matrix metalloproteinase production and secretion via tyrosine kinase dependent pathways in vascular smooth muscle and cardiac fibroblasts [232]. Taken together, reduced Mg²⁺ status promotes dyslipidemia and coronary artery disease by: i) altering the catalytic activity of several enzymes involved in lipid metabolism (namely HMG-CoA reductase, LCAT, Δ-6 desaturase); ii) promoting oxidation of serum lipids; iii) eliciting alterations in vascular wall biology, and iv) promoting increased inflammation and oxidative stress.

Magnesium and obesity

Magnesium and thrombosis

A meta-analysis of randomized clinical trials which enrolled 1266 patients illustrated a salutary effect of Mg²⁺ in lowering the risk of ischemic events [249]. The second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) was the first clinical trial to illustrate a beneficial effect of oral MgSO₄ supplementation in improving long-term survival, and reducing cardiovascular, and all-cause mortality along with reducing left ventricular failure in patients with an acute myocardial infarction, when given before any thrombolytic therapies [250]. Mechanistically, Mg²⁺ may prove beneficial in high-risk patients with an acute myocardial infarction by reducing: platelet aggregation, coronary artery resistance, myocardial O₂ demand, and/or oxidative stress.

There now is compelling basic and clinical science data that Mg²⁺ supplementation, either oral or intravenous, decreases abnormal blood clotting in at-risk populations. Shechter et al. observed a correlation between intra-lymphocyte Mg²⁺, platelet-dependent thrombosis, and platelet P-selectin expression in patients with coronary artery disease [85]. Additionally, Mg²⁺ supplementation has been documented to improve flow mediated brachial vasodilation (endothelial function index), as well as, reduce platelet aggregation, fibrinogen binding with the glycoprotein IIb/IIIa complex, and platelet expression of P-selectin, in patients with symptomatic coronary heart disease [85, 251-253]. The decline in expression of the glycoprotein P-selectin would be expected to interfere with platelet-leukocyte adhesion. Mg²⁺ has also been found to extend bleeding time in patients undergoing successful coronary revascularization with cardiopulmonary bypass, via mechanisms that involve blunted ADP and collagen-dependent platelet aggregation, platelet P-selectin expression and fibrinogen binding to platelet glycoprotein IIb/IIIa receptor [254]. Sheu et al. reported that Mg²⁺ blocks phosphoinositide breakdown, collagen-elicited Ca²⁺ mobilization and thromboxane A₂ formation, in parallel with a decline in phosphorylation of a 47Kda protein [255]. In healthy volunteers, others observed that Mg²⁺ decreased platelet synthesis of thromboxane and β-thromboglobulin independent of acetylsalicylic acid [256]. Also, Hsaio et al. reported that Mg²⁺ prevents PKC activation, phosphoinositide breakdown, and Ca²⁺ mobilization secondary to decreased sodium-hydrogen exchanger activity in thrombin-stimulated platelets [257]. It may that Mg²⁺ decreases platelet aggregation by inducing prostacylin synthesis and release from endothelial cells, or, alternatively, by interfering with platelet stimulating factors (i.e. thromboxane A₂) [156, 247, 252, 255, 256, 258, 259].

Magnesium, inflammation, and oxidative stress

Inflammation

Using National Health and Nutrition Examination Survey (NHANES) data, Ford et al. illustrated that in children and adolescents, serum CRP was related to prevalence of the MetS [278]. Other studies have also reported associations between CRP and prevalent MetS [279-282]. Cross-sectional findings from the Framingham Heart Study have shown that CRP is related to the prevalence of MetS and is a useful risk predictor of incident cardiovascular disease events in subjects with the MetS [19]. Several large-scale prospective cohort studies, including the Women’s Health Study and the West of Scotland Coronary Prevention Study, revealed that high-sensitivity CRP levels are independently associated with the risk for incident MetS [262, 283, 284]. Data from the Women’s Health Study, has shown that Mg²⁺ intake was inversely related with systemic inflammation, gauged by serum CRP levels, and prevalence of MetS in women over the age of 45 [48]. Similar findings have also been reported using NHANES data [285]. In a cross-sectional study of 280 men from the Health Professions Follow-Up study, higher Mg²⁺ intake was associated with higher adiponectin levels [286]. Numerous other researchers have also shown an inverse relation between Mg²⁺ intake, serum Mg²⁺, and TNF-α, IL-6, and CRP levels in healthy children and adults [82, 285, 287-289]. In cross-sectional studies, researchers observed that higher TNF-α levels were correlated with lower serum Mg²⁺ in obese individuals (BMI ≥ 30kg/m²) [289]. Moreover, in multi-variate analysis, those with the lowest serum Mg²⁺ were 80% more likely to have higher TNF-α levels [289]. Interestingly, pharmacologic treatment with a soluble TNF-α receptor (etanercept) reduced CRP, IL-6, and fibrinogen levels in patients with the MetS [290] In animals, several studies have shown that Mg²⁺ deficiency causes marked elevation of several pro-inflammatory molecules including: TNF-α, IL-1β, IL-6, VCAM, and PAI-1 [131, 291-296], increased circulating inflammatory cells [297], and increased hepatic production and release of acute phase proteins (e.g. α2-macroglobulin, α1-acid glycoprotein, complement, haptoglobin, fibrinogen) [292, 297-299]. A direct mechanistic link has been provided by in vitro studies which illustrated that low Mg²⁺ results in increased production and secretion of TNF-α and IL-1β in cultured adipocytes and alveolar macrophages [300, 301].

Oxidative stress and antioxidant defense

In humans and animal models, Mg²⁺ deficiency has been linked with increased oxidative stress and decreased antioxidant defense, due, in part to increased inflammation [42, 296, 308, 309]. Previous studies have shown convincingly that Mg²⁺ deficiency in vitro or in vivo results in: increased production of oxygen-derived free radicals in various tissues, increased free-radical elicited oxidative tissue damage, increased production of superoxide anion by inflammatory cells, decreased antioxidant enzyme expression and activity (e.g. glutathione peroxidase, CuZn superoxide dismutase, catalase), decreased cellular and tissue antioxidant levels (glutathione, ascorbate, selenium, vitamin E), and increased H₂O₂ production [42, 46, 127, 225, 227, 293, 295, 309-319]. In support of this notion, there is data to suggest that Mg²⁺, when present in sufficient amounts, prevents oxygen radical formation by scavenging free radicals and inhibiting xanthine oxidase and NADPH oxidase [320]. Moreover, Calviello et al. found that Mg²⁺ deficiency in rats causes decreases in hepatic glutathione, superoxide dismutase, and vitamin E along with increased lipid peroxidation and malondialdehyde levels secondary to upregulated NADPH oxidase activity [321]. Several interventional studies in animal models of Mg²⁺ deficiency have provided convincing evidence of the link between Mg²⁺ inflammation, oxidative stress, and components of the MetS. Treatment of Mg²⁺ deficient rats with an anti-inflammatory agent (chloroquine) preserves erythrocyte glutathione content, lowers the rise in plasma TBARS levels in parallel with a decline in TNF-α, IL-1, and IL-6 levels [318]. In stroke-prone spontaneously hypertensive rats, Mg²⁺ deficiency results in marked increases in systolic blood pressure, blunted endothelial dysfunction, superoxide accumulation, and MAPK activation, all of which were attenuated with a superoxide dismutase mimetic (tempol) [322]. In experimental diabetes, researchers have observed decreases in serum and erythrocyte Mg²⁺ levels and increased urinary excretion of Mg²⁺ in parallel with increased plasma malondialdehyde, decreased plasma and liver vitamin C and E levels, decreased expression of hepatic superoxide dismutase and glutathione S-transferase; all of which were corrected by Mg²⁺ supplementation [311]. Taken together, Mg²⁺ deficiency results in enhanced oxidative stress and reduced antioxidant defense, which promotes inflammation, lipid oxidation, insulin resistance, pancreatic β-cell dysfunction, vascular remodeling, and atherosclerosis [311, 319, 323-325].

Conclusion

Acknowledgements

References

2 Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome: prevalence in worldwide populations. Endocrinol Metab Clin North Am 2004; 33: 351-75; [table of contents].

3 Reynolds K, He J. Epidemiology of the metabolic syndrome. Am J Med Sci 2005; 330: 273-9.

4 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 356-9.

5 Reisin E, Alpert MA. Definition of the metabolic syndrome: current proposals and controversies. Am J Med Sci 2005; 330: 269-72.

6 Zimmet P, Magliano D, Matsuzawa Y, Alberti G, Shaw J. The metabolic syndrome: a global public health problem and a new definition. J Atheroscler Thromb 2005; 12: 295-300.

7 Hanefeld M, Leonhardt W. Das Metabolische Syndrom. Dt Gesundh Wesen 1981; 36: 545-51.

8 Alberti KG. Impaired glucose tolerance: what are the clinical implications? Diabetes Res Clin Pract 1998; 40(Suppl): S3-S8.

9 Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 1999; 16: 442-3.

10 Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection. Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143-421.

11 Grundy SM, Hansen B, Smith Jr. SC, Cleeman JI, Kahn RA. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation 2004; 109: 551-6.

12 Alberti KG, Zimmet P, Shaw J. Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 2006; 23: 469-80.

13 Kaplan NM. The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 1989; 149: 1514-20.

14 Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-607.

