Eighty one million two hundred ninety two thousand one hundred forty seven
In recent years the attention of researchers in various fields of clinical medicine involved in the problem of magnesium deficiency and its role in the formation of various pathological conditions and pathological processes of the human body.
Normal level of magnesium in human body is recognized as the fundamental constant that controls human health. Among the cations present in the human body, magnesium(Mg2+) concentration is in fourth place, and within the cell second only to potassium among the other cations (potassium, sodium, calcium).
In humans, the distribution of reserves of magnesium has its own characteristics: about 60% of the total magnesium content is in bone, dentin and tooth enamel; 20% in tissues with vysokouglerodistoy activity (heart, muscle cells, liver, adrenal gland, kidney); 20% in brain and nervous tissue, and only 0.3% is in blood plasma
It was found that 90% of magnesium ions are concentrated within cells in the form of phosphate bonds – "Mg2+ — ATPase" (30% in the mitochondria, 50% in the cytosol, 10% in the cell nucleus) and only 10% of the total magnesium in the human body located outside the cells.
Currently, the presence of more than 290 genes and protein compounds in the sequence of the human genome, which is able to bind Mg2+ as co–factor of many enzymes involved in more than 300 intracellular biochemical reactions. Mg2+ is a natural physiological antagonist of Ca2 universal regulator of biochemical and physiological processes in the body, ensures the hydrolysis of ATP, by inhibiting the dissociation of oxidation and phosphorylation; regulates glycolysis, accumulation of lactate; contributes to the fixation of K+ in cells, providing polarization of cell membranes, controls the spontaneous electrical activity of nerve tissue and the cardiac conduction system; monitors the proper functioning of the cardiomyocyte at all levels of cellular and subcellular structures, as a universal cardioprotection.
Magnesium is necessary for the normal course of many biochemical reactions and physiological processes that provide energy and functions of various organs, which determines its leading role in ensuring system functioning and allows to consider it as the most important factor governing the functioning of the human body.
Mg2+ ions are capable of forming reversible gelotophobia compounds with organic substances, allowing their participation in various biochemical reactions, activating more than 300 enzymes. In the role of co–factor he takes part in many enzymatic processes, in particular in glycolysis and the hydrolytic cleavage of ATP. While in complexes with ATP, Mg2+ provides the release of energy through the activity of Mg2+–dependent Atpas. According to the law of uniformity of action of Mg2+ by controlling ATP–dependent reaction, is a necessary element for almost all intracellular energy-generating and energy consuming processes of various organs and systems of the human body.
As a co–factor piruvatdegidrogenzu complex Mg2+ ensures the supply of the products of glycolysis into the Krebs cycle and this prevents the accumulation of lactate. Some reactions of the cycle (for example, the conversion of citrate and a–glutarate), also under the control of Mg2+. It is difficult to overestimate the role of Mg2+ in anabolic processes: it is involved in the synthesis and breakdown of nucleic acids, protein synthesis, fatty acids and lipids, in particular phospholipids, controls the synthesis of cyclic AMP.
Mg2+ is a natural physiological antagonist of calcium ions (Ca2+), competing with them (unlike the blockers of fast and slow calcium channels) not only in the structure of the cell membrane, but also at all levels of the intracellular system. In the muscle cell Mg2+ inhibits the "trigger" entry of Ca2+ into the cell, causing contraction of the myofibrils, not only through competition in the channels of the sarcolemma, but also displaces it from its Association with troponin C, controlling the contractile state of the cardiomyocyte. Such competition-based suppression and other-initiated Ca2+ reactions in the nervous and endocrine systems. If you change the intracellular ratio of Ca2+/Mg2+ and the predominance of Ca2+ activates Ca2+–sensitive proteases and lipases, leading to damage of membranes. Due to antagonism of Ca2+ Mg2+ acts as a membrane and cytoprotective factor. A similar mechanism due to the ability of Mg2+ to decrease the intracellular uncoupling respiration and oxidative phosphorylation in mitochondria and cells need oxygen, resulting in reduced unproductive losses of energy in the form of heat, increases the efficiency of ATP synthesis
Mg2+ contributes to a reduction in Ca2+–dependent impulse transmission in the nerve endings, preventing the release of mediators of the presynaptic membrane, activating reuptake. So, in adrenergic synapses, it ensures inactivation and reservation of norepinephrine by binding it in granules (this process is also mediated via Mg2+–dependent Na+–K+–ATP–ASE, responsible for the reuptake of catecholamines by sympathetic neurons) and in the neuromuscular synapses inhibits dependent on calcium release of acetylcholine. Significant effect on the contraction of various smooth muscle Mg2+ exerts via the inhibition of the release of histamine from mast cells.
