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Biochemical mechanisms of the metabolic syndrome and the role of magnesium


Magnesium Research. Volume 23, Numéro 3, 142-5, september 2010, Letter

DOI : 10.1684/mrh.2010.0210


Auteur(s) : Theodor Günther , Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Institut für Molekularbiologie und Biochemie, Berlin, Germany.

ARTICLE

Auteur(s) : Theodor Günther

Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Institut für Molekularbiologie und Biochemie, Berlin, Germany

The metabolic syndrome is characterized by obesity, insulin resistance, dyslipidemia and hypertension [1-3]. Various hypotheses have been presented during the past as mechanisms of the metabolic syndrome: insulin hypothesis, glucose hypothesis, reactive oxygen species (ROS) hypothesis, ionic hypothesis [4-6].

The primary symptom in metabolic syndrome is insulin resistance, followed by hypertension [7]. The situation is complicated because obesity and insulin resistance are often not associated with hypertension [1, 7].

Hypertension is caused by contraction of smooth muscle cells in arteries, due to an increase in [Ca2+]i. It has also been discussed that increased [Ca2+]i may contribute to insulin resistance and diabetes mellitus type 2 [8]. It was therefore reasonable to suggest the ionic hypothesis as the mechanism of the metabolic syndrome. As shown with erythrocytes in metabolic syndrome, [Ca2+]i and [Na+]i are increased and [Mg2+]i (concentrations of intracellular free Ca2+, Na+, Mg2+) and pHi are decreased [5]. [Na+]i may be increased according to the dietary salt or renin status [5]. Increased [Na+]i may also be caused by a reduction in Na/K ATPase activity as found in obese humans and animals [6]. The alterations in pHi, [Mg2+]i and [Ca2+]i in erythrocytes can be explained by increased glycolysis in hyperglycemia. Hyperglycemia increases glycolysis and yields higher [H+]i due to lactic acid formation. The higher [ATP]i binds more intracellular Mg2+ and reduces [Mg2+]i. The increased [H+]i liberates more bound Ca2+, increasing [Ca2+]i.

A decrease in [Mg2+]i was also found in erythrocytes of spontaneously hypertensive rats (SHR) [9]. Contrarily, [Mg2+]i in erythrocytes of hypertensive subjects showed an increase from 199 μM to 219 μM [10]. The decreased [Mg2+]i in erythrocytes from hypertensives should be the result of fasting [2, 5]. However, fasting and a lower blood glucose concentration should not reduce [Mg2+]i in erythrocytes. For more values of [Mg2+]i in erythrocytes, lymphocytes and platelets from patients with essential hypertension see [11]. [Mg2+]i in these cell types in hypertensives was either unchanged, reduced or increased [11]. Also intralymphocyte [Mg2+]i and [Ca2+]i in essential hypertensive patients showed no significant change in comparison with normotensive subjects [12]. [Mg2+]i in skeletal muscle of obese patients with essential hypertension and insulin resistance was unchanged as measured by 31P-NMR [13].[Ca2+]i and [Na+]i in the aorta of SHR were increased, whereas [Mg2+]i was not significantly reduced, as measured by NMR [14]. These results indicate that [Mg2+]i may play no significant role in essential hypertension.

Hypertension can be experimentally induced by Mg deficiency and chronic hypomagnesemia, particularly when combined with stress [15, 16] due to increased Ca2+ influx and increased [Ca2+]i [17, 18]. Also, chronic hypomagnesemia induced hypertension in patients with a mutation in a mitochondrial transfer RNA [19]. Various generations with this mutation developed hypertension, hypercholesterolemia, increased LDL and VLDL, but they did not develop obesity, insulin resistance and diabetes mellitus. Renin and aldosterone levels were unchanged [19]. These results indicate that chronic hypomagnesemia does not induce insulin resistance but hypertension.

Hypertension in metabolic syndrome may be induced by obesity. Various effectors, among others ghrelin, β-adrenergics and ROS, are produced by adipocytes or are related to obesity. For a review see [20]. A low plasma ghrelin concentration was associated with high BMI, increased systolic and diastolic blood pressure, high fasting blood glucose and plasma insulin [21].