15 DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173-94.

16 Bonora E, Targher G, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, Saggiani F, Poli M, Perbellini S, Raffaelli A, Gemma L, Santi L, Bonadonna RC, Muggeo M. The Metabolic Syndrome is an independent predictor of cardiovascular disease in Type 2 diabetic subjects. Prospective data from the Verona Diabetes Complications Study. Diabet Med 2004; 21: 52-8.

17 Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med 2004; 140: 167-74.

18 Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24: 683-9.

19 Rutter MK, Meigs JB, Sullivan LM, D’Agostino Sr. RB, Wilson PW. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation 2004; 110: 380-5.

20 Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K, Pyorala K. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 2004; 164: 1066-76.

21 Cowey S, Hardy RW. The metabolic syndrome: A high-risk state for cancer? Am J Pathol 2006; 169: 1505-22.

22 Mule G, Cottone S, Nardi E, Andronico G, Cerasola G. Metabolic syndrome in subjects with essential hypertension: relationships with subclinical cardiovascular and renal damage. Minerva Cardioangiol 2006; 54: 173-94.

23 Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 2005; 9: 211-24.

24 Neuschwander-Tetri BA. Nonalcoholic steatohepatitis and the metabolic syndrome. Am J Med Sci 2005; 330: 326-35.

25 Pasquali R, Gambineri A. Polycystic ovary syndrome: a multifaceted disease from adolescence to adult age. Ann N Y Acad Sci 2006; 1092: 158-74.

26 McKeown NM, Meigs JB, Liu S, Saltzman E, Wilson PW, Jacques PF. Carbohydrate nutrition, insulin resistance, and the prevalence of the metabolic syndrome in the Framingham Offspring Cohort. Diabetes Care 2004; 27: 538-46.

27 Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med 2003; 163: 427-36.

28 Carnethon MR, Loria CM, Hill JO, Sidney S, Savage PJ, Liu K. Risk factors for the metabolic syndrome: the Coronary Artery Risk Development in Young Adults (CARDIA) study, 1985-2001. Diabetes Care 2004; 27: 2707-15.

29 Laaksonen DE, Lakka HM, Salonen JT, Niskanen LK, Rauramaa R, Lakka TA. Low levels of leisure-time physical activity and cardiorespiratory fitness predict development of the metabolic syndrome. Diabetes Care 2002; 25: 1612-8.

30 Ford ES. Prevalence of the metabolic syndrome in US populations. Endocrinol Metab Clin North Am 2004; 33: 333-50.

31 Mills GW, Avery PJ, McCarthy MI, Hattersley AT, Levy JC, Hitman GA, Sampson M, Walker M. Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to type 2 diabetes. Diabetologia 2004; 47: 732-8.

32 Phillips C, Lopez-Miranda J, Perez-Jimenez F, McManus R, Roche HM. Genetic and nutrient determinants of the metabolic syndrome. Curr Opin Cardiol 2006; 21: 185-93.

33 Semple RK, Chatterjee VK, O’Rahilly S. PPAR gamma and human metabolic disease. J Clin Invest 2006; 116: 581-9.

34 Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26: 76-80.

35 Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx JA. Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 1998; 20: 284-7.

36 Luan J, Browne PO, Harding AH, Halsall DJ, O’Rahilly S, Chatterjee VK, Wareham NJ. Evidence for gene-nutrient interaction at the PPARgamma locus. Diabetes 2001; 50: 686-9.

37 Wilson FH, Hariri A, Farhi A, Zhao H, Petersen KF, Toka HR, Nelson-Williams C, Raja KM, Kashgarian M, Shulman GI, Scheinman SJ, Lifton RP. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science 2004; 306: 1190-4.

38 Sullivan VK. Prevention and treatment of the metabolic syndrome with lifestyle intervention: where do we start? J Am Diet Assoc 2006; 106: 668-71.

39 Esmaillzadeh A, Kimiagar M, Mehrabi Y, Azadbakht L, Hu FB, Willett WC. Fruit and vegetable intakes, C-reactive protein, and the metabolic syndrome. Am J Clin Nutr 2006; 84: 1489-97.

40 Millen BE, Pencina MJ, Kimokoti RW, Zhu L, Meigs JB, Ordovas JM, D’Agostino RB. Nutritional risk and the metabolic syndrome in women: opportunities for preventive intervention from the Framingham Nutrition Study. Am J Clin Nutr 2006; 84: 434-41.

41 Azadbakht L, Mirmiran P, Esmaillzadeh A, Azizi T, Azizi F. Beneficial effects of a Dietary Approaches to Stop Hypertension eating plan on features of the metabolic syndrome. Diabetes Care 2005; 28: 2823-31.

42 Mazur A, Maier JA, Rock E, Gueux E, Nowacki W, Rayssiguier Y. Magnesium and the inflammatory response: potential physiopathological implications. Arch Biochem Biophys 2007; 458: 48-56.

43 Rayssiguier Y, Gueux E, Nowacki W, Rock E, Mazur A. High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation. Magnes Res 2006; 19: 237-43.

44 Rayssiguier Y, Mazur A. Clin Calcium 2005; 15: 245-8; [Magnesium and inflammation: lessons from animal models].

45 Rayssiguier Y, Gueux E, Weiser D. Effect of magnesium deficiency on lipid metabolism in rats fed a high carbohydrate diet. J Nutr 1981; 111: 1876-83.

46 Busserolles J, Gueux E, Rock E, Mazur A, Rayssiguier Y. High fructose feeding of magnesium deficient rats is associated with increased plasma triglyceride concentration and increased oxidative stress. Magnes Res 2003; 16: 7-12.

47 Guerrero-Romero F, Rodriguez-Moran M. Low serum magnesium levels and metabolic syndrome. Acta Diabetol 2002; 39: 209-13.

48 Song Y, Ridker PM, Manson JE, Cook NR, Buring JE, Liu S. Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care 2005; 28: 1438-44.

49 Bo S, Durazzo M, Guidi S, Carello M, Sacerdote C, Silli B, Rosato R, Cassader M, Gentile L, Pagano G. Dietary magnesium and fiber intakes and inflammatory and metabolic indicators in middle-aged subjects from a population-based cohort. Am J Clin Nutr 2006; 84: 1062-9.

50 Corica F, Corsonello A, Ientile R, Cucinotta D, Di Benedetto A, Perticone F, Dominguez LJ, Barbagallo M. Serum ionized magnesium levels in relation to metabolic syndrome in type 2 diabetic patients. J Am Coll Nutr 2006; 25: 210-5.

51 He K, Liu K, Daviglus ML, Morris SJ, Loria CM, Van Horn L, Jacobs Jr. DR, Savage PJ. Magnesium intake and incidence of metabolic syndrome among young adults. Circulation 2006; 113: 1675-82.

52 Touyz RM. Magnesium in clinical medicine. Front Biosci 2004; 9: 1278-93.

53 Saris NE, Mervaala E, Karppanen H, Khawaja JA, Lewenstam A. Magnesium. An update on physiological, clinical and analytical aspects. Clin Chim Acta 2000; 294: 1-26.

54 Zhang A, Cheng TP, Altura BM. Magnesium regulates intracellular free ionized calcium concentration and cell geometry in vascular smooth muscle cells. Biochim Biophys Acta 1992; 1134: 25-9.

55 Chakraborti S, Chakraborti T, Mandal M, Mandal A, Das S, Ghosh S. Protective role of magnesium in cardiovascular diseases: a review. Mol Cell Biochem 2002; 238: 163-79.

56 Wang M, Tashiro M, Berlin JR. Regulation of L-type calcium current by intracellular magnesium in rat cardiac myocytes. J Physiol 2004; 555: 383-96.

57 Kawano S. Dual mechanisms of Mg2+ block of ryanodine receptor Ca2+ release channel from cardiac sarcoplasmic reticulum. Receptors Channels 1998; 5: 405-16.

58 Koss KL, Grubbs RD. Elevated extracellular Mg2+ increases Mg2+ buffering through a Ca-dependent mechanism in cardiomyocytes. Am J Physiol 1994; 267: C633-C641.

59 Gunther T. Mechanisms, regulation and pathologic significance of Mg2+ efflux from erythrocytes. Magnes Res 2006; 19: 190-8.

60 Reinhart RA. Magnesium metabolism. A review with special reference to the relationship between intracellular content and serum levels. Arch Intern Med 1988; 148: 2415-20.

61 Chubanov V, Gudermann T, Schlingmann KP. Essential role for TRPM6 in epithelial magnesium transport and body magnesium homeostasis. Pflugers Arch 2005; 451: 228-34.

62 Elin RJ, Hosseini JM, Gill Jr. JR. Erythrocyte and mononuclear blood cell magnesium concentrations are normal in hypomagnesemic patients with chronic renal magnesium wasting. J Am Coll Nutr 1994; 13: 463-6.

63 Quamme GA, de Rouffignac C. Epithelial magnesium transport and regulation by the kidney. Front Biosci 2000; 5: D694-D711.

64 Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 1999; 285: 103-6.

65 Schmitz C, Deason F, Perraud A. Molecular components of vertebrate magnesium homeostasis regulation. Magnes Res 2007; 20: 6-18.