The antagonism of Ca2+ is associated reduced by the action of ions of Mg2+ ADP–induced platelet aggregation and suppression of other calcium–dependent reactions in cascades of blood coagulation.
The intracellular bioavailability of magnesium in the body is regulated by a number of genes controlling Assembly and functioning of proteins on the surface of cell membranes, performing realizatorov or ion channels, including TRPM–6 (Transient Receptor Potential Cation Channel), and TRPМ–7 are the most important. Protein TRPM–6 is an ion channel regulating the transport of divalent cations. TRPM–6, specifically interacting with a different Mg2+–permeable channel TRPM–7, promotes the formation ("the Assembly") functional TRPM–6/TRPM–7 protein complexes on the surface of cell membranes. Experimental and clinical studies indicate that changes in the functional state of the TRPM–7 under the action of catecholamines on the background emotional stress contribute to the development of intracellular "magnesium deficiency".
The most common effect of Mg2+ on any fabric is that Mg2+ ions stabilize the structure of transfer RNA, which controls the overall rate of resynthesis of proteins. Predefinite of magnesium occurs destabilization of transport – non-coding RNA (an increasing number of dysfunctional RNA molecules), accompanied by a decline and a slowdown in the rate of synthesis of protein structures of cells with a relative predominance of apoptosis (one of the mechanisms of aging).
The "ionic hypothesis" of aging supposes the existence of violations of the intracellular mechanisms of calcium/magnesium, leading to the violation of blood rheology (increased platelet aggregation, increased rigidity of erythrocyte membranes and reducing their mobility), increase of blood coagulation, atherogenesis, which is typical for elderly people. Biological changes associated with aging of the body due to accumulation resulting from the depletion of the antioxidant system against the background of "magnesium deficiency" of free radicals, which cause lipid peroxidation of low density, lipid peroxidation of cell membranes, amino acids in proteins cell receptors (insulin resistance). Y. Rayssiguier and colleagues (France, 1993) showed that in animals with magnesium deficiency increases sensitivity to oxidative stress (increase in the sensitivity of tissues to oxidation), accompanied by an increase in products of lipid peroxidation, the accumulation of which contributes to early "aging" of cells (particularly endothelial cells).
Regulation of electrolyte balance in the cell (along with the influence on the energy exchange) due to the ability of Mg2+ to suppress automatism, conductivity and excitability, and increase absolute and shorten the relative refractory tissue, possessing all or some of these functions (e.g. in the myocardium, myometrium, etc.).
Taking part in the release of energy required for the functioning of muscle cells and playing a major role in the coupling of "contraction – relaxation" of Miorita, Mg2+ controls the activity of muscles, particularly the myocardium. Describes mechanisms play an important role in vasodilative activity of Mg2+, which probably is mediated through the synthesis of cyclic AMP, a powerful vazodilatiruushimi factor, through the overwhelming influence of the renin–angiotensin–aldosterone system and the sympathetic innervation, as well as through the strengthening of natriuresis by increasing renal blood flow via activation of prostacyclin.
In the experiment, it was shown the inhibitory effect of Mg2+ on the release of endothelin, the improvement of which, accompanying thrombosis of the coronary artery in myocardial infarction, leading to severe local vasoconstriction in the area of ischemic risk. These studies demonstrated hypocoagulation effect of Mg2+ in the inactivation of prothrombin, thrombin, factor Christmas, prokonvertina and plasma thromboplastin component, as well as its antiplatelet effect on the formed elements of blood (erythrocytes, platelets, leukocytes).
