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Tuesday, April 2, 2013

Magnesium



Magnesium
Magnesium is the eleventh most abundant element by mass in the human body. The adult body content is 25 g distributed in the skeleton and soft tissues. The chemical is essential in manipulating important biological polyphosphate such as ATP, DNA, and RNA and in functionming enzymes(a).
A. Magnesium and hypertension
B. Magnesium sulphate  
C. Magnesium deficiency complications
D. Magnesium and Asthma
Magnesium and Type II diabetes
1. High dietary magnesium intake is associated with low insulin resistance in the Newfoundland population
In the study to investigate the association between magnesium intake and IR in normal-weight (NW), overweight (OW) and obese (OB) along with pre- and post- menopausal women, showed that subjects with the highest intakes of dietary magnesium had the lowest levels of circulating insulin, HOMA-IR, and HOMA-ß and subjects with the lowest intake of dietary magnesium had the highest levels of these measures, suggesting a dose effect. Multiple regression analysis revealed a strong inverse association between dietary magnesium with IR. In addition, adiposity and menopausal status were found to be critical factors revealing that the association between dietary magnesium and IR was stronger in OW and OB along with Pre-menopausal women(1).

2. Magnesium intake and risk of type 2 diabetes
In the study to assess the association between magnesium intake and risk of type 2 diabetes with retrieved studies published in any language by systematically searching MEDLINE from 1966 to February 2007 and by manually examining the references of the original articles, found that magnesium intake was inversely associated with incidence of type 2 diabetes. This finding suggests that increased consumption of magnesium-rich foods such as whole grains, beans, nuts, and green leafy vegetables may reduce the risk of type 2 diabetes(2).

3. Fiber and magnesium intake and incidence of type 2 diabetes
In the study to examine associations between fiber and magnesium intake and risk of type 2 diabetes and summarized existing prospective studies by meta-analysis, found that during 176 117 person-years of follow-up, we observed 844 incident cases of type 2 diabetes in the European Prospective Investigation Into Cancer and Nutrition-Potsdam. Higher cereal fiber intake was inversely associated with diabetes risk (RR for extreme quintiles, 0.72 [95% confidence interval [CI], 0.56-0.93]), while fruit fiber (0.89 [95% CI, 0.70-1.13]) and vegetable fiber (0.93 [95% CI, 0.74-1.17]) were not significantly associated. Meta-analyses showed a reduced diabetes risk with higher cereal fiber intake (RR for extreme categories, 0.67 [95% CI, 0.62-0.72]), but no significant associations for fruit (0.96 [95% CI, 0.88-1.04]) and vegetable fiber (1.04 [95% CI, 0.94-1.15]). Magnesium intake was not related to diabetes risk in the European Prospective Investigation Into Cancer and Nutrition-Potsdam (RR for extreme quintiles, 0.99 [95% CI, 0.78-1.26]); however, meta-analysis showed a significant inverse association (RR for extreme categories, 0.77 [95% CI, 0.72-0.84])(3).

4. Dietary calcium and magnesium, major food sources, and risk of type 2 diabetes in U.S. black women
In a a prospective cohort study including 41,186 participants of the Black Women's Health Study without a history of diabetes who completed validated food frequency questionnaires at baseline, during 8 years of follow-up (1995-2003), we documented 1,964 newly diagnosed cases of type 2 diabetes, showed that
a diet high in magnesium-rich foods, particularly whole grains, is associated with a substantially lower risk of type 2 diabetes in U.S. black women(4).

5. Serum and dietary magnesium and the risk for type 2 diabetes mellitus
In the study to assess the risk for type 2 diabetes associated with low serum magnesium level and low dietary magnesium intake in a cohort of nondiabetic middle-aged adults (N = 12,128) from the Atherosclerosis Risk in Communities Study during 6 years of follow-up, found that aassessed the risk for type 2 diabetes associated with low serum magnesium level and low dietary magnesium intake in a cohort of nondiabetic middle-aged adults (N = 12,128) from the Atherosclerosis Risk in Communities Study during 6 years of follow-up(5).

6.  Associations of serum and urinary magnesium with the pre-diabetes, diabetes and diabetic complications in the Chinese Northeast population
In the study to investigate the association of Mg level in the serum or urine of the patients, lived in the Northeast areas of China, with either pre-diabetes or diabetes with and without complications, from January 2010 to October 2011, patients with type 1 diabetes (T1D, n = 25), type 2 diabetes (T2D, n = 137), impaired fasting glucose (IFG, n = 12) or impaired glucose tolerance (IGT, n = 15), and age/gender matched control (n = 50) enrolled in the First Hospital of Jilin University, showed that serum Mg levels in the patients with IGT, IFG, T2D, and T1D were significantly lower than that of control. The urinary Mg levels were significantly increased only in T2D and T1D patients compared to control. There was no difference for these two changes among T2D with and without complications; In addition, there was a significantly positive correlation of serum Mg levels with serum Ca levels only in T2D patients, and also a significantly positive correlation of urinary Mg levels with urinary Ca levels in control, IGT patients, and T2D patients. Simvastatin treatment in T2D patients selectively reduced serum Ca levels and urinary Mg levels(6).

7. Efficacy and safety of oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes
In the study to evaluate the efficacy and safety of oral magnesium supplementation, with magnesium chloride (MgCl2), in the treatment of newly diagnosed depression in the elderly with type 2 diabetes and hypomagnesemia, found that at baseline, there were no differences by age (69 +/- 5.9 and 66.4 +/- 6.1 years, p = 0.39), duration of diabetes (11.8 +/- 7.9 and 8.6 +/- 5.7 years, p = 0.33), serum magnesium levels (1.3 +/- 0.04 and 1.4 +/- 0.04 mg/dL, p = 0.09), and Yasavage and Brink Score (17.9 +/- 3.9 and 16.1 +/- 4.5 point, p = 0.34) in the groups with MgCl2 and imipramine, respectively. At end of follow-up, there were no significant differences in the Yasavage and Brink score (11.4 +/- 3.8 and 10.9 +/- 4.3, p = 0.27) between the groups in study; whereas serum magnesium levels were significantly higher in the group with MgCl2 (2.1 +/- 0.08 mg/dL) than in the subjects with imipramine (1.5 +/- 0.07 mg/dL), p < 0.0005. In conclusion, MgCl2 is as effective in the treatment of depressed elderly type 2 diabetics with hypomagnesemia as imipramine 50 mg daily(7).