66 Ryan MP, Devane J, Ryan MF, Counihan TB. Effects of diuretics on the renal handling of magnesium. Drugs 1984; 28(Suppl 1): 167-81.

67 Lostroh AJ, Krahl ME. Insulin action. Accumulation in vitro of Mg 2 + and K + in rat uterus: ion pump activity. Biochim Biophys Acta 1973; 291: 260-8.

68 Hwang DL, Yen CF, Nadler JL. Insulin increases intracellular magnesium transport in human platelets. J Clin Endocrinol Metab 1993; 76: 549-53.

69 Paolisso G, Sgambato S, Passariello N, Giugliano D, Scheen A, D’Onofrio F, Lefebvre PJ. Insulin induces opposite changes in plasma and erythrocyte magnesium concentrations in normal man. Diabetologia 1986; 29: 644-7.

70 Romani A, Marfella C, Scarpa A. Regulation of Mg2+ uptake in isolated rat myocytes and hepatocytes by protein kinase C. FEBS Lett 1992; 296: 135-40.

71 Corica F, Allegra A, Ientile R, Buemi M, Corsonello A, Bonanzinga S, Macaione S, Ceruso D. Changes in plasma, erythrocyte, and platelet magnesium levels in normotensive and hypertensive obese subjects during oral glucose tolerance test. Am J Hypertens 1999; 12: 128-36.

72 Touyz RM, Schiffrin EL. Angiotensin II and vasopressin modulate intracellular free magnesium in vascular smooth muscle cells through Na+-dependent protein kinase C pathways. J Biol Chem 1996; 271: 24353-8.

73 Ebel H, Gunther T. Na+/Mg2+ antiport in erythrocytes of spontaneously hypertensive rats: role of Mg2+ in the pathogenesis of hypertension. Magnes Res 2005; 18: 175-85.

74 Touyz RM, Yao G. Modulation of vascular smooth muscle cell growth by magnesium-role of mitogen-activated protein kinases. J Cell Physiol 2003; 197: 326-35.

75 Laires MJ, Monteiro CP, Bicho M. Role of cellular magnesium in health and human disease. Front Biosci 2004; 9: 262-76.

76 Altura BM, Altura BT. Magnesium and cardiovascular biology: an important link between cardiovascular risk factors and atherogenesis. Cell Mol Biol Res 1995; 41: 347-59.

77 Amighi J, Sabeti S, Schlager O, Mlekusch W, Exner M, Lalouschek W, Ahmadi R, Minar E, Schillinger M. Low serum magnesium predicts neurological events in patients with advanced atherosclerosis. Stroke 2004; 35: 22-7.

78 Ascherio A, Rimm EB, Hernan MA, Giovannucci EL, Kawachi I, Stampfer MJ, Willett WC. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men. Circulation 1998; 98: 1198-204.

79 Chang C, Varghese PJ, Downey J, Bloom S. Magnesium deficiency and myocardial infarct size in the dog. J Am Coll Cardiol 1985; 5: 280-9.

80 de Valk HW. Magnesium in diabetes mellitus. Neth J Med 1999; 54: 139-46.

81 Gomez MN. Magnesium and cardiovascular disease. Anesthesiology 1998; 89: 222-40.

82 Guerrero-Romero F, Rodriguez-Moran M. Hypomagnesemia, oxidative stress, inflammation, and metabolic syndrome. Diabetes Metab Res Rev 2006; 22: 471-6.

83 Neri LC, Johansen HL, Hewitt D, Marier J, Langner N. Magnesium and certain other elements and cardiovascular disease. Sci Total Environ 1985; 42: 49-75.

84 Rayssiguier Y, Gueux E. Magnesium and lipids in cardiovascular disease. J Am Coll Nutr 1986; 5: 507-19.

85 Shechter M, Merz CN, Rude RK, Paul Labrador MJ, Meisel SR, Shah PK, Kaul S. Low intracellular magnesium levels promote platelet-dependent thrombosis in patients with coronary artery disease. Am Heart J 2000; 140: 212-8.

86 Sharrett AR, Feinleib M. Water constituents and trace elements in relation to cardiovascular diseases. Prev Med 1975; 4: 20-36.

87 Sharrett AR. The role of chemical constituents of drinking water in cardiovascular diseases. Am J Epidemiol 1979; 110: 401-19.

88 Adachi M, Nara Y, Mano M, Ikeda K, Horie R, Yamori Y. Intralymphocytic free calcium and magnesium in stroke-prone spontaneously hypertensive rats and effects of blood pressure and various antihypertensive agents. Clin Exp Pharmacol Physiol 1993; 20: 587-93.

89 Altura BM, Altura BT, Carella A, Turlapaty PD. Hypomagnesemia and vasoconstriction: possible relationship to etiology of sudden death ischemic heart disease and hypertensive vascular diseases. Artery 1981; 9: 212-31.

90 Altura BM, Kostellow AB, Zhang A, Li W, Morrill GA, Gupta RK, Altura BT. Expression of the nuclear factor-kappaB and proto-oncogenes c-fos and c-jun are induced by low extracellular Mg2+ in aortic and cerebral vascular smooth muscle cells: possible links to hypertension, atherogenesis, and stroke. Am J Hypertens 2003; 16: 701-7.

91 Ameen M, Davies JE, Ng LL. A comparison of free intracellular calcium and magnesium levels in the vascular smooth muscle and striated muscle cells of the spontaneously hypertensive and Wistar Kyoto normotensive rat. Ann N Y Acad Sci 1991; 639: 550-3.

92 Berthelot A, Luthringer C, Meyers E, Exinger A. Disturbances of magnesium metabolism in the spontaneously hypertensive rat. J Am Coll Nutr 1987; 6: 329-32.

93 Berthon N, Laurant P, Fellmann D, Berthelot A. Effect of magnesium on mRNA expression and production of endothelin-1 in DOCA-salt hypertensive rats. J Cardiovasc Pharmacol 2003; 42: 24-31.

94 Kisters K, Krefting ER, Kosch M, Rahn KH, Hausberg M. Intracellular Mg++ concentrations in smooth and striated muscle cells in spontaneously hypertensive rats. Am J Hypertens 2000; 13: 427-30.

95 Kisters K, Krefting ER, Spieker C, Zidek W, Barenbrock M, Rahn KH. Increased Na+ and decreased Mg2+ intracellular concentrations in vascular smooth muscle cells from spontaneously hypertensive rats. Clin Sci (Lond) 1998; 95: 583-7.

96 Kisters K, Spieker C, Krefting ER, Scholz U, Tepel M, Zidek W, Barenbrock M. Electron-probe X-ray Microanalysis of Magnesium and Sodium Ion Content in Vascular Smooth Muscle Cells from Spontaneously Hypertensive and Normotensive Rats. Int J Angiol 1999; 8: 70-2.

97 Laurant P, Berthelot A. Endothelin-1-induced contraction in isolated aortae from normotensive and DOCA-salt hypertensive rats: effect of magnesium. Br J Pharmacol 1996; 119: 1367-74.

98 Laurant P, Berthelot A. Influence of endothelium on Mg(2+)-induced relaxation in noradrenaline-contracted aorta from DOCA-salt hypertensive rat. Eur J Pharmacol 1994; 258: 167-72.

99 Mahboob T, Mumtaz M, Haleem MA. Electrolyte content of serum, erythrocyte, kidney and heart tissue in salt induced hypertensive rats. Life Sci 1996; 59: 731-7.

100 Matuura T, Kohno M, Kanayama Y, Yasunari K, Murakawa K, Takeda T, Ishimori K, Morishima I, Yonezawa T. Decreased intracellular free magnesium in erythrocytes of spontaneously hypertensive rats. Biochem Biophys Res Commun 1987; 143: 1012-7.

101 Northcott CA, Watts SW. Low [Mg2+]e enhances arterial spontaneous tone via phosphatidylinositol 3-kinase in DOCA-salt hypertension. Hypertension 2004; 43: 125-9.

102 Rayssiguier Y, Mbega JD, Durlach V, Gueux E, Durlach J, Giry J, Dalle M, Mazur A, Laurant P, Berthelot A. Magnesium and blood pressure. I. Animal studies. Magnes Res 1992; 5: 139-46.

103 Wallach S, Verch RL. Tissue magnesium in spontaneously hypertensive rats. Magnesium 1986; 5: 33-8.

104 Buemi M, Corica F, Squadrito F, Ceruso D, Frisina N. Plasma and erythrocyte magnesium concentrations in essential arterial hypertension. Kidney Int Suppl 1988; 25: S14-S15.

105 Corica F, Allegra A, Ientile R, Buemi M. Magnesium concentrations in plasma, erythrocytes, and platelets in hypertensive and normotensive obese patients. Am J Hypertens 1997; 10: 1311-3.

106 Kisters K, Tepel M, Spieker C, Dietl KH, Barenbrock M, Rahn KH, Zidek W. Decreased cellular Mg2+ concentrations in a subgroup of hypertensives--cell models for the pathogenesis of primary hypertension. J Hum Hypertens 1997; 11: 367-72.

107 Kisters K, Tepel M, Spieker C, Zidek W, Barenbrock M, Tokmak F, Kosch M, Hausberg M, Rahn KH. Decreased membrane Mg2+ concentrations in a subgroup of hypertensives: membrane model for the pathogenesis of primary hypertension. Am J Hypertens 1998; 11: 1390-3.