Among the metabolic functions manifested at the level of the whole organism, it is necessary to emphasize its role in maintaining normal lipid metabolism, involved in providing the response of tissues to insulin and the inhibition of parathyroid hormone.
"Magnesium deficiency" syndrome, due to a decrease in intracellular magnesium content in various organs and systems, many of the symptoms which testify to the multi-organ disorders of the functional state of the whole organism in various age groups.
The main clinical conditions are pathogenetically related to "magnesium deficiency", highlight: metabolic syndrome (MS), chronic fatigue syndrome, heart disease (coronary artery disease, congestive heart failure (CHF), dilated cardiomyopathy), syndrome of connective tissue dysplasia (DST), the syndrome of an elongated Q–T interval, a "reperfusion syndrome", mitral valve prolapse; asthma, complications of pregnancy and childbirth. Aggravation "magnesium deficiency" is associated with the recurrence and worsening course of these diseases with the development of complications.
Numerous epidemiological studies indicate that in regions where food and drinking water (hard water) is rich in magnesium significantly less likely to record patients with signs of MS (hypertension, type 2 diabetes, atherogenic dyslipidemia, insulin resistance), connective dysplasia syndrome of prolonged interval Q–T. Low levels of free cytosolic magnesium and high levels of free intracellular calcium are associated with insulin resistance and compensatory hyperinsulinemia not only in hypertension and type 2 diabetes, but in case of isolated atherogenic dyslipidemia, obesity, hypercoagulability States, and the elderly.
Reliable detection of magnesium deficiency is challenging, therefore its diagnosis in practice is often based on clinical signs. A screening study conducted in the USA showed that hypomagnesaemia (serum Mg2+ below 0.74 mmol/l) is found in 47.1% of cases, and clinical signs of "magnesium deficiency" identified in more than 72% of adult Americans [Wang H. 1994].
Hypomagnesaemia (according to various authors) is recorded in 7-11% of hospitalized patients and patients in intensive care, twice as often – in 25% of cases.
However, statistics indicate that 40% of the patients in the hospitals have clinical signs of "magnesium deficiency", in 70% of cases "magnesium deficiency" is recorded in patients in intensive care units, 90% of "magnesium deficiency" occurs in patients with acute coronary syndrome . In Russia, according to epidemiological studies, about 30% of the residents get a day less than 70% of the daily dose of magnesium, "magnesium deficiency" manifestoes much more often in women than in men .
According to etiology there are primary and secondary "magnesium deficiency" .
Primary (constitutional, latent) "magnesium deficiency" is caused by defects in the genes responsible for the transmembrane exchange of magnesium in the body, clinically manifested convulsive syndrome (spasmophilia), "constitutional tetany" or "normocalcaemia a tetany" with a normal content of Mg2+ in blood serum.
Secondary deficiency of magnesium due to social conditions and lifestyle, environmental conditions and dietary habits, different stress situations and diseases. Causes "magnesium deficiency"; related to the conditions of life:
• Stress – acute and chronic (especially!!!): according to the Ministry of health and social development of the Russian Federation, about 80% of the Russian population live in conditions of chronic stress;
• Intense physical work and physical stress;
• Alcohol abuse;
• Exposure to high temperatures (hot climate, hot plant, excess visits to steam baths);
• Pregnancy and lactation;
• Hormonal contraception.
Causes "magnesium deficiency", nutrition-related:
• Consumption of products with a limited content of magnesium (meat, poultry, potatoes, milk and dairy products);
• Consumption of foods with a high content of animal fats and proteins, phosphorus, calcium, which inhibit (prevent) the absorption of Mg2+ in the gastrointestinal tract.
Causes "magnesium deficiency" related to pathological processes:
• Impaired absorption in the digestive tract in connection with diseases or age-related changes (small absorption syndrome, chronic duodenitis, goiter, ulcerative enterocolitis, etc.);
• Diabetes mellitus (insulin resistance, hyperinsulinemia, hyperglycemia, diabetic nephropathy);
• Acute coronary syndrome;
Iatrogenic causes "magnesium deficiency»:
• An overdose of cardiac glycosides;
• The abuse of diuretics;
• Hormonal kontracepcija;
• The use of glucocorticoids;
• Cytostatic therapy. It should be noted that a negative role in the lack of magnesium plays use food type "Fast food".