8. The effect of magnesium supplementation on primary insomnia in elderly
In a double-blind randomized clinical trial conducted in 46 elderly subjects, randomly allocated into the magnesium or the placebo group and received 500 mg magnesium or placebo daily for 8 weeks with Questionnaires of insomnia severity index (ISI), physical activity, and sleep log completed at baseline and after the intervention period, showed that no significant differences were observed in assessed variables between the two groups at the baseline. As compared to the placebo group, in the experimental group, dietary magnesium supplementation brought about statistically significant increases in sleep time (P = 0.002), sleep efficiency (P = 0.03), concentration of serum renin (P < 0.001), and melatonin (P = 0.007), and also resulted in significant decrease of ISI score (P = 0.006), sleep onset latency (P = 0.02) and serum cortisol concentration (P = 0.008). Supplementation also resulted in marginally between-group significant reduction in early morning awakening (P = 0.08) and serum magnesium concentration (P = 0.06). Although total sleep time (P = 0.37) did not show any significant between-group differences(8).

9. Correlation of magnesium intake with metabolic parameters, depression and physical activity in elderly type 2 diabetes patients
In a cross-sectional study involved 210 type 2 diabetes patients aged 65 years and above with participants were interviewed to obtain information on lifestyle and 24-hour dietary recall. Assessment of depression was based on DSM-IV criteria, showed that among all patients, 88.6% had magnesium intake which was less than the dietary reference intake, and 37.1% had hypomagnesaemia. Metabolic syndromes and depression were associated with lower magnesium intake (p < 0.05). A positive relationship was found between magnesium intake and HDL-cholesterol (p = 0.005). Magnesium intake was inversely correlated with triglyceride, waist circumference, body fat percent and body mass index (p < 0.005). After controlling confounding factor, HDL-cholesterol was significantly higher with increasing quartile of magnesium intake (p for trend = 0005). Waist circumference, body fat percentage, and body mass index were significantly lower with increase quartile of magnesium intake (p for trend < 0.001). The odds of depression, central obesity, high body fat percentage, and high body mass index were significantly lower with increasing quartile of magnesium intake (p for trend < 0.05). In addition, magnesium intake was related to high physical activity level and demonstrated lower serum magnesium levels. Serum magnesium was not significantly associated with metabolic parameters(9).

10. Depressive symptoms and hypomagnesemia in older diabetic subjects
In the study to to assess the hypothesis that hypomagnesemia is associated with depressive symptoms in older people with diabetes, showed that serum magnesium levels were significantly lower among depressive than control diabetic subjects (0.74 +/- 0.25 vs. 0.86 +/- 0.29 mmol/L, p = 0.02). Twenty four (43.6%) and 7 (12.7%) individuals in the case and control group exhibited low serum magnesium levels (p = 0.0006). The adjusted logistic regression analysis showed an independent association between hypomagnesemia and depressive symptoms (OR 1.79; CI(95%) 1.1-6.9, p = 0.03)(10).

Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/23472169
(2) http://www.ncbi.nlm.nih.gov/pubmed/17645588
(3) http://www.ncbi.nlm.nih.gov/pubmed/17502538
(4) http://www.ncbi.nlm.nih.gov/pubmed/17003299
(5) http://www.ncbi.nlm.nih.gov/pubmed/10527292
(6) http://www.ncbi.nlm.nih.gov/pubmed/23418599
(7) http://www.ncbi.nlm.nih.gov/pubmed/19271419
(8) http://www.ncbi.nlm.nih.gov/pubmed/23853635
(9) http://www.ncbi.nlm.nih.gov/pubmed/22695027
(10) http://www.ncbi.nlm.nih.gov/pubmed/17845894

Magnesium and Muscles
1. Magnesium for skeletal muscle cramps
Skeletal muscle cramps are common and often presented to physicians in association with pregnancy, advanced age, exercise or disorders of the motor neuron (such as amyotrophic lateral sclerosis). In a andomized controlled trials (RCTs) of magnesium supplementation (in any form) to prevent skeletal muscle cramps in any patient group (i.e. all clinical presentations of cramp) and to considere comparisons of magnesium with no treatment, placebo control, or other therapy, found that it is unlikely that magnesium supplementation provides clinically meaningful cramp prophylaxis to older adults experiencing skeletal muscle cramps. In contrast, for those experiencing pregnancy-associated rest cramps the literature is conflicting and further research in this patient population is needed. We found no randomized controlled trials evaluating magnesium for exercise-associated muscle cramps or disease state-associated muscle cramps (for example amyotrophic lateral sclerosis/motor neuron disease)(1).

2. Clinical aspects and treatment of calf muscle cramps during pregnancy
According to the study by Riss P, Bartl W, and Jelincic D., muscle cramps were noticed most often in the second half of pregnancy. Gravidae with muscle cramps were on the average older and of higher parity; there was no relationship between muscle cramps and complications during pregnancy or unfavorable fetal outcome. In an uncontrolled therapeutic trial 21 women with muscle cramps received 1,8 g monomagnesium-aspartate twice daily per mouth for 4 weeks. 21 women with muscle cramps had no therapy. 4 weeks after the initiation of magnesium therapy 19/21 women were free of symptoms, compared to only 7/21 patients in the control group. Muscle cramps during pregnancy do not have to be considered a risk factor; they can be significantly improved by the administration of oral magnesium(2).

3. The effect of oral magnesium substitution on pregnancy-induced leg cramps
In the study to  to determine whether women with pregnancy-related leg cramps would benefit from oral magnesium supplementation, indicated that serum magnesium levels in these patients were at or below the lower reference limit, as is also often the case in healthy pregnant patients. Oral magnesium substitution decreased leg cramp distress (p < 0.05 compared with the placebo group, p < 0.001 compared with initial complaints), but did not significantly increase serum magnesium levels, excess magnesium being excreted as measured by an increase in urinary magnesium levels (p < 0.002). Oral magnesium supplementation seems to be a valuable therapeutic tool in the treatment of pregnancy-related leg cramps(3).

