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Journal of the American College of Nutrition, Vol. 26, No. 2, 121-132 (2007)
Published by the American College of Nutrition

Dietary Magnesium Deficiency Induces Heart Rhythm Changes, Impairs Glucose Tolerance, and Decreases Serum Cholesterol in Post Menopausal Women

Forrest H. Nielsen, PhD, David B. Milne, PhD**, Leslie M. Klevay, MD*, Sandra Gallagher, BS and LuAnn Johnson, MS

US Department of Agriculture a,b, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota
a The US Department of Agriculture, Agricultural Research Service, Northern Plains Area, is an equal opportunity/affirmative action employer, and all agency services are available without discrimination
b Mention of a trademark or proprietary product does not constitute a guarantee or warranty by the US Department of Agriculture and does not imply its approval to the exclusion of other products that also might be suitable

Address reprint requests to: Forrest H. Nielsen, PhD, USDA, ARS, Grand Forks Human Nutrition Research Center, PO Box 9034, Grand Forks, ND, 58202-9034. E-mail: fnielsen{at}gfhnrc.ars.usda.gov


   ABSTRACT
TOP
 FOOTNOTES
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Objective: To determine whether or not dietary magnesium restriction to about 33% of the Recommended Dietary Allowance (RDA) causes changes in glucose, cholesterol and electrolyte metabolism that could lead to pathologic consequences.

Design: The length of the experiment was 136 days. Subjects were fed a basal Western-type diet that provided 4.16 mmol (101 mg) magnesium per 8.4 MJ (2000 kcal) for 78 days then replenished with magnesium by supplementing the diet with 200 mg magnesium as the gluconate per day for 58 days. If a subject exhibited adverse heart rhythm changes before 78 days of depletion were completed, she entered the repletion period early.

Setting: The metabolic research unit of the Grand Forks Human Nutrition Research Center.

Subjects: A total of 14 post menopausal women were recruited by advertisement throughout the United States. Thirteen women (ages 47 to 75 years) completed the study.

Results: During magnesium depletion, heart rhythm changes appeared in 5 women and resulted in 4 prematurely entering the magnesium repletion period (42 to 64 days of depletion instead of 78). Three women exhibited atrial fibrillation and flutter that responded quickly to magnesium supplementation. Magnesium deprivation resulted in a non-positive magnesium balance that became highly positive with magnesium repletion. Magnesium deprivation decreased red blood cell membrane magnesium, serum total cholesterol and erythrocyte superoxide dismutase concentrations, increased the urinary excretion of sodium and potassium, and increased serum glucose concentration.

Conclusions: Magnesium balance may be a suitable indicator of magnesium depletion under experimental conditions. Magnesium deficiency resulting from feeding a diet that would not be considered having an atypical menu induces heart arrhythmias, impairs glucose homeostasis, and alters cholesterol and oxidative metabolism in post menopausal women. A dietary intake of about 4.12 mmol (100 mg) Mg/8.4 MJ is inadequate for healthy adults and may result in compromised cardiovascular health and glycemic control in post menopausal women.

Key words: magnesium deficiency, magnesium balance, heart arrhythmia, glucose tolerance, cholesterol


   INTRODUCTION
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Epidemiological surveys, supplementation trials, and animal studies have suggested that magnesium deficiency in humans may result in impaired glucose, lipid and electrolyte metabolism. Because of these impairments, magnesium deficiency has been suggested to be a factor in some cardiac arrhythmias, changing lipid metabolism conducive to increased risk of cardiovascular disease, and contributing to complications of diabetes. However, direct evidence that primary dietary magnesium deficiency of a severity similar to that which may occur in the general population (e.g., 10% of women over the age of 70 yr consume less than 42% of the RDA) provokes changes in glucose, lipid and electrolyte metabolism that result in pathologic consequences is limited.