Metabolic syndrome is complex of metabolic disorders and cardiovascular diseases, pathogenetically interrelated, including insulin resistance (IR), impaired glucose tolerance (IGT), atherogenic dyslipidemia (increase of triglycerides – TG, low-density lipoproteins – LDL, reduced high density lipoproteins – HDL), arterial hypertension (AH) combined with abdominal obesity. These disorders are more common in the elderly, so aging is mentioned among the States that occur in the metabolic syndrome [2,3].
Little known is the fact that all these States were identified low levels of magnesium in the cells and increased content of intracellular calcium, although long known that patients suffering from diabetes, have low levels of magnesium in the blood. A number of studies have provided evidence of a low intracellular concentration of magnesium in Association with high levels of calcium in hypertension, as well as other disorders included in metabolic syndrome [4-6].
Two interrelated States are characteristic for each of the violations observed in the metabolic syndrome.
The first condition is a magnesium deficiency causing insulin resistance and impaired response to insulin, in turn, prevents cell capture of glucose and the transport of magnesium into the cell. Moreover, magnesium deficiency prevents insulin secretion and normal insulin activity, thus, it is closely associated with insulin resistance. And magnesium deficiency and insulin resistance affect the utilization of fat. It is shown that the appointment of magnesium as a dietary Supplement, persons of all ages with hypertension and/or insulin-resistant form of diabetes type 2 has corrected their insulin resistance, and impaired levels of blood cholesterol (dyslipidemia), simultaneously affecting a reduction in blood pressure [7,8].
The second condition faced by researchers, although it is less often found in discussions of metabolic syndrome, is a disturbed oxidative metabolism, which contributes to insufficiency of the Mg2+ and/or deficiency of antioxidant vitamins (E and C, ubiquinone, coenzyme Q10).
In numerous randomized studies have shown that hyperactivity of the sympathetic nervous system that occurs during MS, accompanied by a decrease in the level of intracellular magnesium. This has been observed in patients with hypertension with obesity and without it, in diabetic patients independently of blood pressure . Among the middle-aged patients with labile hypertension a response in the form of blood pressure reduction by 3–month acceptance Magnerota (6 tablets per day) was recorded only in those patients who initially was reduced magnesium levels in erythrocytes (<1.5 mmol/l) . Manufacturing workers associated with a high level of noise, as well as students preparing for final exams, whose diet contained the source of Mg2+ less than 5 mg per kg per day (about 350 mg per day for body weight of 70 kg), showed an increase in blood pressure. Increase daily intake of Mg2+ to 6-7 mg / kg (up to 3 g of Mg2+ per day), prevented the increase in blood pressure caused by stress .
In some clinical studies, inversely proportional dependence between the level of magnesium and insulin resistance in type 2 diabetes, which are accompanied by atherogenic "dyslipidemia" (increase in triglycerides and reduced HDL cholesterol).
In the U.S., based on data from Commission of the American Association of diabetologists on the prevalence and consequences of magnesium deficiency in diabetic patients with cardiovascular complications, a series of studies among patients with diabetes, 70% of whom had concomitant CVD. Among patients with diabetes and concomitant pathology by SSS in 78% of cases occurred hypomagnesemia (Mg2+ levels in plasma of <1.6 mmol/l) and one third of these patients to standard therapy was added magnesium preparations . In the group of patients with DM, combined with the "magnesium deficiency", with the addition of the program of treatment drugs magnesium – MgCl2 (1 g / day) for 1 year were noted: increased sensitivity to insulin, normalization of lipid profile (reduction of triglycerides concentration and increase the level of high-density lipoproteins), reduce the incidence of cardiovascular complications compared to a control group of similar patients without adding magnesium.