4. Pathophysiology and therapy of magnesium deficiency in pregnancy
In the study to determine serum magnesium(Mg)-levels in 67 pregnant women in late pregnancy. 42 gravidae complained of nightly muscle cramps; 21 of them received 1.8 g monomagnesiumaspartate twice daily per mouth for 4 weeks, found that serum Mg-levels were lower in pregnant women as compared to a control group of non pregnant women. Gravidae complaining of muscle cramps had significantly lower serum Mg-levels than women without muscle cramps. The administration of Mg was associated with a significant rise in serum Mg-levels as early as 2 weeks after the initiation of therapy.The Our study indicates that nightly muscle cramps during pregnancy might be a sign of a latent magnesium deficiency which can be influenced by oral magnesium(4).

5. Serum magnesium level in preterm labour
Preterm labour, (PTL) defined as labour after 28 weeks but before 37 completed week of gestation, is an ill omen for our country as the incidence is 5-10% leading to 70-80% of perinatal deaths. According to the study by the  Indira Gandhi Institute of Medical Sciences, varied hypomagnesemia was observed in Preterm labour cases (1.47 mg/dl +/- 0.22 S.D.), normal value of serum magnesium was found in normal non-pregnant ladies and slightly low value were observed in pregnant ladies of same gestational age. Age and parity had no significant effect on serum magnesium level in our study. As far as socio-economic study is concerned, it was found to be higher in high socio-economic group and low in lower group. Thus from this study it can be concluded that estimation of serum magnesium in pregnancy may prove to be a valuable tool in predicting preterm onset of labour(5).

6. Relationship between hypermagnesaemia in preterm labour and adverse health outcomes in babies
In the study of the Magnesium and Neurologic Endpoints Trial (the so-called MagNET Trial) undertaken to establish whether the antenatal usage of magnesium sulphate could protect neonates from having adverse neurologic outcomes, showed that unfortunately, the trial was suspended after 15 months of enrolment because of excess total paediatric mortality among those exposed to magnesium sulphate. Following our original report and contrary to the original hypotheses, additional analyses of our data have actually shown a statistically significant increase in the risk of neonatal intraventricular hemorrhage, as well as total adverse paediatric outcomes, among those with higher levels of ionized magnesium at delivery. Nonetheless, it has been postulated, but not established, that anions of magnesium other than sulphate could have a more benign, or even beneficial, effect on health outcomes in the neonate(6).

7. Nocturnal leg cramps
Up to 60 percent of adults report that they have had nocturnal leg cramps. The recurrent, painful tightening usually occurs in the calf muscles and can cause severe insomnia. According to the study by the St. Mark's Family Medicine Residency, nocturnal leg cramps are associated with vascular disease, lumbar canal stenosis, cirrhosis, hemodialysis, pregnancy, and other medical conditions. Medications that are strongly associated with leg cramps include intravenous iron sucrose, conjugated estrogens, raloxifene, naproxen, and teriparatide. A history and physical examination are usually sufficient to differentiate nocturnal leg cramps from other conditions, such as restless legs syndrome, claudication, myositis, and peripheral neuropathy. Laboratory evaluation and specialized testing usually are unnecessary to confirm the diagnosis. Limited evidence supports treating nocturnal leg cramps with exercise and stretching, or with medications such as magnesium, calcium channel blockers, carisoprodol, or vitamin B(12). Quinine is no longer recommended to treat leg cramps(7).

8. Stretching before sleep reduces the frequency and severity of nocturnal leg cramps in older adults
According to the study by the Hanze University of Applied Sciences, in the study of nighty adults aged over 55 years with nocturnal leg cramps who were not being treated with quinine, with the experimental group performed stretches of the calf and hamstring muscles nightly, immediately before going to sleep, for six weeks. The control group performed no specific stretching exercises. Both groups continued other usual activities, showed that nightly stretching before going to sleep reduces the frequency and severity of nocturnal leg cramps in older adults(8).

9. The effect of magnesium infusion on rest cramps
Rest cramps (also known as nocturnal leg cramps) are very common in a geriatric population. In a double blind, placebo controlled randomized controlled trial conducted on 46 community-dwelling older adult (69.3 ± 7.7 years) rest cramp sufferers to determine whether 5 consecutive days infusion of 20-mmol (5 g) magnesium sulfate would reduce the frequency of leg cramps per week in the 30 days immediately pre and post infusions and whether the response to treatment varied with the extent to which infused magnesium was retained (as measured by 24-hour urinary magnesium excretion), found that intravenous magnesium infusion did not reduce the frequency of leg cramps in a group of older adult rest cramp sufferers regardless of the extent to which infused magnesium was retained. Although oral magnesium is widely marketed to older adults for the prophylaxis of leg cramps, our data suggest that magnesium therapy is not indicated for the treatment of rest cramps in a geriatric population(9).

10. Muscle cramps--differential diagnosis and therapy
Calf cramps are sudden, involuntary, painful contractions of part of or the entire calf muscle that are visible, persist for seconds to minutes and then spontaneously resolve. According to the study by Kompetenzzentrum für Bewegungsstörungen, Paracelsusklinik Zwickau, Muscle cramps can occur with no identifiable cause, and are then referred to as common calf cramps. They may also be symptoms associated with diseases of the peripheral and central nervous system and muscle diseases. They also occur in association with metabolic disorders. In such cases the cramps are more extensive, intense and persist for longer. Cramp-fasciculation-myalgia syndrome additionally involves paresthesias and other signs of hyperexcitability of peripheral nerves. The recommended treatment for patients with frequent calf cramps causing significant impairment of well-being is oral administration of quinidine and/or botulinum toxin treatment of the calf muscles. During pregnancy both products are contraindicated, while probatory administration of magnesium is indicated(10).


Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/22972143
(2) http://www.ncbi.nlm.nih.gov/pubmed/6553557
(3) http://www.ncbi.nlm.nih.gov/pubmed/7631676
(4) http://www.ncbi.nlm.nih.gov/pubmed/6891868
(5) http://www.ncbi.nlm.nih.gov/pubmed/15022938
(6) http://www.ncbi.nlm.nih.gov/pubmed/12635881
(7) http://www.ncbi.nlm.nih.gov/pubmed/22963024
(8) http://www.ncbi.nlm.nih.gov/pubmed/22341378
(9) http://www.ncbi.nlm.nih.gov/pubmed/21289017
(10) http://www.ncbi.nlm.nih.gov/pubmed/19402333

Magnesium deficiency
1. Magnesium metabolism and its disorders
Magnesium is the fourth most abundant cation in the body and plays an important physiological role in many of its functions. Magnesium balance is maintained by renal regulation of magnesium reabsorption. According to the study by the Department of Chemical Pathology, St Thomas' Hospital, magnesium deficiency and hypomagnesaemia can result from a variety of causes including gastrointestinal and renal losses. Magnesium deficiency can cause a wide variety of features including hypocalcaemia, hypokalaemia and cardiac and neurological manifestations. Chronic low magnesium state has been associated with a number of chronic diseases including diabetes, hypertension, coronary heart disease, and osteoporosis. The use of magnesium as a therapeutic agent in asthma, myocardial infarction, and pre-eclampsia is also discussed. Hypermagnesaemia is less frequent than hypomagnesaemia and results from failure of excretion or increased intake. Hypermagnesaemia can lead to hypotension and other cardiovascular effects as well as neuromuscular manifestations(1).

2. Implications of magnesium deficiency in type 2 diabetes
Magnesium is the fourth most abundant cation in the body and plays an important physiological role in many of its functions. It plays a fundamental role as a cofactor in various enzymatic reactions involving energy metabolism. According to the study by the Punjab Agricultural University, magnesium is a cofactor of various enzymes in carbohydrate oxidation and plays an important role in glucose transporting mechanism of the cell membrane. It is also involved in insulin secretion, binding, and activity. Magnesium deficiency and hypomagnesemia can result from a wide variety of causes, including deficient magnesium intake, gastrointestinal, and renal losses. Chronic magnesium deficiency has been associated with the development of insulin resistance. The present review discusses the implications of magnesium deficiency in type 2 diabetes(2).


3. Magnesium (Mg) status in patients with cardiovascular diseases
Mg is an important cofactor for many enzymes especially those involved in phosphate transfer reactions. Mg is therefore essential in the regulation of the metabolism of other ions and cellular functionsé According to the study by the, deficiency has been shown to be associated with fatal cardiovascular diseases such as cardiac arrhythmias and coronary heart disease, as well as with risk factors for these diseases, such as hypertension, and diabetes mellitus. Our findings showed that serum total Mg was similar in all groups, but patients with arrhythmias and diabetes mellitus revealed lower levels of serum ionized Mg. On the other hand, patients with essential hypertension exhibited higher intraerythrocyte Mg concentrations than healthy controls(3).

4. Hypokalemia and hypomagnesemia in a cirrhotic patient. Correction of metabolic disorders by magnesium
According to the study by Bletry O, Certin M, Herreman G, Wechsler B, and Godeau P., there is a report of a case of a cirrhotic with severe hypokalemia (2 mEq/l) responding incompletely to attempts at correction by classical treatments. The findings of a serum and red cell magnesium deficiency led to administration of this electrolyte which proved efficacous. They then recall the mechanism of hypokalemia and hypomagnesemia in alcoholics, study the possible relationship between these abnormalities, their noxious effects and suggest a treatment(4).

5. Symptomatic hypomagnesemia in children

Hypocalcemia and hyperphosphatemia suggesting impaired parathyroid function were the most common electrolyte disorders. Hypokalemia was also frequently noted. The related symptoms including seizure, tetany, and weakness were common. According to the National Taiwan University Hospital, hypocalcemia and hyperphosphatemia suggesting impaired parathyroid function were the most common electrolyte disorders. Hypokalemia was also frequently noted. The related symptoms including seizure, tetany, and weakness were common. Drug-induced renal magnesium wasting was the most common cause of symptomatic hypomagnesemia, and tended to occur in older children using aminoglycoside, furosemide, and amphotericin-B. The associated gastrointestinal causes might add a minor contribution to the development of hypomagnesemia. Analyses of PTH levels in 13 children suggested that inhibition of PTH synthesis or secretion was responsible for hypomagnesemic hypocalcemia in most patients. However, peripheral PTH resistance might also account for the mechanism in a few patients. In most patients, symptomatic hypomagnesemia was transient, and improved after magnesium provision. Only one child with congenital renal magnesium wasting and two with primary hypomagnesemia needed long-term magnesium treatment(5).

6. Hypomagnesemia: an evidence-based approach to clinical cases
Hypomagnesemia is defined as a serum magnesium level less than 1.8 mg/dL (< 0.74 mmol/L). Hypomagnesemia may result from inadequate magnesium intake, increased gastrointestinal or renal losses, or redistribution from extracellular to intracellular space. Increased renal magnesium loss can result from genetic or acquired renal disorders. According to the Rush University Medical Center, Chicago, most patients with hypomagnesemia are asymptomatic and symptoms usually do not arise until the serum magnesium concentration falls below 1.2 mg/dL. One of the most life-threatening effects of hypomagnesemia is ventricular arrhythmia. The first step to determine the likely cause of the hypomagnesemia is to measure fractional excretion of magnesium and urinary calcium-creatinine ratio. The renal response to magnesium deficiency due to increased gastrointestinal loss is to lower fractional excretion of magnesium to less than 2%. A fractional excretion above 2% in a subject with normal kidney function indicates renal magnesium wasting. Barter syndrome and loop diuretics which inhibit sodium chloride transport in the ascending loop of Henle are associated with hypokalemia, metabolic alkalosis, renal magnesium wasting, hypomagnesemia, and hypercalciuria. Gitelman syndrome and thiazide diuretics which inhibit sodium chloride cotransporter in the distal convoluted tubule are associated with hypokalemia, metabolic alkalosis, renal magnesium wasting, hypomagnesemia, and hypocalciuria. Familial renal magnesium wasting is associated with hypercalciuria, nephrocalcinosis, and nephrolithiasis. Asymptomatic patients should be treated with oral magnesium supplements. Parenteral magnesium should be reserved for symptomatic patients with severe magnesium deficiency (< 1.2 mg/dL). Establishment of adequate renal function is required before administering any magnesium supplementation(6).