108 Kosch M, Hausberg M, Westermann G, Koneke J, Matzkies F, Rahn KH, Kisters K. Alterations in calcium and magnesium content of red cell membranes in patients with primary hypertension. Am J Hypertens 2001; 14: 254-8.

109 Touyz RM. Role of magnesium in the pathogenesis of hypertension. Mol Aspects Med 2003; 24: 107-36.

110 Touyz RM. Magnesium and hypertension. Curr Opin Nephrol Hypertens 2006; 15: 141-4.

111 Touyz RM, Milne FJ, Reinach SG. Intracellular Mg2+, Ca2+, Na2+ and K+ in platelets and erythrocytes of essential hypertension patients: relation to blood pressure. Clin Exp Hypertens A 1992; 14: 1189-209.

112 Touyz RM, Milne FJ, Seftel HC, Reinach SG. Magnesium, calcium, sodium and potassium status in normotensive and hypertensive Johannesburg residents. S Afr Med J 1987; 72: 377-81.

113 Touyz RM, Panz V, Milne FJ. Relations between magnesium, calcium, and plasma renin activity in black and white hypertensive patients. Miner Electrolyte Metab 1995; 21: 417-22.

114 Gilles-Baillien M, Cogneau M. Magnesium uptake by intestinal brush-border membranes of spontaneously hypertensive rats. Proc Soc Exp Biol Med 1992; 201: 119-24.

115 Wells IC, Agrawal DK. Abnormal magnesium metabolism in two rat models of genetic hypertension. Can J Physiol Pharmacol 1992; 70: 1225-9.

116 Picado MJ, de la Sierra A, Aguilera MT, Coca A, Urbano-Marquez A. Increased activity of the Mg2+/Na+ exchanger in red blood cells from essential hypertensive patients. Hypertension 1994; 23: 987-91.

117 Touyz RM, Schiffrin EL. Activation of the Na(+)-H+ exchanger modulates angiotensin II-stimulated Na(+)-dependent Mg2+ transport in vascular smooth muscle cells in genetic hypertension. Hypertension 1999; 34: 442-9.

118 Touyz RM, Yao G. Inhibitors of Na+/Mg2+ exchange activity attenuate the development of hypertension in angiotensin II-induced hypertensive rats. J Hypertens 2003; 21: 337-44.

119 Hermansen K. Diet, blood pressure and hypertension. Br J Nutr 2000; 83(Suppl 1): S113-S119.

120 Mizushima S, Cappuccio FP, Nichols R, Elliott P. Dietary magnesium intake and blood pressure: a qualitative overview of the observational studies. J Hum Hypertens 1998; 12: 447-53.

121 Joffres MR, Reed DM, Yano K. Relationship of magnesium intake and other dietary factors to blood pressure: the Honolulu heart study. Am J Clin Nutr 1987; 45: 469-75.

122 Ma J, Folsom AR, Melnick SL, Eckfeldt JH, Sharrett AR, Nabulsi AA, Hutchinson RG, Metcalf PA. Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study. Atherosclerosis Risk in Communities Study. J Clin Epidemiol 1995; 48: 927-40.

123 Peacock JM, Folsom AR, Arnett DK, Eckfeldt JH, Szklo M. Relationship of serum and dietary magnesium to incident hypertension: the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 1999; 9: 159-65.

124 Song Y, Sesso HD, Manson JE, Cook NR, Buring JE, Liu S. Dietary magnesium intake and risk of incident hypertension among middle-aged and older US women in a 10-year follow-up study. Am J Cardiol 2006; 98: 1616-21.

125 Simons-Morton DG, Hunsberger SA, Van Horn L, Barton BA, Robson AM, McMahon RP, Muhonen LE, Kwiterovich PO, Lasser NL, Kimm SY, Greenlick MR. Nutrient intake and blood pressure in the Dietary Intervention Study in Children. Hypertension 1997; 29: 930-6.

126 Kesteloot H, Joossens JV. Relationship of dietary sodium, potassium, calcium, and magnesium with blood pressure. Belgian Interuniversity Research on Nutrition and Health. Hypertension 1988; 12: 594-9.

127 Blache D, Devaux S, Joubert O, Loreau N, Schneider M, Durand P, Prost M, Gaume V, Adrian M, Laurant P, Berthelot A. Long-term moderate magnesium-deficient diet shows relationships between blood pressure, inflammation and oxidant stress defense in aging rats. Free Radic Biol Med 2006; 41: 277-84.

128 Laurant P, Hayoz D, Brunner HR, Berthelot A. Effect of magnesium deficiency on blood pressure and mechanical properties of rat carotid artery. Hypertension 1999; 33: 1105-10.

129 Laurant P, Robin S, Berthelot A. Magnesium deficiency increases vasoconstrictor activity without affecting blood pressure of aged spontaneously hypertensive rats. Magnes Res 1997; 10: 107-17.

130 Luthringer C, Rayssiguier Y, Gueux E, Berthelot A. Effect of moderate magnesium deficiency on serum lipids, blood pressure and cardiovascular reactivity in normotensive rats. Br J Nutr 1988; 59: 243-50.

131 Maier JA, Malpuech-Brugere C, Zimowska W, Rayssiguier Y, Mazur A. Low magnesium promotes endothelial cell dysfunction: implications for atherosclerosis, inflammation and thrombosis. Biochim Biophys Acta 2004; 1689: 13-21.

132 Murasato Y, Harada Y, Ikeda M, Nakashima Y, Hayashida Y. Effect of magnesium deficiency on autonomic circulatory regulation in conscious rats. Hypertension 1999; 34: 247-52.

133 Adrian M, Laurant P, Berthelot A. Effect of magnesium on mechanical properties of pressurized mesenteric small arteries from old and adult rats. Clin Exp Pharmacol Physiol 2004; 31: 306-13.

134 Tammaro P, Smith AL, Crowley BL, Smirnov SV. Modulation of the voltage-dependent K+ current by intracellular Mg2+ in rat aortic smooth muscle cells. Cardiovasc Res 2005; 65: 387-96.

135 Gamble J, Blackfan KD, Hamilton B. A Study of the Diuretic Action of Acid Producing Salts. J Clin Invest 1925: 359-88.

136 Dyckner T, Wester PO. Effect of magnesium on blood pressure. Br Med J (Clin Res Ed) 1983; 286: 1847-9.

137 Lind L, Lithell H, Pollare T, Ljunghall S. Blood pressure response during long-term treatment with magnesium is dependent on magnesium status. A double-blind, placebo-controlled study in essential hypertension and in subjects with high-normal blood pressure. Am J Hypertens 1991; 4: 674-9.

138 Ryan MP, Brady HR. The role of magnesium in the prevention and control of hypertension. Ann Clin Res 1984; 16(Suppl 43): 81-8.

139 Widman L, Wester PO, Stegmayr BK, Wirell M. The dose-dependent reduction in blood pressure through administration of magnesium. A double blind placebo controlled cross-over study. Am J Hypertens 1993; 6: 41-5.

140 Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neilson J, Smith D. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002; 359: 1877-90.

141 Yamamoto ME, Applegate WB, Klag MJ, Borhani NO, Cohen JD, Kirchner KA, Lakatos E, Sacks FM, Taylor JO, Hennekens CH. Lack of blood pressure effect with calcium and magnesium supplementation in adults with high-normal blood pressure. Results from Phase I of the Trials of Hypertension Prevention (TOHP). Trials of Hypertension Prevention (TOHP) Collaborative Research Group. Ann Epidemiol 1995; 5: 96-107.

142 Jee SH, Miller 3rd ER, Guallar E, Singh VK, Appel LJ, Klag MJ. The effect of magnesium supplementation on blood pressure: a meta-analysis of randomized clinical trials. Am J Hypertens 2002; 15: 691-6.

143 Altura BM, Altura BT. Magnesium ions and contraction of vascular smooth muscles: relationship to some vascular diseases. Fed Proc 1981; 40: 2672-9.

144 Yang Z, Wang J, Altura BT, Altura BM. Extracellular magnesium deficiency induces contraction of arterial muscle: role of PI3-kinases and MAPK signaling pathways. Pflugers Arch 2000; 439: 240-7.

145 Yang ZW, Altura BT, Altura BM. Low extracellular Mg2+ contraction of arterial muscle: role of protein kinase C and protein tyrosine phosphorylation. Eur J Pharmacol 1999; 378: 273-81.

146 Yang ZW, Wang J, Zheng T, Altura BT, Altura BM. Low [Mg(2+)](o) induces contraction of cerebral arteries: roles of tyrosine and mitogen-activated protein kinases. Am J Physiol Heart Circ Physiol 2000; 279: H185-H194.

147 Yang ZW, Wang J, Zheng T, Altura BT, Altura BM. Low [Mg(2+)](o) induces contraction and [Ca(2+)](i) rises in cerebral arteries: roles of ca(2+), PKC, and PI3. Am J Physiol Heart Circ Physiol 2000; 279: H2898-H2907.

148 Howard AB, Alexander RW, Taylor WR. Effects of magnesium on nitric oxide synthase activity in endothelial cells. Am J Physiol 1995; 269: C612-C618.