There are numerous reports indicating that hypomagnesmia may be associated with complications in diabetic patients [1]. However, whether the hypomagnesmia is a cause or an effect of diabetes is uncertain [2]. Some studies have shown that magnesium deficiency in otherwise healthy adults impairs some aspects of blood glucose homeostasis. Nadler et al [3] fed 12 normal subjects a liquid diet providing only 0.5 mmol (12 mg) Mg/d for four weeks. The diet reduced both serum and red blood cell magnesium and decreased insulin sensitivity during an intravenous glucose tolerance test (IVGTT). Paolisso et al [4] in a double blind, randomized, crossover study gave a placebo or a supplement providing 16.2 mmol (394 mg) Mg/d to 12 elderly subjects with low erythrocyte magnesium concentration. The magnesium supplement increased erythrocyte magnesium concentration and improved insulin response and action during an IVGTT. They also stated that the increase in erythrocyte magnesium significantly and positively correlated with a decrease in erythrocyte membrane microviscosity and with total-body and oxidative glucose metabolism. In healthy adults, an acute oral load of magnesium (30 mmol or 730 mg) after an overnight fast induced a decrease in blood glucose concentrations four hours after the magnesium ingestion, apparently by increasing insulin sensitivity [5].

Although magnesium deficiency has been suggested to be a factor in the development of cardiovascular disease partly through increasing circulating concentrations of cholesterol and cholesterol fractions in humans [6,7], support for this suggestion is not strong. In order to show that magnesium deficiency affects serum cholesterol in rats, experiments had to be long-term, use pair-feeding techniques with severe deficiency, or required high dietary cholesterol [8]. Instead of an increase, a decrease in serum cholesterol concentration was found with magnesium deprivation in one human study [9]. Animal studies also suggested that hypertriglyceridemia may be a sign of magnesium deficiency [8]. However, like with cholesterol, changes in triglycerides induced by magnesium deficiency were dependent upon the presence of certain experimental and dietary conditions. Thus, the effect of dietary magnesium deprivation on lipid metabolism in humans has not been clearly defined.

There are numerous reports indicating that magnesium has a role in maintaining normal heart rhythm. One study found that low dietary magnesium increased supraventricular ectopy in postmenopausal women [10]. Also, acute high doses of magnesium have been used to successfully convert atrial fibrillation to sinus rhythm and to overcome multifocal atrial tachycardia [11]. Hypomagnesemia can increase the risk of supraventricular and ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation [12,13]. Some of these dysrhythmias may be the result of an imbalance in electrolytes such as potassium, sodium and calcium caused by low dietary magnesium [14].

Although magnesium deficiency caused by drugs and disease is not rare [15], deficiency caused by dietary restriction has been questioned. One expert group stated that a "dietary deficiency of magnesium of a severity sufficient to provoke pathologic change is rare" [16]. Other magnesium experts have concluded that chronic primary magnesium deficiency occurs frequently and has various pathological consequences resulting from altered carbohydrate, lipid and electrolyte metabolism [7,17,18]. The objective of the experiment described in this report was to determine if an inadequate magnesium intake (about 30% of the RDA) achieved through a diet that would not be considered having an atypical menu can cause changes in glucose, cholesterol and electrolyte metabolism. As a result, dietary magnesium deficiency causing pathologic consequences may be of more significance than currently acknowledged.


   SUBJECTS AND METHODS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
Fourteen post-menopausal women were recruited for the study after they had been informed in detail both verbally and in writing about the nature of the research and associated risks, and after medical, psychological, and nutritional evaluation had established that they were healthy and emotionally suited for the project. One subject decided not to enter the study. The 13 women (12 Caucasian and 1 African-American) who completed the study were not on hormone replacement therapy, did not smoke, and had a mean age 61.8 ± 8.2 (range of 47 to 75 years with five aged 65 years or older). The women ranged in height from 149.7 to 167.7 cm, in weight from 49.9 to 96.8 kg and in body mass index of 19.9 to 34.4 (mean of 25.5 with only one woman greater than 30). Before entry into the study, a physical examination in a local clinic that included a pap smear, lung x-ray, tuberculosis test and electrocardiogram (EKG), and laboratory tests to assess liver, kidney and thyroid function established that the women had no underlying disease. The subjects resided for the entire study in the metabolic research unit of the Grand Forks Human Nutrition Research Center that provided a common environment for strict control of food consumption, weight, exercise, and data collection. Subjects consumed only food and beverages provided by the dietary staff and were chaperoned on all outings from the metabolic unit to ensure compliance with the study protocol.