7. Abnormal renal magnesium handling
The normal fractional urinary excretion of filtered magnesium is about 5%. In magnesium deficiency in man, the kidneys can normally reduce the 24-hour urinary magnesium excretion to less than 1 mmol (24 mg) via unknown mechanisms, and initially without a fall in plasma magnesium concentration.  According to the University of British Columbia, congenital renal magnesium wasting occurs in several syndromes including Bartter's syndrome in which it is associated with hypercalciuria, and the defect may be in the thick ascending limb of Henle's loop, and Gitelman's syndrome in which there is hypocalciuria, and the defect may be in the distal convoluted tubule. Other causes of renal magnesium wasting include diabetes mellitus, hypercalcemia and diuretics. Magnesium wasting may also result from various toxicities including those of cis-platinum, in which the biochemical features resemble Gitelman's syndrome, and those of aminoglycosides, pentamidine and cyclosporin. Calcitriol deficiency may also contribute to renal magnesium wasting in some circumstances. Mild hypermagnesemia may occur in familial hypocalciuric hypercalcemia and may reflect abnormal sensitivity of the loop of Henle to calcium and magnesium ions. By contrast, the hypermagnesemia that occurs in chronic renal failure results from the reduced glomerular filtration of magnesium(7).

8. Hypomagnesemia: renal magnesium handling
Magnesium is an important constituent of the intracellular space that affects a number of intracellular and whole body functions. Magnesium balance depends on intake and renal excretion, which is regulated mainly in the thick ascending limb of the loop of Henle.  According to the University of Pennsylvania School of Medicine, hypomagnesemia may result from gastrointestinal losses or renal losses, the latter due to primary renal magnesium wasting or in association with sodium loss. Hypomagnesemia may arise together with and contribute to the persistence of hypokalemia and hypocalcemia. The major direct toxicity of hypomagnesemia is cardiovascular. When urgent correction of hypomagnesemia is required, as with myocardial ischemia, post cardiopulmonary bypass, and torsades de pointes, intravenous or intramuscular magnesium sulfate should be used. Oral magnesium preparations are available for chronic use(8).

9. Magnesium metabolism in health and disease
Magnesium (Mg) is the main intracellular divalent cation, and under basal conditions the small intestine absorbs 30-50% of its intake. Normal serum Mg ranges between 1.7-2.3 mg/dl (0.75-0.95 mmol/l), at any age. According to the study by Hospital Italiano de Buenos Aires, eEven though eighty percent of serum Mg is filtered at the glomerulus, only 3% of it is finally excreted in the urine. Altered magnesium balance can be found in diabetes mellitus, chronic renal failure, nephrolithiasis, osteoporosis, aplastic osteopathy, and heart and vascular disease. Three physiopathologic mechanisms can induce Mg deficiency: reduced intestinal absorption, increased urinary losses, or intracellular shift of this cation. Intravenous or oral Mg repletion is the main treatment, and potassium-sparing diuretics may also induce renal Mg saving. Because the kidney has a very large capacity for Mg excretion, hypermagnesemia usually occurs in the setting of renal insufficiency and excessive Mg intake. Body excretion of Mg can be enhanced by use of saline diuresis, furosemide, or dialysis depending on the clinical situation(9).

10. Magnesium deficiency: pathogenesis, prevalence, and clinical implications
Hypomagnesemia is probably the most underdiagnosed electrolyte deficiency in current medical practice. Patients with cardiovascular disease who are at greatest risk for the development of magnesium deficiency are those treated with diuretics or digitalis. According to the study by the, both potassium and magnesium deficiencies are associated with increased ventricular ectopy and may increase the risk of sudden unexpected death. Refractory potassium repletion can be caused by concomitant magnesium depletion, and can be corrected with magnesium supplementation. Routine serum magnesium determination is recommended whenever the testing of electrolyte levels is required, especially in patients taking diuretic drugs or digitalis. Because hypomagnesemia is not necessarily present in a magnesium-deficient state, it is recommended that both potassium and magnesium be repleted in patients with hypokalemia. Potassium-/magnesium-sparing diuretics may be helpful in the prevention of these electrolyte deficiencies(10).

Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/18568054
(2) http://www.ncbi.nlm.nih.gov/pubmed/19629403
(3) http://www.ncbi.nlm.nih.gov/pubmed/10375959
(4) http://www.ncbi.nlm.nih.gov/pubmed/198892
(5) http://www.ncbi.nlm.nih.gov/pubmed/9926514
(6) http://www.ncbi.nlm.nih.gov/pubmed/20081299
(7) http://www.ncbi.nlm.nih.gov/pubmed/8264509
(8) http://www.ncbi.nlm.nih.gov/pubmed/9459289
(9) http://www.ncbi.nlm.nih.gov/pubmed/19274487
(10) http://www.ncbi.nlm.nih.gov/pubmed/3565424

Magnesium and heart failure
1. Significance of magnesium in congestive heart failure
Electrolyte balance has been regarded as a factor important to cardiovascular stability, particularly in congestive heart failure. According to the study by the Irvine Medical Center,, magnesium is important as a cofactor in several enzymatic reactions contributing to stable cardiovascular hemodynamics and electrophysiologic functioning. Its deficiency is common and can be associated with risk factors and complications of heart failure. Typical therapy for heart failure (digoxin, diuretic agents, and ACE inhibitors) are influenced by or associated with significant alteration in magnesium balance. Magnesium therapy, both for deficiency replacement and in higher pharmacologic doses, has been beneficial in improving hemodynamics and in treating arrhythmias. Magnesium toxicity rarely occurs except in patients with renal dysfunction(1).

2. Magnesium in congestive heart failure, acute myocardial infarction and dysrhythmias
Magnesium plays an important role in the functioning of the cardiovascular system. According to the study by the Hackettstown Community Hospital, a decrease in magnesium has been linked with tachydysrhythmias, increased mortality in patients with congestive heart failure, and increased mortality after an acute myocardial infarction. The research shows that the use of magnesium supplements in these situations may be beneficial for treating and preventing life-threatening conditions. Magnesium supplements can be administered safely either orally or parenterally depending on the situation(2).