149 O’Brien WF, Williams MC, Benoit R, Sawai SK, Knuppel RA. The effect of magnesium sulfate infusion on systemic and renal prostacyclin production. Prostaglandins 1990; 40: 529-38.

150 Yang ZW, Gebrewold A, Nowakowski M, Altura BT, Altura BM. Mg(2+)-induced endothelium-dependent relaxation of blood vessels and blood pressure lowering: role of NO. Am J Physiol Regul Integr Comp Physiol 2000; 278: R628-R639.

151 Pearson PJ, Evora PR, Seccombe JF, Schaff HV. Hypomagnesemia inhibits nitric oxide release from coronary endothelium: protective role of magnesium infusion after cardiac operations. Ann Thorac Surg 1998; 65: 967-72.

152 Maier JA, Bernardini D, Rayssiguier Y, Mazur A. High concentrations of magnesium modulate vascular endothelial cell behaviour in vitro. Biochim Biophys Acta 2004; 1689: 6-12.

153 Ramchandra R, Barrett CJ, Malpas SC. Nitric oxide and sympathetic nerve activity in the control of blood pressure. Clin Exp Pharmacol Physiol 2005; 32: 440-6.

154 Briel RC, Lippert TH, Zahradnik HP. Action of magnesium sulfate on platelet prostacyclin interaction and prostacyclin of blood vessels. Am J Obstet Gynecol 1985; 153: 232.

155 Satake K, Lee JD, Shimizu H, Uzui H, Mitsuke Y, Yue H, Ueda T. Effects of magnesium on prostacyclin synthesis and intracellular free calcium concentration in vascular cells. Magnes Res 2004; 17: 20-7.

156 Watson KV, Moldow CF, Ogburn PL, Jacob HS. Magnesium sulfate: rationale for its use in preeclampsia. Proc Natl Acad Sci USA 1986; 83: 1075-8.

157 Laurant P, Berthelot A. Arch Mal Coeur Vaiss 1992; 85: 1223-6; [In vitro study of the role of endothelium on the vasorelaxant effect of magnesium on the aorta from DOCA-salt hypertensive rats].

158 Angerio AD. The role of endothelin in heart failure. Crit Care Nurs Q 2005; 28: 355-9.

159 Berthon N, Laurant P, Hayoz D, Fellmann D, Brunner HR, Berthelot A. Magnesium supplementation and deoxycorticosterone acetate--salt hypertension: effect on arterial mechanical properties and on activity of endothelin-1. Can J Physiol Pharmacol 2002; 80: 553-61.

160 Weglicki WB, Phillips TM, Freedman AM, Cassidy MM, Dickens BF. Magnesium-deficiency elevates circulating levels of inflammatory cytokines and endothelin. Mol Cell Biochem 1992; 110: 169-73.

161 Prasad A, Quyyumi AA. Renin-angiotensin system and angiotensin receptor blockers in the metabolic syndrome. Circulation 2004; 110: 1507-12.

162 Corica F, Corsonello A, Buemi M, De Gregorio T, Malara A, Mauro VN, Macaione S, Ientile R. Platelet magnesium depletion in normotensive and hypertensive obese subjects: the role of salt-regulating hormones and catecholamines. Magnes Res 1999; 12: 287-96.

163 Resnick LM, Laragh JH, Sealey JE, Alderman MH. Divalent cations in essential hypertension. Relations between serum ionized calcium, magnesium, and plasma renin activity. N Engl J Med 1983; 309: 888-91.

164 Ichihara A, Suzuki H, Saruta T. Effects of magnesium on the renin-angiotensin-aldosterone system in human subjects. J Lab Clin Med 1993; 122: 432-40.

165 Laurant P, Dalle M, Berthelot A, Rayssiguier Y. Time-course of the change in blood pressure level in magnesium-deficient Wistar rats. Br J Nutr 1999; 82: 243-51.

166 Altura BM, Altura BT, Carella A. Magnesium deficiency-induced spasms of umbilical vessels: relation to preeclampsia, hypertension, growth retardation. Science 1983; 221: 376-8.

167 Shimosawa T, Takano K, Ando K, Fujita T. Magnesium inhibits norepinephrine release by blocking N-type calcium channels at peripheral sympathetic nerve endings. Hypertension 2004; 44: 897-902.

168 Touyz RM, Laurant P, Schiffrin EL. Effect of magnesium on calcium responses to vasopressin in vascular smooth muscle cells of spontaneously hypertensive rats. J Pharmacol Exp Ther 1998; 284: 998-1005.

169 De Martin R, Hoeth M, Hofer-Warbinek R, Schmid JA. The transcription factor NF-kappa B and the regulation of vascular cell function. Arterioscler Thromb Vasc Biol 2000; 20: E83-E88.

170 Colditz GA, Manson JE, Stampfer MJ, Rosner B, Willett WC, Speizer FE. Diet and risk of clinical diabetes in women. Am J Clin Nutr 1992; 55: 1018-23.

171 Kao WH, Folsom AR, Nieto FJ, Mo JP, Watson RL, Brancati FL. Serum and dietary magnesium and the risk for type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study. Arch Intern Med 1999; 159: 2151-9.

172 Lima Mde L, Pousada J, Barbosa C, Cruz T. Arq Bras Endocrinol Metabol 2005; 49: 959-63; [Magnesium deficiency and insulin resistance in patients with type 2 diabetes mellitus].

173 Lopez-Ridaura R, Willett WC, Rimm EB, Liu S, Stampfer MJ, Manson JE, Hu FB. Magnesium intake and risk of type 2 diabetes in men and women. Diabetes Care 2004; 27: 134-40.

174 Song Y, Manson JE, Buring JE, Liu S. Dietary magnesium intake in relation to plasma insulin levels and risk of type 2 diabetes in women. Diabetes Care 2004; 27: 59-65.

175 van Dam RM, Hu FB, Rosenberg L, Krishnan S, Palmer JR. Dietary calcium and magnesium, major food sources, and risk of type 2 diabetes in U.S. black women. Diabetes Care 2006; 29: 2238-43.

176 Corica F, Ientile R, Allegra A, Romano G, Cangemi F, Di Benedetto A, Buemi M, Cucinotta D, Ceruso D. Magnesium levels in plasma, erythrocyte, and platelet in hypertensive and normotensive patients with type II diabetes mellitus. Biol Trace Elem Res 1996; 51: 13-21.

177 Paolisso G, Barbagallo M. Hypertension, diabetes mellitus, and insulin resistance: the role of intracellular magnesium. Am J Hypertens 1997; 10: 346-55.

178 Paolisso G, Ravussin E. Intracellular magnesium and insulin resistance: results in Pima Indians and Caucasians. J Clin Endocrinol Metab 1995; 80: 1382-5.

179 Resnick LM, Altura BT, Gupta RK, Laragh JH, Alderman MH, Altura BM. Intracellular and extracellular magnesium depletion in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1993; 36: 767-70.

180 Schnack C, Bauer I, Pregant P, Hopmeier P, Schernthaner G. Hypomagnesaemia in type 2 (non-insulin-dependent) diabetes mellitus is not corrected by improvement of long-term metabolic control. Diabetologia 1992; 35: 77-9.

181 Reinhart RA, Marx Jr. JJ, Broste SK, Haas RG. Myocardial magnesium: relation to laboratory and clinical variables in patients undergoing cardiac surgery. J Am Coll Cardiol 1991; 17: 651-6.

182 Djurhuus MS, Skott P, Hother-Nielson O, Klitgaard NA, Beck-Nielsen H. Insulin increases renal magnesium excretion: a possible cause of magnesium depletion in hyperinsulinaemic states. Diabet Med 1995; 12: 664-9.

183 Djurhuus MS. New data on the mechanisms of hypermagnesuria in type I diabetes mellitus. Magnes Res 2001; 14: 217-23.

184 Paolisso G, Scheen A, Cozzolino D, Di Maro G, Varricchio M, D’Onofrio F, Lefebvre PJ. Changes in glucose turnover parameters and improvement of glucose oxidation after 4-week magnesium administration in elderly noninsulin-dependent (type II) diabetic patients. J Clin Endocrinol Metab 1994; 78: 1510-4.

185 Rodriguez-Moran M, Guerrero-Romero F. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care 2003; 26: 1147-52.

186 Song Y, He K, Levitan EB, Manson JE, Liu S. Effects of oral magnesium supplementation on glycaemic control in Type 2 diabetes: a meta-analysis of randomized double-blind controlled trials. Diabet Med 2006; 23: 1050-6.

187 Laughlin MR, Thompson D. The regulatory role for magnesium in glycolytic flux of the human erythrocyte. J Biol Chem 1996; 271: 28977-83.

188 Barbagallo M, Dominguez LJ, Galioto A, Ferlisi A, Cani C, Malfa L, Pineo A, Busardo A, Paolisso G. Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X. Mol Aspects Med 2003; 24: 39-52.

189 Suarez A, Pulido N, Casla A, Casanova B, Arrieta FJ, Rovira A. Impaired tyrosine-kinase activity of muscle insulin receptors from hypomagnesaemic rats. Diabetologia 1995; 38: 1262-70.

190 Paxton R, Ye L. Regulation of heart insulin receptor tyrosine kinase activity by magnesium and spermine. Mol Cell Biochem 2005; 277: 7-17.