The participants gave their written informed consents to participate in the experimental protocol that was approved by the Institutional Review Board of the University of North Dakota and the Human Studies Review Committee of the United States Department of Agriculture, and followed the guidelines of the Department of Health and Human Services and the Helsinki Doctrine regarding the use of human subjects.

Experimental Protocol
Because potentially harmful electrocardiographic changes have been found in people deficient in magnesium [10–14], a 20-hr EKG using a Holter Recorder was performed on each volunteer every two weeks during the study. Tapes obtained were machine (Model 363, Accuplus, Del Mar Avionics, Irvine, CA) scanned for signs of abnormal rhythm by trained nurses under the direction of a physician who confirmed the findings of the nurses. If the EKG showed a significant increase (four times baseline obtained from the initial two Holter EKGs) in ventricular premature discharges, the appearance of AV heart blocks, or the appearance of atrial flutter and fibrillation, the change was confirmed by immediately performing another Holter EKG. Confirmation of one these changes while consuming the low magnesium diet prompted a premature entry into the magnesium repletion dietary period.

Because magnesium deficiency has been correlated with hypertension [19], blood pressures were measured daily during the study. Upon wakening in the morning, each volunteer would notify by intercom the on-duty nurse trained in blood pressure measurement. The nurse then went to the room of each woman and determined their blood pressure by using a mercury sphygmomanometer while she was lying in bed. If the volunteer had to use the toilet upon wakening, she was required to return to her bed and recline for 20 minutes before her blood pressure was determined.

Upon arrival in the metabolic unit, all women immediately began consuming the basal magnesium-deficient diet. The original design of the experiment was to have the magnesium deprivation period to last 93 days, but because of heart arrhythmias, this was shortened to 78 days. The subjects were replenished with magnesium for 58 days by supplementing the diet with 8.23 mmol (200 mg) of magnesium as magnesium gluconate per day. The supplementation resulted in a magnesium intake near the 1989 U.S. Recommended Dietary Allowance (RDA) of 11.52 mmol (280 mg) per day [20] that was in place at the time of the study. Two of the women were fed an additional 4.12 mmol (100 mg) of magnesium per day for four weeks because increased ventricular premature discharges (VPD) did not quickly return to baseline.

The diet used in the study was based on ordinary Western foods and is shown in Table 1. A three-day menu rotation was used to give some variety but assured that variation in nutrient intake was not consequential. As shown in Table 2 the diet supplied approximately 101 mg (4.16 mmol) magnesium per 8.4 KJ (2,000 kcal). This intake was near the first percentile intake of women aged over 51 years according to the 1994 Continuing Survey of Food Intake of Individuals (CSFII) [21]. The diet energy distribution was 9.7% protein, 36.1% fat and 54.2% carbohydrate. The diet was based on the 1989 Recommended Dietary Allowances (RDA) [20] because it was formulated before the issuance of the current Dietary Reference Intakes. To assure adequacy, supplements were used for nutrients present in low or unknown quantities in the diet. These supplements were (per day) 625 mg (16 mmol) potassium as potassium chloride, 270 mg (6.74 mmol) calcium as calcium gluconate, 20 mg (0.36 mmol) iron as ferrous gluconate, 6 mg zinc (92 µmol) as zinc sulfate, 1.1 mg (17 µmol) copper as copper sulfate, 0.33 mg boron (31 µmol) as boric acid, 133 µg (301 mmol) of folic acid, 100 µg biotin, and 400 IU of vitamin D3. Although formulating a diet low in magnesium resulted in a relatively low protein intake of 48 g/8.4 KJ, the protein intake of all women was near the RDA of 46 mg/d. Dietary iron was provided in excess of the RDA to mitigate the decline in iron status as a result of phlebotomy during the experiment. All food was weighed with an accuracy of 0.1 g during preparation in the metabolic kitchen and was completely consumed by the subjects with the aid of spatulas and rinse bottles. Deionized water was consumed ad libitum. The initial energy requirement for each subject was determined by using the Harris and Benedict equation [22] and adding 50% to compensate for normal daily activities. Individually prescribed exercise was performed three times weekly to maintain body composition and physical work capacity. Energy intake was adjusted in 0.84 KJ (200 kcal) increments during the course of the study to maintain body weight (measured daily) within ± 2% of admission weight.