3. Potassium and magnesium depletions in congestive heart failure--pathophysiology, consequences and replenishment
Congestive heart failure (CHF) is becoming more frequent worldwide. According to the study by the Volgograd State Medical University, both potassium (K) and magnesium (Mg) deficiencies are common and can be associated with risk factors and complications of heart failure (HF). The major causes of K and Mg depletions are the effects of compensatory neuroendocrine mechanisms (activation of the renin-angiotensin-aldosterone and sympathoadrenergic systems), digoxin therapy, and administration of thiazide or loop diuretic therapy in CHF. Particular attention should be paid to K and Mg restoration in CHF, because of the consequences of both deficiencies (increased arrhythmic risk, vasoconstriction), and the co-supplementation of both ions is necessary in order to achieve K repletion. Mg and K should be employed as first-line therapy in digitalis intoxication and drug-related arrhythmias, and should be considered an important adjuvant therapy in diuretic treated patients with CHF. Another possibility to restore normal K and Mg status is usage of a K, Mg sparing diuretics(3).

4.  Calcium, magnesium and potassium intake and mortality in women with heart failure
In the study of the 161 808 participants in the Women's Health Initiative (WHI), we studied 3340 who experienced a HF hospitalisation to hypothesised that Ca, Mg and K would be inversely associated with mortality in people with HF, showed that intake was assessed using questionnaires on food and supplement intake. Hazard ratios (HR) and 95 % CI were calculated using Cox proportional hazards models adjusted for demographics, physical function, co-morbidities and dietary covariates. Over a median of 4·6 years of follow-up, 1433 (42·9 %) of the women died. HR across quartiles of dietary Ca intake were 1·00 (referent), 0·86 (95 % CI 0·73, 1·00), 0·88 (95 % CI 0·75, 1·04) and 0·92 (95 % CI 0·76, 1·11) (P for trend = 0·63). Corresponding HR were 1·00 (referent), 0·86 (95 % CI 0·71, 1·04), 0·88 (95 % CI 0·69, 1·11) and 0·84 (95 % CI 0·63, 1·12) (P for trend = 0·29), across quartiles of dietary Mg intake, and 1·00 (referent), 1·20 (95 % CI 1·01, 1·43), 1·06 (95 % CI 0·86, 1·32) and 1·16 (95 % CI 0·90, 1·51) (P for trend = 0·35), across quartiles of dietary K intake(4).

5. Functional reserves of the heart under conditions of alimentary magnesium deficit
In the study to assess functional reserves of myocardium in animals with deficit of magnesium during stress tests with magnesium deficit was modeled by 10 week long magnesium deficient diet, showed that
in animals with magnesium deficit we noted smaller increases of left ventricular pressure, myocardial contraction and relaxation rates under conditions of all functional tests, and of systolic arterial pressure during loading with volume and adrenaline. Lowering of myocardial reactivity under conditions of volume and adrenaline loading as well as isometric work load could constitute a basis of genesis of heart failure in magnesium deficit(5).

6. Complications of association magnesium sulfate with nicardipine during preeclampsia
There is a report of a heart failure and a collapse following concurrently administration of nicardipine and magnesium sulfate. These two drugs have potential negative inotropic effect and decrease systemic vascular resistance. Magnesium sulfate is the first-line treatment for the prevention of primary and recurrent eclamptic seizures. Combination with calcium channel blockers should be used cautiously, according to Service de gynécologie-obstétrique, centre hospitalier Franck-Joly(6).

7. Magnesium deficiency in heart failure patients with diabetes mellitus
In the study to assess the serum magnesium level in heart failure patients with diabetes mellitus conducted at Basic Medical Sciences Institute (BMSI), Jinnah Postgraduate Medical Centre (JPMC), Karachi, in collaboration with National Institute of Cardiovascular Diseases (NICVD), Karachi, from April 2003 to December 2003, showed that out of 45 cases of heart failure, 15 were diabetic. Of these, eleven (73.3%) had low serum magnesium (<1.8 mg/dl), one (6.7%) was within normal range (1.8-2.0 mg/dl) and three (20%) were in the high level range(>2.0 mg/dl). Low serum magnesium level in heart failure patients with diabetes mellitus(7).

8. Associations of dietary magnesium intake with mortality from cardiovascular disease
In the study to to investigate the relationship between dietary magnesium intake and mortality from cardiovascular disease in a population-based sample of Asian adults, based on dietary magnesium intake in 58,615 healthy Japanese aged 40-79 years, in the Japan Collaborative Cohort (JACC) Study, found that
dietary magnesium intake was inversely associated with mortality from hemorrhagic stroke in men and with mortality from total and ischemic strokes, coronary heart disease, heart failure and total cardiovascular disease in women. The multivariable hazard ratio (95% CI) for the highest vs. the lowest quintiles of magnesium intake after adjustment for cardiovascular risk factor and sodium intake was 0.49 (0.26-0.95), P for trend = 0.074 for hemorrhagic stroke in men, 0.68 (0.48-0.96), P for trend = 0.010 for total stroke, 0.47 (0.29-0.77), P for trend < 0.001 for ischemic stroke, 0.50 (0.30-0.84), P for trend = 0.005 for coronary heart disease, 0.50 (0.28-0.87), P for trend = 0.002 for heart failure and 0.64 (0.51-0.80), P for trend < 0.001 for total cardiovascular disease in women. The adjustment for calcium and potassium intakes attenuated these associations(8).

9. Parameters of mineral metabolism predict midterm clinical outcome in end-stage heart failure patients
In the study to investigate to which extent disturbances in mineral metabolism predict 90-day clinical outcome in end-stage heart failure patients, found that of the study cohort, 33.4% reached the primary endpoint. In detail, 19% were transplanted (the vast majority was listed "high urgent"), 8.8% died and 5.6% received MCS implants. As determined by logistic regression analysis, all aforementioned biochemical parameters were independently related to the primary endpoint. Results did not change substantially when transplanted patients were censored. A risk score (0-5 points) was developed. Of the patients who scored 5 points 89.5% reached the primary endpoint whereas of the patients with a zero score only 3.8% reached the primary endpoint. The data demonstrate that in addition to the well-known predictive value of disturbed sodium metabolism, derangements in calcium, phosphate, and magnesium metabolism also predict midterm clinical outcome in end-stage heart failure patients(9).