191 McCarty MF. PKC-mediated modulation of L-type calcium channels may contribute to fat-induced insulin resistance. Med Hypotheses 2006; 66: 824-31.

192 McCarty MF. Up-regulation of intracellular signalling pathways may play a central pathogenic role in hypertension, atherogenesis, insulin resistance, and cancer promotion--the ’PKC syndrome’. Med Hypotheses 1996; 46: 191-221.

193 Gueux E, Rayssiguier Y. The effect of magnesium deficiency on glucose stimulated insulin secretion in rats. Horm Metab Res 1983; 15: 594-7.

194 Ziegler B, Wilke B, Woltanski KP, Knospe S, Hahn HJ. Protection of insulin secretion by magnesium during islet culture: independence of cAMP/or insulin accumulation. Exp Clin Endocrinol 1983; 82: 199-207.

195 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340: 115-26.

196 Ueshima K. Magnesium and ischemic heart disease: a review of epidemiological, experimental, and clinical evidences. Magnes Res 2005; 18: 275-84.

197 Chipperfield B, Chipperfield JR. Heart-muscle magnesium, potassium, and zinc concentrations after sudden death from heart-disease. Lancet 1973; 2: 293-6.

198 Elwood PC, Beasley WH. Myocardial magnesium and ischaemic heart disease. Artery 1981; 9: 200-4.

199 Iskra M, Majewski W, Piorunska-Stolzmann M. Modifications of magnesium and copper concentrations in serum and arterial wall of patients with vascular diseases related to ageing, atherosclerosis and aortic aneurysm. Magnes Res 2002; 15: 279-85.

200 Vlad M, Uza G, Porr PJ, Caseanu E, Petrescu M. Magnesium and calcium concentration in the abdominal aorta of patients deceased by ischemic heart disease. Magnes Res 2000; 13: 37-41.

201 Millane TA, Jennison SH, Mann JM, Holt DW, McKenna WJ, Camm AJ. Myocardial magnesium depletion associated with prolonged hypomagnesemia: a longitudinal study in heart transplant recipients. J Am Coll Cardiol 1992; 20: 806-12.

202 Abbott RD, Ando F, Masaki KH, Tung KH, Rodriguez BL, Petrovitch H, Yano K, Curb JD. Dietary magnesium intake and the future risk of coronary heart disease (the Honolulu Heart Program). Am J Cardiol 2003; 92: 665-9.

203 Liao F, Folsom AR, Brancati FL. Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 1998; 136: 480-90.

204 Rasmussen HS, Aurup P, Goldstein K, McNair P, Mortensen PB, Larsen OG, Lawaetz H. Influence of magnesium substitution therapy on blood lipid composition in patients with ischemic heart disease. A double-blind, placebo controlled study. Arch Intern Med 1989; 149: 1050-3.

205 Singh RB, Rastogi SS, Mani UV, Seth J, Devi L. Does dietary magnesium modulate blood lipids? Biol Trace Elem Res 1991; 30: 59-64.

206 Singh RB, Rastogi SS, Sharma VK, Saharia RB, Kulshretha SK. Can dietary magnesium modulate lipoprotein metabolism? Magnes Trace Elem 1990; 9: 255-64.

207 Cohen H, Sherer Y, Shaish A, Shoenfeld Y, Levkovitz H, Bitzur R, Harats D. Atherogenesis inhibition induced by magnesium-chloride fortification of drinking water. Biol Trace Elem Res 2002; 90: 251-9.

208 Ravn HB, Korsholm TL, Falk E. Oral magnesium supplementation induces favorable antiatherogenic changes in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2001; 21: 858-62.

209 Sherer Y, Bitzur R, Cohen H, Shaish A, Varon D, Shoenfeld Y, Harats D. Mechanisms of action of the antiatherogenic effect of magnesium: lessons from a mouse model. Magnes Res 2001; 14: 173-9.

210 Sherer Y, Shaish A, Levkovitz H, Keren P, Janackovic Z, Shoenfeld Y, Harats D. Magnesium fortification of drinking water suppresses atherogenesis in male LDL-receptor-deficient mice. Pathobiology 1999; 67: 207-13.

211 Sherer Y, Shoenfeld Y, Shaish A, Levkovitz H, Bitzur R, Harats D. Suppression of atherogenesis in female low-density lipoprotein receptor knockout mice following magnesium fortification of drinking water: the importance of diet. Pathobiology 2000; 68: 93-8.

212 Altura BT, Brust M, Bloom S, Barbour RL, Stempak JG, Altura BM. Magnesium dietary intake modulates blood lipid levels and atherogenesis. Proc Natl Acad Sci USA 1990; 87: 1840-4.

213 Evans DA, Tariq M, Sujata B, McCann G, Sobki S. The effects of magnesium sulphate and EDTA in the hypercholesterolaemic rabbit. Diabetes Obes Metab 2001; 3: 417-22.

214 Atabek ME, Kurtoglu S, Pirgon O, Baykara M. Serum magnesium concentrations in type 1 diabetic patients: relation to early atherosclerosis. Diabetes Res Clin Pract 2006; 72: 42-7.

215 Tzanakis I, Virvidakis K, Tsomi A, Mantakas E, Girousis N, Karefyllakis N, Papadaki A, Kallivretakis N, Mountokalakis T. Intra- and extracellular magnesium levels and atheromatosis in haemodialysis patients. Magnes Res 2004; 17: 102-8.

216 Hasham SN, Pillarisetti S. Vascular lipases, inflammation and atherosclerosis. Clin Chim Acta 2006; 372: 179-83.

217 Rayssiguier Y, Noe L, Etienne J, Gueux E, Cardot P, Mazur A. Effect of magnesium deficiency on post-heparin lipase activity and tissue lipoprotein lipase in the rat. Lipids 1991; 26: 182-6.

218 Field FJ, Henning B, Mathur SN. In vitro regulation of 3-hydroxy-3-methylglutarylcoenzyme A reductase and acylcoenzyme A: cholesterol acyltransferase activities by phosphorylation-dephosphorylation in rabbit intestine. Biochim Biophys Acta 1984; 802: 9-16.

219 Jonas A. Lecithin cholesterol acyltransferase. Biochim Biophys Acta 2000; 1529: 245-56.

220 Rayssiguier Y. Magnesium, lipids and vascular diseases. Experimental evidence in animal models. Magnesium 1986; 5: 182-90.

221 Gueux E, Rayssiguier Y, Piot MC, Alcindor L. Reduction of plasma lecithin--cholesterol acyltransferase activity by acute magnesium deficiency in the rat. J Nutr 1984; 114: 1479-83.

222 Nozue T, Ide N, Okabe H, Narui K, Kobayashi A. Correlation of serum HDL-cholesterol and LCAT levels with the fraction of ionized magnesium in children. Magnes Res 1999; 12: 297-301.

223 Mahfouz MM, Kummerow FA. Effect of magnesium deficiency on delta 6 desaturase activity and fatty acid composition of rat liver microsomes. Lipids 1989; 24: 727-32.

224 Rosanoff A, Seelig MS. Comparison of mechanism and functional effects of magnesium and statin pharmaceuticals. J Am Coll Nutr 2004; 23: 501S-505S.

225 Gueux E, Azais-Braesco V, Bussiere L, Grolier P, Mazur A, Rayssiguier Y. Effect of magnesium deficiency on triacylglycerol-rich lipoprotein and tissue susceptibility to peroxidation in relation to vitamin E content. Br J Nutr 1995; 74: 849-56.

226 Gueux E, Cubizolles C, Bussiere L, Mazur A, Rayssiguier Y. Oxidative modification of triglyceride-rich lipoproteins in hypertriglyceridemic rats following magnesium deficiency. Lipids 1993; 28: 573-5.

227 Bussiere L, Mazur A, Gueux E, Nowacki W, Rayssiguier Y. Triglyceride-rich lipoproteins from magnesium-deficient rats are more susceptible to oxidation by cells and promote proliferation of cultured vascular smooth muscle cells. Magnes Res 1995; 8: 151-7.

228 Mahfouz MM, Zhou Q, Kummerow FA. Cholesterol oxides in plasma and lipoproteins of magnesium-deficient rabbits and effects of their lipoproteins on endothelial barrier function. Magnes Res 1994; 7: 207-22.

229 Yokoyama S, Nishida HI, Smith TL, Kummerow FA. Combined effects of magnesium deficiency and an atherogenic level of low density lipoprotein on uptake and metabolism of low density lipoprotein by cultured human endothelial cells. I. Biochemical data. Magnes Res 1994; 7: 87-95.

230 Bernardini D, Nasulewic A, Mazur A, Maier JA. Magnesium and microvascular endothelial cells: a role in inflammation and angiogenesis. Front Biosci 2005; 10: 1177-82.

231 Guo H, Lee JD, Uzui H, Yue H, Wang J, Toyoda K, Geshi T, Ueda T. Effects of folic acid and magnesium on the production of homocysteine-induced extracellular matrix metalloproteinase-2 in cultured rat vascular smooth muscle cells. Circ J 2006; 70: 141-6.

232 Yue H, Lee JD, Shimizu H, Uzui H, Mitsuke Y, Ueda T. Effects of magnesium on the production of extracellular matrix metalloproteinases in cultured rat vascular smooth muscle cells. Atherosclerosis 2003; 166: 271-7.