In another double-blind, placebo–controlled study, patients in prescribing magnesium calculated as 500 mg of Mg2+ per day for 4 weeks was statistically shown a reduction of urinary excretion of noradrenaline in urine and in blood pressure compared to the placebo group . Similar data have been traced in the group of patients with uncomplicated essential hypertension (borderline hypertension), which after 4–week treatment with magnesium at the rate of 1 g per day was an increase in magnesium content in erythrocytes and reduced sodium in the normalization of BP levels and triglycerides .
Endothelial dysfunction contributes to the formation and progression of hypertension in MS. In recent years, the damage of endothelial cells is associated with high levels of homocysteine (amino acid produced in the body during the metabolism of methionine), which is controlled ionized magnesium. Homocysteine is an independent risk factor of atherosclerosis and atherothrombosis through activation of free radical oxidation processes leading to endothelial dysfunction, activation, adhesion of platelets and activation of coagulation of blood factors underlying atherogenesis and intravascular thrombosis.
Magnesium deficiency plays a crucial role in the development of oxidative disorders in metabolic syndrome. The lack of magnesium acts as a prooxidants, directly causing the formation of free radicals and reduces the levels of antioxidants and their activity in the body. The importance of magnesium deficiency, as prooxidants, was first shown on the example of reducing the amount of damage caused by lack of magnesium intake of other antioxidants. This was demonstrated over a decade ago in the Syrian hamsters. Antioxidants vitamins E and C reduced the damaging effects of free radicals on the heart caused by lack of magnesium [15,16]. Elevated titers of indicators of oxidative stress in young mice with a magnesium deficiency and lipid peroxidation, they have been able to prevent the application of vitamin E . A lack of magnesium and vitamin E caused in mice atherosclerotic changes .
Weglicki with a group of researchers in the US showed that free radicals produced in the heart of hamsters with magnesium deficiency are involved in the damage, suggested that the mechanism of heart damage by free radicals include predopredeleno state, which is activated and damaged endothelial cells of blood vessels . Many of the damage caused by free radicals are associated with damage to the endothelium. Dysfunction of the endothelium leads to hypercholesterolemia, thrombosis, increased adhesion of leukocytes to the vascular wall factors contributing to the development of atherosclerosis and the narrowing of blood vessels in hypertension, as with other components of MS such as diabetes and aging. Paradoxically, endothelial cells damaged by free radicals, themselves produce them .
Rayssiguier and Durlach and colleagues (France) found that in animals with magnesium deficiency increased sensitivity to oxidative stress with an increase in the sensitivity of tissues to oxidation . They provided evidence that the accumulation of oxidation products plays an important role in aging of cells, and that the main targets of free radicals are unsaturated fatty acids of cell membranes, amino acids, proteins and nucleic acids. Oxidation of proteins in the cell occurs earlier with a lack of magnesium and contributes to tissue damage and disruption of their function, which are observed in the later stages of magnesium deficiency changes promoting aging. In a recent study conducted in Poland, it was shown that the magnesium level in plasma was reduced in mice with deficiency in the diet, along with reducing the level of antioxidants in the kidneys and heart .
Prolonged exposure to oxidative stress on isolated cells has violated the insulin–dependent glucose metabolism, allowing insulin receptors and activating the enzyme (protein kinase). This observation convinced Israeli scientists that this oxidative mechanism that causes insulin resistance [4-7]. British and American researchers believe that insulin resistance and vascular complications of diabetes arise (at least partly) due to activation of protein kinase enzyme, which also affects the calcium–dependent constrictio vessels, especially when the magnesium deficiency . In Japan, Amano et al. have provided evidence that insulin regulates the level of intracellular free magnesium in the heart, probably through the activation of protein kinase thereby preventing adrenergic system induced a decrease in the level of free magnesium in the heart .
Thus, the data of multicenter studies indicate that low levels of magnesium is one of the main factors in the pathogenesis of the disturbances of carbohydrate and lipid metabolism, hypertension and obesity in patients with metabolic syndrome. published
Authors: Shilov, A. M., Miller V. M., Hosea A., Sviridov A., Gryaznov D. A.