10. Magnesium and anabolic hormones in older men
Optimal nutritional and hormonal statuses are determinants of successful ageing. The age associated decline in anabolic hormones such as testosterone and insulin-like growth factor 1 (IGF-1) is a strong predictor of metabolic syndrome, diabetes and mortality in older men. Studies have shown that magnesium intake affects the secretion of total IGF-1 and increase testosterone bioactivity. In the study to  evaluate of 399 ≥65-year-old men of CHIANTI, a study population representative of two municipalities of Tuscany (Italy) with complete data on testosterone, total IGF-1, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS) and serum magnesium levels, showed that
after adjusting for age, magnesium was positively associated with total testosterone (β ± SE, 34.9 ± 10.3; p = 0.001) and with total IGF-1 (β ± SE, 15.9 ± 4.8; p = 0.001). After further adjustment for body mass index (BMI), log (IL-6), log (DHEAS), log (SHBG), log (insulin), total IGF-1, grip strength, Parkinson's disease and chronic heart failure, the relationship between magnesium and total testosterone remained strong and highly significant (β ± SE, 48.72 ± 12.61; p = 0.001). In the multivariate analysis adjusted for age, BMI, log (IL-6), liver function, energy intake, log (insulin), log (DHEAS), selenium, magnesium levels were also still significantly associated with IGF-1 (β ± SE, 16.43 ± 4.90; p = 0.001) and remained significant after adjusting for total testosterone (β ± SE, 14.4 ± 4.9; p = 0.01). In a cohort of older men, magnesium levels are strongly and independently associated with the anabolic hormones testosterone and IGF-1.© 2011 The Authors. International Journal of Andrology © 2011 European Academy of Androlo(10).










Sources
(1)  http://www.ncbi.nlm.nih.gov/pubmed/8800040
(2) http://www.ncbi.nlm.nih.gov/pubmed/8106895 
(3) http://www.ncbi.nlm.nih.gov/pubmed/16272623 
(4)  http://www.ncbi.nlm.nih.gov/pubmed/23199414
(5) http://www.ncbi.nlm.nih.gov/pubmed/23098349 
(6) http://www.ncbi.nlm.nih.gov/pubmed/22981126 
(7) http://www.ncbi.nlm.nih.gov/pubmed/22360033 
(8) http://www.ncbi.nlm.nih.gov/pubmed/22341866 
(9) http://www.ncbi.nlm.nih.gov/pubmed/21905973 
(10) http://www.ncbi.nlm.nih.gov/pubmed/21675994 

Magnesium and Bone health 
1. Nutrition and bone health. Magnesium and bone
Magnesium is related to a number of biological enzymatic reactions such as catalytic role for the reaction of kinases in ATP production. On the other hand, magnesium is one of the essential minerals for bone formation. According to the study by the National Institute of Health and Nutrition., in the magnesium-deficient rats, apparent bone loss caused by increase in bone resorption and decrease in bone formation was observed. Although, epidemiological studies suggest that magnesium deficiency is one of the risk factor for osteoporosis, a relationship between magnesium intake and bone mineral density is not clear. This may be due to the differences in the population, decrease in sex hormone secretion, and the possibility that magnesium-deficiency is also accompanied with another nutrient insufficiency, e.g., calcium(1).

2. Skeletal and hormonal effects of magnesium deficiency
Magnesium (Mg) is the second most abundant intracellular cation where it plays an important role in enzyme function and trans-membrane ion transport. Mg deficiency has been associated with a number of clinical disorders including osteoporosis. Osteoporosis is common problem accounting for 2 million fractures per year in the United States at a cost of over $17 billion dollars. The average dietary Mg intake in women is 68% of the RDA, indicating that a large proportion of our population has substantial dietary Mg deficits. In the study to review the evidence for Mg deficiency-induced osteoporosis and potential reasons why this occurs, including a cumulative review of work in our laboratories and well as a review of other published studies linking Mg deficiency to osteoporosis, showed that pidemiological studies have linked dietary Mg deficiency to osteoporosis. As diets deficient in Mg are also deficient in other nutrients that may affect bone, studies have been carried out with select dietary Mg depletion in animal models. Severe Mg deficiency in the rat (Mg at <0.0002% of total diet; normal = 0.05%) causes impaired bone growth, osteopenia and skeletal fragility. This degree of Mg deficiency probably does not commonly exist in the human population. We have therefore induced dietary Mg deprivation in the rat at 10%, 25% and 50% of recommended nutrient requirement. We observed bone loss, decrease in osteoblasts, and an increase in osteoclasts by histomorphometry. Such reduced Mg intake levels are present in our population(2).

3. Magnesium deficiency and osteoporosis: animal and human observations
Although osteoporosis is a major health concern for our growing population of the elderly, there continues to be a need for well-designed clinical and animal studies on the link between dietary magnesium (Mg) intake and osteoporosis. According to the study by the University of Southern California and The Orthopaedic Hospital, Los Angeles, relatively few animal studies have assessed the skeletal and hormonal impact of long-term low Mg intake; however, these studies have demonstrated that Mg deficiency results in bone loss. Potential mechanisms include a substance P-induced release of inflammatory cytokines as well as impaired production of parathyroid hormone and 1,25-dihydroxyvitamin D. Abnormal mineralization of bones may also contribute to skeletal fragility. Clinical studies have often varied greatly in study design, subject age, menopausal status and outcome variables that were assessed. Most studies focused on female subjects, thus pointing to the great need for studies on aging males. According to the U.S. Department of Agriculture, the mean Mg intake for males and females is 323 and 228 mg/day, respectively. These intake levels suggest that a substantial number of people may be at risk for Mg deficiency, especially if concomitant disorders and/or medications place the individual at further risk for Mg depletion(3).

4. Nutrition and bone health. Magnesium-rich foods and bone health
According to the study by the Kagawa Nutrition University, about 60% of magnesium in human body is present in the skeleton. Various foods are containing magnesium. The major sources are foods of plant origin like grain, vegetable and pulse. EAR (estimated average requirement) and RDA (recommended dietary allowance) are set for age 1 year or over in Japan. There may be a large number of people who have inadequate intake of magnesium judging by the results of the national nutrition survey. Adequate intakes of magnesium and also other nutrients related bone health are desired(4).

5. Magnesium and osteoporosis: current state of knowledge and future research directions
According to the study by the University of Milan,, a  tight control of magnesium homeostasis seems to be crucial for bone health. On the basis of experimental and epidemiological studies, both low and high magnesium have harmful effects on the bones. Magnesium deficiency contributes to osteoporosis directly by acting on crystal formation and on bone cells and indirectly by impacting on the secretion and the activity of parathyroid hormone and by promoting low grade inflammation. Less is known about the mechanisms responsible for the mineralization defects observed when magnesium is elevated. Overall, controlling and maintaining magnesium homeostasis represents a helpful intervention to maintain bone integrity(5).