233 Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004; 25: 4-7.

234 Vaskonen T. Dietary minerals and modification of cardiovascular risk factors. J Nutr Biochem 2003; 14: 492-506.

235 Lelovics Z. Relation between calcium and magnesium intake and obesity. Asia Pac J Clin Nutr 2004; 13: S144.

236 Rodriguez-Hernandez H, Gonzalez JL, Rodriguez-Moran M, Guerrero-Romero F. Hypomagnesemia, insulin resistance, and non-alcoholic steatohepatitis in obese subjects. Arch Med Res 2005; 36: 362-6.

237 Yakinci C, Pac A, Kucukbay FZ, Tayfun M, Gul A. Serum zinc, copper, and magnesium levels in obese children. Acta Paediatr Jpn 1997; 39: 339-41.

238 Mataix J, Aranda P, Lopez-Jurado M, Sanchez C, Planells E, Llopis J. Factors influencing the intake and plasma levels of calcium, phosphorus and magnesium in southern Spain. Eur J Nutr 2006; 45: 349-54.

239 Singh RB, Beegom R, Rastogi SS, Gaoli Z, Shoumin Z. Association of low plasma concentrations of antioxidant vitamins, magnesium and zinc with high body fat per cent measured by bioelectrical impedance analysis in Indian men. Magnes Res 1998; 11: 3-10.

240 Mazur A, Gueux E, Remesy C, Demigne C, Rayssiguier Y. Plasma and red blood cell magnesium concentrations in Zucker rats: influence of a high fibre diet. Magnes Res 1989; 2: 189-92.

241 Begin-Heick N. The effect of the divalent cations Mg2+ and Mn2+ on adenylate cyclase activity in white and brown adipose tissue of lean and obese (ob/ob) mice. Can J Biochem Cell Biol 1985; 63: 7-15.

242 Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006; 444: 847-53.

243 Kandeel FR, Balon E, Scott S, Nadler JL. Magnesium deficiency and glucose metabolism in rat adipocytes. Metabolism 1996; 45: 838-43.

244 Festa A, D’Agostino Jr. R, Tracy RP, Haffner SM. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 2002; 51: 1131-7.

245 Schneider DJ. Abnormalities of coagulation, platelet function, and fibrinolysis associated with syndromes of insulin resistance. Coron Artery Dis 2005; 16: 473-6.

246 Corica F, Allegra A, Buemi M, Ientile R, Corsonello A, Di Benedetto A, Bonanzinga S, Ruello A, D’Angelo R, Cucinotta D, Ceruso D. Altered platelet magnesium and plasma and urinary soluble form of intercellular adhesion molecule I (sICAM-1) concentrations in insulin dependent diabetes mellitus (IDDM) patients with microalbuminuria. Magnes Res 1996; 9: 307-12.

247 Nadler JL, Malayan S, Luong H, Shaw S, Natarajan RD, Rude RK. Intracellular free magnesium deficiency plays a key role in increased platelet reactivity in type II diabetes mellitus. Diabetes Care 1992; 15: 835-41.

248 Takaya J, Higashino H, Kotera F, Kobayashi Y. Intracellular magnesium of platelets in children with diabetes and obesity. Metabolism 2003; 52: 468-71.

249 Teo KK, Yusuf S, Collins R, Held PH, Peto R. Effects of intravenous magnesium in suspected acute myocardial infarction: overview of randomised trials. BMJ 1991; 303: 1499-503.

250 Woods KL, Fletcher S. Long-term outcome after intravenous magnesium sulphate in suspected acute myocardial infarction: the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 1994; 343: 816-9.

251 Gawaz M, Reininger A, Neumann FJ. Platelet function and platelet-leukocyte adhesion in symptomatic coronary heart disease. Effects of intravenous magnesium. Thromb Res 1996; 83: 341-9.

252 Shechter M. The role of magnesium as antithrombotic therapy. Wien Med Wochenschr 2000; 150: 343-7.

253 Sheu JR, Hsiao G, Shen MY, Lee YM, Yen MH. Antithrombotic effects of magnesium sulfate in in vivo experiments. Int J Hematol 2003; 77: 414-9.

254 Gries A, Bode C, Gross S, Peter K, Bohrer H, Martin E. The effect of intravenously administered magnesium on platelet function in patients after cardiac surgery. Anesth Analg 1999; 88: 1213-9.

255 Sheu JR, Hsiao G, Shen MY, Fong TH, Chen YW, Lin CH, Chou DS. Mechanisms involved in the antiplatelet activity of magnesium in human platelets. Br J Haematol 2002; 119: 1033-41.

256 Ravn HB, Vissinger H, Kristensen SD, Wennmalm A, Thygesen K, Husted SE. Magnesium inhibits platelet activity--an infusion study in healthy volunteers. Thromb Haemost 1996; 75: 939-44.

257 Hsiao G, Shen MY, Chou DS, Lin CH, Chen TF, Sheu JR. Involvement of the antiplatelet activity of magnesium sulfate in suppression of protein kinase C and the Na+/H+ exchanger. J Biomed Sci 2004; 11: 19-26.

258 Nadler JL, Buchanan T, Natarajan R, Antonipillai I, Bergman R, Rude R. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension 1993; 21: 1024-9.

259 Ravn HB, Vissinger H, Kristensen SD, Husted SE. Magnesium inhibits platelet activity--an in vitro study. Thromb Haemost 1996; 76: 88-93.

260 Barzilay J, Freedland E. Inflammation and its association with glucose disorders and cardiovascular disease. Treat Endocrinol 2003; 2: 85-94.

261 Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE, Tracy RP. The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes 2001; 50: 2384-9.

262 Ridker PM. High-sensitivity C-reactive protein and cardiovascular risk: rationale for screening and primary prevention. Am J Cardiol 2003; 92: 17K-22K.

263 Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836-43.

264 Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000; 101: 2149-53.

265 Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-72.

266 Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. C-reactive protein and the risk of developing hypertension. JAMA 2003; 290: 2945-51.

267 Rodriguez-Moran M, Guerrero-Romero F. Increased levels of C-reactive protein in noncontrolled type II diabetic subjects. J Diabetes Complications 1999; 13: 211-5.

268 Aso Y, Wakabayashi S, Yamamoto R, Matsutomo R, Takebayashi K, Inukai T. Metabolic syndrome accompanied by hypercholesterolemia is strongly associated with proinflammatory state and impairment of fibrinolysis in patients with type 2 diabetes: synergistic effects of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor. Diabetes Care 2005; 28: 2211-6.

269 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860-7.

270 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91.

271 Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 1995; 95: 2111-9.

272 Mantzoros CS, Moschos S, Avramopoulos I, Kaklamani V, Liolios A, Doulgerakis DE, Griveas I, Katsilambros N, Flier JS. Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans. J Clin Endocrinol Metab 1997; 82: 3408-13.

273 Yang WS, Chuang LM. Human genetics of adiponectin in the metabolic syndrome. J Mol Med 2006; 84: 112-21.

274 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257: 79-83.

275 Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000; 20: 1595-9.

276 Kazumi T, Kawaguchi A, Sakai K, Hirano T, Yoshino G. Young men with high-normal blood pressure have lower serum adiponectin, smaller LDL size, and higher elevated heart rate than those with optimal blood pressure. Diabetes Care 2002; 25: 971-6.

277 Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol 2004; 24: 29-33.

278 Ford ES, Ajani UA, Mokdad AH. The metabolic syndrome and concentrations of C-reactive protein among U.S. youth. Diabetes Care 2005; 28: 878-81.

279 Cankurtaran M, Halil M, Yavuz BB, Dagli N, Oyan B, Ariogul S. Prevalence and correlates of metabolic syndrome (MS) in older adults. Arch Gerontol Geriatr 2006; 42: 35-45.

280 Nakanishi N, Shiraishi T, Wada M. C-reactive protein concentration is more strongly related to metabolic syndrome in women than in men: the Minoh Study. Circ J 2005; 69: 386-91.

281 Saijo Y, Kiyota N, Kawasaki Y, Miyazaki Y, Kashimura J, Fukuda M, Kishi R. Relationship between C-reactive protein and visceral adipose tissue in healthy Japanese subjects. Diabetes Obes Metab 2004; 6: 249-58.

282 Tamakoshi K, Yatsuya H, Kondo T, Hori Y, Ishikawa M, Zhang H, Murata C, Otsuka R, Zhu S, Toyoshima H. The metabolic syndrome is associated with elevated circulating C-reactive protein in healthy reference range, a systemic low-grade inflammatory state. Int J Obes Relat Metab Disord 2003; 27: 443-9.

283 Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean ME, Haffner SM. Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care 2002; 25: 2016-21.

284 Laaksonen DE, Niskanen L, Nyyssonen K, Punnonen K, Tuomainen TP, Valkonen VP, Salonen R, Salonen JT. C-reactive protein and the development of the metabolic syndrome and diabetes in middle-aged men. Diabetologia 2004; 47: 1403-10.

285 King DE, Mainous 3rd AG, Geesey ME, Woolson RF. Dietary magnesium and C-reactive protein levels. J Am Coll Nutr 2005; 24: 166-71.