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  		Table 1. Food Composition of the 3-Day Rotation Diet

 

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  		Table 2. Calculated and Analyzed Nutrient Composition of the Diet per 8.4 MJ (2000 kcal)

 
For magnesium balance determinations, duplicate diets of 8.4 MJ (2,000 kcal) were prepared daily for analysis and blended in a plastic blender with stainless steel blades. Urine and feces were collected in plastic containers and bags, respectively, to avoid mineral contamination. Venous blood, collected in plastic syringes from antecubital veins that had been distended by the temporary use of a tourniquet after the subjects had fasted for 12 hr, was obtained weekly for routine health assessment and mineral and cholesterol determinations; additional blood was obtained during weeks 3, 6, 9, 11 and 13 for the determination of other experimental variables, and during week 12 of depletion and week 6 of repletion for an intravenous glucose tolerance test (IVGTT). Total blood collected was limited to ≤250 mL/mo.

At the time the Holter EKGs were performed, standard neuromuscular magnesium deficiency tests, checking for Trousseau's and Chvostek's signs (reflexes) were done. The test for Trousseau's sign involves inflating a sphygmomanometer cuff to 10 mm above systolic blood pressure and holding this pressure for two minutes. Carpal spasm with relaxation 5 to 10 s after deflation is considered positive. The test for Chvostek's sign involves tapping the facial nerve just anterior to the ear lobe and just below the zygomatic arch (or between the arch and the corner of the mouth). A positive response ranges from a simple twitching of the corner of the mouth to a twitching of all facial muscles on the stimulated side.

Laboratory Methods
The magnesium content of 6-d composites of diets and feces were determined throughout the experiment by inductively coupled argon plasma emission spectroscopy (ICAP) (Jarrell-Ash Atom Comp 1140, Thermo Elemental, Franklin, MA) [23] after wet digestion of lyophilized blended samples with nitric and perchloric acids [24]. Urinary minerals (magnesium, calcium, sodium, and potassium) were determined by ICAP of a diluted aliquot. For diets and feces, concurrent replicate analysis of a standard reference material, NIST 1577a bovine liver (National Institute of Standards and Technology, Gaithersburg, MD) yielded a mean ± standard deviation of 568 ± 12 µg/g compared with certified values (means ± confidence values) of 600 ± 15 µg/g for magnesium. For urine, concurrent replicate analysis of UriChem 1 & 2 (Fisher Scientific, Orangeburg, NY) yielded a mean ± standard deviation of 167 ± 10 mg/L compared with a certified value of 160 ± 58 mg/L. Magnesium balance was calculated as the difference between intake and excretion (feces plus urine) for all days and for the last 36 days of each dietary period. The 36-d data are presented because they correspond to the time that the biochemical variables that were statistically compared were determined. The balance or retention calculations did not include surface or phlebotomy losses.