6. Magnesium metabolism in 4 to 8 year old children




Magnesium (Mg) is a key factor in bone health, but few studies have evaluated Mg intake or absorption and their relationship with bone mineral content (BMC) or bone mineral density (BMD) in children. In the study to measure Mg intake, absorption, and urinary excretion in a group of children 4 to 8 yrs of age, found that a small, but significantly greater Mg absorption efficiency (percentage absorption) in males than females (67 ± 12% vs 60 ± 8%, p = 0.02) but no difference in estimated net Mg retention (average of 37 mg/day in both males and females). Relating dietary Mg intake to estimated Mg retention showed that an intake of 133 mg/day, slightly above the current Estimated Average Requirement (EAR) of 110 mg/day led to a net average retention of 10 mg/day, the likely minimum growth-related need for this age group. Covariate analysis showed that Mg intake and total Mg absorption, but not calcium intake or total absorption were significantly associated with both total body BMC and BMD. These results suggest that usual Mg intakes in small children in the United States meet dietary requirements in most but not all children. Within the usual range of children's diets in the United States, dietary Mg intake and absorption may be important, relatively unrecognized factors in bone health(6).

7. Maternal first-trimester diet and childhood bone mass
In the study to assess the association of maternal first-trimester dietary intake during pregnancy with childhood bone mass, showed that higher first-trimester maternal protein, calcium, and phosphorus intakes and vitamin B-12 concentrations were associated with higher childhood bone mass, whereas carbohydrate intake and homocysteine concentrations were associated with lower childhood bone mass (all P-trend < 0.01). Maternal fat, magnesium intake, and folate concentrations were not associated with childhood bone mass. In the fully adjusted regression model that included all dietary factors significantly associated with childhood bone mass, maternal phosphorus intake and homocysteine concentrations most-strongly predicted childhood bone mineral content (BMC) [β = 2.8 (95% CI: 1.1, 4.5) and β = -1.8 (95% CI: -3.6, 0.1) g per SD increase, respectively], whereas maternal protein intake and vitamin B-12 concentrations most strongly predicted BMC adjusted for bone area [β = 2.1 (95% CI: 0.7, 3.5) and β = 1.8 (95% CI: 0.4, 3.2) g per SD increase, respectively(7).

8. Magnesium intake mediates the association between bone mineral density and lean soft tissue in elite swimmers
In the study to o understand if Mg intake mediates the association between bone mineral density (BMD) and lean soft tissue (LST) in elite swimmers, showed that males presented lower values than the normative data for BMD. Mg, phosphorus (P) and vitamin D intake were significantly lower than the recommended daily allowance. A linear regression model demonstrated a significant association between LST and BMD. When Mg intake was included, we observed that this was a significant, independent predictor of BMD, with a significant increase of 24% in the R(2) of the initial predictive model. When adjusted for energy, vitamin D, calcium, and P intake, Mg remained a significant predictor of BMD. In conclusion, young athletes engaged in low impact sports, should pay special attention to Mg intake, given its potential role in bone mineral mass acquisition during growth(8).

9. Bone and nutrition in elderly women: protein, energy, and calcium as main determinants of bone mineral density
In a cross-sectional study of 136 healthy Caucasian, postmenopausal women, free of medications known to affect bone, with bone mineral density (BMD) and body composition (lean and fat tissue) were measured by dual X-ray absorptiometry using specialized software for different skeletal sites, showed that independent influence of calcium, energy, and protein, examined separately and in multiple regression models on BMD of several skeletal sites. Magnesium, zinc and vitamin C were significantly related to BMD of several skeletal sites in multiple regression models (controlled for age, fat and lean tissue, physical activity and energy intake), each contributing more than 1% of variance. Serum PTH and 25(OH)D did not show significant association with bone mass(9).

10. Evaluation of magnesium intake and its relation with bone quality in healthy young Korean women
In a study to  evaluate Mg intake in healthy adults and its relation with bone quality of a total of 484 healthy young women in their early 20s, with anthropometric measurements, dietary intake survey using 3-day dietary records, and the bone quality of the calcaneus using quantitative ultrasounds were obtained and analyzed and average age, height, and weight of the subjects were respectively 20.20 years, 161.37 cm, and 54.09 kg, respectively, showed that the subject's average intake of energy was 1,543.19 kcal, and the average Mg intake was 185.87 mg/day. Mg intake per 1,000 kcal of consumed energy in our subjects was 119.85 mg. Subjects consumed 63.11% of the recommended intake for Mg. Food groups consumed with high Mg content in our subjects included cereals (38.62 mg), vegetables (36.97 mg), milk (16.82 mg), legumes (16.72 mg), and fish (16.50 mg). The level of Mg intake per 1,000 kcal showed significant correlation to the SOS in the calcaneus (r = 0.110, p < 0.05) after adjustment for age, BMI, and percent body fat. In addition, the intakes of Mg from potatoes (p < 0.001), legumes (p < 0.05), and fungi and mushrooms (p < 0.05) positively correlated with the SOS of the calcaneus. Tthe magnesium intake status of young Korean women aged 19-25 years is unsatisfactory. Improving dietary intake of Mg may positively impact bone quality in this population(10).

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Sources
(1)  http://www.ncbi.nlm.nih.gov/pubmed/20445288
(2) http://www.ncbi.nlm.nih.gov/pubmed/19828898 
(3) http://www.ncbi.nlm.nih.gov/pubmed/15607643 
(4) http://www.ncbi.nlm.nih.gov/pubmed/20445289 
(5) http://www.ncbi.nlm.nih.gov/pubmed/23912329 
(6) http://www.ncbi.nlm.nih.gov/pubmed/23787702 
(7) http://www.ncbi.nlm.nih.gov/pubmed/23719545 
(8) http://www.ncbi.nlm.nih.gov/pubmed/23015157 
(9) http://www.ncbi.nlm.nih.gov/pubmed/12700617 
(10) http://www.ncbi.nlm.nih.gov/pubmed/21465282