286 Qi L, Rimm E, Liu S, Rifai N, Hu FB. Dietary glycemic index, glycemic load, cereal fiber, and plasma adiponectin concentration in diabetic men. Diabetes Care 2005; 28: 1022-8.

287 King D, Mainous A, Geesey M, Ellis T. Magnesium intake and serum C-reactive protein levels in children. Magnes Res 2007; 20: 32-6.

288 Guerrero-Romero F, Rodriguez-Moran M. Relationship between serum magnesium levels and C-reactive protein concentration, in non-diabetic, non-hypertensive obese subjects. Int J Obes Relat Metab Disord 2002; 26: 469-74.

289 Rodriguez-Moran M, Guerrero-Romero F. Elevated concentrations of TNF-alpha are related to low serum magnesium levels in obese subjects. Magnes Res 2004; 17: 189-96.

290 Bernstein LE, Berry J, Kim S, Canavan B, Grinspoon SK. Effects of etanercept in patients with the metabolic syndrome. Arch Intern Med 2006; 166: 902-8.

291 Kramer JH, Mak IT, Phillips TM, Weglicki WB. Dietary magnesium intake influences circulating pro-inflammatory neuropeptide levels and loss of myocardial tolerance to postischemic stress. Exp Biol Med (Maywood) 2003; 228: 665-73.

292 Malpuech-Brugere C, Nowacki W, Daveau M, Gueux E, Linard C, Rock E, Lebreton J, Mazur A, Rayssiguier Y. Inflammatory response following acute magnesium deficiency in the rat. Biochim Biophys Acta 2000; 1501: 91-8.

293 Malpuech-Brugere C, Nowacki W, Gueux E, Kuryszko J, Rock E, Rayssiguier Y, Mazur A. Accelerated thymus involution in magnesium-deficient rats is related to enhanced apoptosis and sensitivity to oxidative stress. Br J Nutr 1999; 81: 405-11.

294 Malpuech-Brugere C, Nowacki W, Rock E, Gueux E, Mazur A, Rayssiguier Y. Enhanced tumor necrosis factor-alpha production following endotoxin challenge in rats is an early event during magnesium deficiency. Biochim Biophys Acta 1999; 1453: 35-40.

295 Petrault I, Zimowska W, Mathieu J, Bayle D, Rock E, Favier A, Rayssiguier Y, Mazur A. Changes in gene expression in rat thymocytes identified by cDNA array support the occurrence of oxidative stress in early magnesium deficiency. Biochim Biophys Acta 2002; 1586: 92-8.

296 Weglicki WB, Phillips TM. Pathobiology of magnesium deficiency: a cytokine/neurogenic inflammation hypothesis. Am J Physiol 1992; 263: R734-R737.

297 Kurantsin-Mills J, Cassidy MM, Stafford RE, Weglicki WB. Marked alterations in circulating inflammatory cells during cardiomyopathy development in a magnesium-deficient rat model. Br J Nutr 1997; 78: 845-55.

298 Bussiere FI, Tridon A, Zimowska W, Mazur A, Rayssiguier Y. Increase in complement component C3 is an early response to experimental magnesium deficiency in rats. Life Sci 2003; 73: 499-507.

299 Nakagawa M, Ike T, Kawabe K, Fujii M, Miyamoto A, Ishiguro S, Nishio A. In vivo and in vitro effects of magnesium deficiency on hepatic haptoglobin mRNA levels. Magnes Res 2001; 14: 19-25.

300 Oono H, Nakagawa M, Miyamoto A, Ishiguro S, Nishio A. Mechanisms underlying the enhanced elevation of IL-1beta and TNF-alpha mRNA levels following endotoxin challenge in rat alveolar macrophages cultured with low-Mg2+ medium. Magnes Res 2002; 15: 153-60.

301 Tchoukalova YD, Grider A, Mouat MF, Hausman GJ. Priming with magnesium-deficient media inhibits preadipocyte differentiation via potential upregulation of tumor necrosis factor-alpha. Biol Trace Elem Res 2000; 74: 11-21.

302 Lee DS, Evans JC, Robins SJ, Wilson PW, Albano I, Fox CS, Wang TJ, Benjamin EJ, D’Agostino RB, Vasan RS. Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2007; 27: 127-33.

303 Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer L. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes Metab Res Rev 2001; 17: 189-212.

304 Evans JL, Maddux BA, Goldfine ID. The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal 2005; 7: 1040-52.

305 Barbagallo M, Dominguez LJ, Tagliamonte MR, Resnick LM, Paolisso G. Effects of vitamin E and glutathione on glucose metabolism: role of magnesium. Hypertension 1999; 34: 1002-6.

306 Paolisso G, D’Amore A, Balbi V, Volpe C, Galzerano D, Giugliano D, Sgambato S, Varricchio M, D’Onofrio F. Plasma vitamin C affects glucose homeostasis in healthy subjects and in non-insulin-dependent diabetics. Am J Physiol 1994; 266: E261-E268.

307 Paolisso G, Tagliamonte MR, Barbieri M, Zito GA, Gambardella A, Varricchio G, Ragno E, Varricchio M. Chronic vitamin E administration improves brachial reactivity and increases intracellular magnesium concentration in type II diabetic patients. J Clin Endocrinol Metab 2000; 85: 109-15.

308 Weglicki WB, Mak IT, Kramer JH, Dickens BF, Cassidy MM, Stafford RE, Philips TM. Role of free radicals and substance P in magnesium deficiency. Cardiovasc Res 1996; 31: 677-82.

309 Nasulewicz A, Zimowska W, Bayle D, Dzimira S, Madej J, Rayssiguier Y, Opolski A, Mazur A. Changes in gene expression in the lungs of Mg-deficient mice are related to an inflammatory process. Magnes Res 2004; 17: 259-63.

310 Dickens BF, Weglicki WB, Li YS, Mak IT. Magnesium deficiency in vitro enhances free radical-induced intracellular oxidation and cytotoxicity in endothelial cells. FEBS Lett 1992; 311: 187-91.

311 Hans CP, Chaudhary DP, Bansal DD. Effect of magnesium supplementation on oxidative stress in alloxanic diabetic rats. Magnes Res 2003; 16: 13-9.

312 Kumar BP, Shivakumar K. Depressed antioxidant defense in rat heart in experimental magnesium deficiency. Implications for the pathogenesis of myocardial lesions. Biol Trace Elem Res 1997; 60: 139-44.

313 Rayssiguier Y, Durlach J, Gueux E, Rock E, Mazur A. Magnesium and ageing. I. Experimental data: importance of oxidative damage. Magnes Res 1993; 6: 369-78.

314 Yang Y, Wu Z, Chen Y, Qiao J, Gao M, Yuan J, Nie W, Guo Y. Magnesium deficiency enhances hydrogen peroxide production and oxidative damage in chick embryo hepatocyte in vitro. Biometals 2006; 19: 71-81.

315 Zhou Q, Olinescu RM, Kummerow FA. Influence of low magnesium concentrations in the medium on the antioxidant system in cultured human arterial endothelial cells. Magnes Res 1999; 12: 19-29.

316 Zhu Z, Kimura M, Itokawa Y. Selenium concentration and glutathione peroxidase activity in selenium and magnesium deficient rats. Biol Trace Elem Res 1993; 37: 209-17.

317 Hsu JM, Smith Jr. JC, Yunice AA, Kepford G. Impairment of ascorbic acid synthesis in liver extracts of magnesium-deficient rats. J Nutr 1983; 113: 2041-7.

318 Mak IT, Stafford R, Weglicki WB. Loss of red blood cell glutathione during Mg deficiency: prevention by vitamin E, D-propranolol, and chloroquine. Am J Physiol 1994; 267: C1366-C1370.

319 Shivakumar K, Kumar BP. Magnesium deficiency enhances oxidative stress and collagen synthesis in vivo in the aorta of rats. Int J Biochem Cell Biol 1997; 29: 1273-8.

320 Afanas’ev IB, Suslova TB, Cheremisina ZP, Abramova NE, Korkina LG. Study of antioxidant properties of metal aspartates. Analyst 1995; 120: 859-62.

321 Calviello G, Ricci P, Lauro L, Palozza P, Cittadini A. Mg deficiency induces mineral content changes and oxidative stress in rats. Biochem Mol Biol Int 1994; 32: 903-11.

322 Touyz RM, Pu Q, He G, Chen X, Yao G, Neves MF, Viel E. Effects of low dietary magnesium intake on development of hypertension in stroke-prone spontaneously hypertensive rats: role of reactive oxygen species. J Hypertens 2002; 20: 2221-32.

323 Freedman AM, Mak IT, Stafford RE, Dickens BF, Cassidy MM, Muesing RA, Weglicki WB. Erythrocytes from magnesium-deficient hamsters display an enhanced susceptibility to oxidative stress. Am J Physiol 1992; 262: C1371-C1375.

324 Weglicki WB, Bloom S, Cassidy MM, Freedman AM, Atrakchi AH, Dickens BF. Antioxidants and the cardiomyopathy of Mg-deficiency. Am J Cardiovasc Pathol 1992; 4: 210-5.

325 Gilardini L, McTernan PG, Girola A, da Silva NF, Alberti L, Kumar S, Invitti C. Adiponectin is a candidate marker of metabolic syndrome in obese children and adolescents. Atherosclerosis 2006; 189: 401-7.