Blood was processed within 90 min to obtain serum or plasma. The blood was allowed to clot for 20 min before centrifuging at 2000 RPM for 10 min to obtain serum. To determine the amount of magnesium in serum loosely bound to albumin and more tightly bound to {alpha}-macroglobulin, the {alpha}-macroglobulin was precipitated from serum with polyethylene glycol 6000 (PEG). The PEG solution was prepared by adding 100 g PEG, 3.03 g (50 mmol) Tris and 0.1 g sodium azide to 400 mL of deionized water. The pH was adjusted to 7.1 with glacial acetic acid before filtering through a 0.45 µm Millipore filter (Millipore, Bedford, MA). The PEG solution was stored at 0° to 4°C. A 0.5 mL aliquot of clear serum was transferred to each of four tubes; 1.5 mL of 6.7% trichloroacetic acid (TCA) was added to two of the tubes for duplicate analysis of serum total magnesium. For obtaining the albumin fraction in duplicate, 0.5 mL of the PEG reagent was added to each of two tubes. All tubes were centrifuged at 2550 RPM for 30 min. An aliquot of 0.5 mL was taken from each of the tubes containing PEG and placed in a separate set of tubes to which 0.5 mL of 10% TCA solution was added before centrifuging again at 2550 RPM for 30 min; the supernatant contained the albumin-bound magnesium. The ultrafiltrable fraction of serum was obtained from serum that was collected under anaerobic conditions. The Millipore Ultrafree-PF system (Cat. No. UFP1 TGC 24, Millipore, Bedford, MA) was used to obtain the ultrafiltrate. One mL of serum was placed in the filter cup before being capped tightly with and pressured applied through the top cap by a 30 mL syringe with a luer lock hub. Pressure was maintained by using a wide rubber band extending over the top of the syringe and surrounding the lower sample collection cup. The assembly was placed in a refrigerator at 4°C for 3 days to obtain the ultrafiltrable serum fraction. The total serum, albumin-bound, and ultrafiltrable magnesium concentrations were determined by ICAP. Concurrent analysis of Sera Chem controls (Fisher Scientific, Orangeburg, NY) yielded the value of 21.1 ± 1.6 mg/L compared with the certified value of 22.4 ± 6.2 mg/L for magnesium. The {alpha}-macroglobulin-bound magnesium was calculated as the difference between total serum and albumin-bound magnesium. The method of Dodge et al [25] was used to obtain red blood cell membranes from 10 mL of blood collected using EDTA as the anticoagulant. The protein content of the membranes was determined by using a commercially available kit (Biorad Protein Kit #500-0006, Standard #500-0007, Biorad, Hercules, CA). Each membrane sample was diluted by a factor of 5 with deionized water before analyzing for magnesium by ICAP.

Red blood cell number, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), hemoglobin concentration and hematocrit of blood were determined by using a Coulter Counter (Model S+4, Coulter Electronics, Hialeah FL). Serum total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, iron, sodium and potassium were determined by standard methods using the Cobas Fara Centrifugal Analyzer (Roche Diagnostics Systems, Sommerville, NJ). Dividing triglyceride values by five indicates the serum concentration of very low-density lipoprotein (VLDL) [26] and low-density lipoprotein (LDL)-cholesterol was calculated by difference between total cholesterol and other cholesterol fractions. Commercially available kits were used to determine ferritin (CA590 Gamma DAB, Baxter Travenol Diagnostic, Inc., Cambridge, MA) and aldosterone (TKAL 1, Diagnostic Products, Los Angeles, CA). Erythrocyte superoxide dismutase (ESOD) was determined by using the method of Winterbourne et al [27].

The IVGTT determination was made after an overnight fast. A glucose load of 0.5 g/kg body weight in 110 mL of water was infused into an antecubital vein of one arm. Blood was obtained from the contralateral arm by using a butterfly needle tubing system. Blood for serum insulin and glucose and plasma glucagon was taken at 0, 2.5, 5, 10, 20, 30, 45 and 60 minutes after glucose infusion. Serum glucose was determined by using the standard method of Cobas Fara Centrifugal Analyzer (Roche Diagnostic Systems, Sommerville, NJ). Commercially available radioimmunoassay kits were used to determine insulin (TKIN 1, Diagnostic Products Corp., Los Angeles, CA) and glucagon (Kit #133, ICN Biomedical, Inc., Carson, CA).

Data Analysis
All balance and biochemical determinations made during the last 36 days in each dietary period were used in the statistical analyses. These determinations were used because longitudinal graphing of primary variables of interest (Figs. 1–4) showed that the response to the low and supplemental dietary magnesium had occurred during the last five weeks of each dietary period. Figs. 1–4 also indicate the baseline or initial values for the primary variables of interest. The data were analyzed by repeated measures analysis of variance with a SAS general linear model program (SAS 8.02, SAS Institute, Cary, NC). A p ≤ 0.05 was considered significant. Variances in the data are expressed as a pooled standard deviation, calculated as the square root of the mean square error from the analysis of variance.


Figure 1
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  		Fig. 1. Erythrocyte membrane magnesium concentrations. +Value does not contain four subjects that began magnesium repletion after 42, 52 and 64 days of magnesium depletion.

 

Figure 4
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  		Fig. 4. Erythrocyte superoxide dismutase concentrations. +Value does not contain four subjects that began magnesium repletion after 42, 52 and 64 days of magnesium depletion.