Obese Zucker fat rats were used as an animal model to study the metabolic syndrome. These rats developed hypertension [22-24]. The increased blood pressure in obese rats was associated with increased angiotensin II (Ang II) sensitivity [22, 25], increased adrenergic activity [20, 22] and with reduced activity of membrane Ca ATPase [23].

Hypertension may be caused by increased Ca2+ influx and increased [Ca2+]i. Increased Ca2+ influx in arterial smooth muscle cells is caused by hyperglycemia via activation of protein kinase A (PKA) [25, 26] and by Ang II [25]. PKA is targeted to the cell membrane by A-kinase anchoring protein and interacts with L-type Ca2+ channels [25, 26]. Ang II increases [Ca2+]i through mobilization from sarcoplasmic stores via inositol 1,4,5-trisphosphate [27, 28], followed by Ca2+ influx [27].

The hypertensive effect of Ang II has been intensively studied [28-31]. In these experiments Ang II-induced hypertension was associated with a decrease in [Mg2+]i and an increase in [Na+]i, [Ca2+]i and pHi. Hypertension and the alterations in [Mg2+]i and partly in [Na+]i were inhibited by imipramine and quinidine, which also inhibit the Na+/Mg2+ antiport. The Ang II- induced decrease in [Mg2+]i amounted to 0.1-0.2 mM, whereas [Na+]i was increased by about 20 mM. In Na+/Mg2+ antiport the stoichiometric ratio of transported Na+: Mg2+ is 1:1 or 2:1. For a review see [32]. These results indicate that Ang II also affects other Na+-dependent transport systems. Ang II activates Na+/H+ antiport [30, 33], causing an increase in [Na+]i and pHi [30]. The pHi behaved differently from the pHi in erythrocytes from patients with metabolic syndrome [5]. The reason may be a different extracellular glucose concentration in these studies. At an increased pHi more intracellular Mg2+ is bound, reducing [Mg2+]i [34]. This effect may explain the modulation of the Na+/Mg2+ antiport by the Na+/H+ antiport.

Ang II activates various protein kinases [28], which in turn activate the Na+/H+ antiport [35-37]. Additionally, the Na+/H+ antiport is activated by Ca2+ via calmodulin [38].

The Ang II-induced increase in [Ca2+]i may be additionally caused by inhibition of the Na+/Ca2+ antiport as a consequence of the increased [Na+]i and of the reduction of the extra-intracellular Na+ gradient when Na+/H+ antiport and Na+/Mg2+ antiport are activated. On the other hand, at increased [Ca2+]i, the Na+/Ca2+ antiport is stimulated [39]. The interaction of these mechanisms results in an increase in [Ca2+]i.

Imipramine and quinidine are unspecific inhibitors of Na+/Mg2+ antiport. They may antagonize the Ang II-induced hypertension independent of their effect on the change in cell ions [40]. The Na+/Mg2+ antiport was not directly measured in these experiments [29-31]. Therefore the contribution of the Na+/Mg2+ antiport to the Ang II-induced alterations of [Na+]i and [Mg2+]i cannot be quantified.

Ang II activates NADPH oxidase and elevates the concentration of ROS [28]. ROS are also increased by catecholamines [41] and Mg deficiency [20]. ROS increase [Ca2+]i [42]. However, studies with human subjects failed to demonstrate significant beneficial effects of antioxidants on blood pressure [43].

In summary, the role of intracellular Mg2+ in hypertension is controversial and [Mg2+]i may have a minor function in hypertension.

Chronic hypomagnesemia and increased β-adrenergics develop hypertension via increased [Ca2+]i. Hypomagnesemia is not the primary cause of insulin resistance and metabolic syndrome.

Obesity may be the cause of the metabolic syndrome. In obesity various adipokines and cytokines are increased, inducing insulin resistance. In obesity and in insulin resistance, Ang II and hyperglycemia induce hypertension via an increase in [Ca2+]i.

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