 

   RESULTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
During the low dietary magnesium period, heart rhythm changes appeared in 4 of the 13 subjects that resulted in premature entry into the magnesium repletion dietary period (Table 3). When the fifth subject showed a heart rhythm at 75 days, all remaining subjects started the magnesium repletion period after 78 days of deprivation. All the heart rhythm changes were confirmed by a repeat 20-hour Holter EKG. The first woman (age 59.5 years) began the magnesium repletion period after 42 days of deprivation because of the appearance of atrial flutter and fibrillation. These heart rhythm changes disappeared two weeks after the magnesium repletion was started and did not reappear for the remainder of the study. After 52 days of magnesium deprivation, two more subjects showed heart rhythm changes. One subject (age 67.3 years) exhibited increased ventricular premature discharges (VPDs) and second degree AV heart blocks of Mobitz types I and II. Her last Holter EKG in the magnesium repletion period showed neither of these arrhythmias. The second subject (age 75.3 years) exhibited increased VPDs; the number of VPDs decreased by the end of magnesium repletion but did not reach baseline levels. After 64 days of magnesium depletion, a subject (age 65.2 years) exhibited atrial flutter and fibrillation that disappeared shortly after magnesium repletion and did not reappear. At 75 days, another subject (age 47.2 years) exhibited an increase in VPDs and atrial flutter. The atrial flutter disappeared two weeks after magnesium repletion began and the VPDs declined to below baseline at the end of the magnesium repletion period. Although it did not prompt a premature entry into the magnesium repletion period, one subject (age 67.0 years) exhibited occasional supraventricular tachycardia during magnesium deprivation period; she did not exhibit this during the magnesium repletion period.


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  		Table 3. Heart Rhythm Changes Prompting Premature Entry into Magnesium Repletion Period per Protocol Design

 
Blood pressure was not significantly affected by magnesium depletion. During the last five weeks of depletion and repletion the mean systolic/diastolic pressures of the 13 volunteers were 114/70 mm and 113/70 mm, respectively. However, the volunteer that showed heart rhythm changes after 42 days of depletion had an elevated mean blood pressure of 146/89 mm during depletion that decreased to an average 126/81 mm during the last five weeks of magnesium repletion. This decrease was countered by small unremarkable increases in blood pressure during magnesium repletion in some women (including two women that exhibited heart rhythm changes) whose mean systolic pressure during depletion did not exceed 122 mm and mean diastolic pressure did not exceed 75 mm.

Table 4 shows that magnesium balance was positive when the diet provided an average of 12.67 to 13.13 mmol (308 to 319 mg) Mg/d. Urinary magnesium excretion was significantly decreased when the diet provided a mean of only 4.28 to 4.44 mmol (104 to 108 mg) Mg/d. This homeostatic response was not enough to prevent a non-positive (negative value but not significantly different than zero) magnesium balance based on just fecal and urine excretion during the magnesium depletion dietary period. Including estimated blood and surface losses (~0.08 mmol/d), the volunteers lost between 5 and 10 mg (0.2 and 0.4 mmol) Mg/d during the magnesium depletion period.


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  		Table 4. Mean Magnesium Balance during Magnesium Depletion and Repletion

 
Red blood cell membrane magnesium was also significantly lower at the end of magnesium deprivation than the end of magnesium repletion (Table 5). Fig. 1 shows that red blood cell membrane magnesium concentration increased during the magnesium repletion period. Fig. 2 indicates that serum magnesium concentration responded differently than red blood cell membrane concentration to magnesium deprivation. Initially, serum magnesium decreased, but rebounded to the admission value on day 40 and appeared to decline slightly the last 20 days of the magnesium deprivation period. Consuming the diet providing 12.67 to 13.13 mmol (308 to 319 mg) Mg/d did not increase the serum magnesium concentration. If just the last five weeks in each dietary period are used for the comparison, serum magnesium concentration was higher during magnesium depletion than repletion (Table 5). Both the albumin-bound and macroglobulin serum fractions were involved in this significant serum difference (Table 5). Ultrafiltrable magnesium was not significantly affected by the dietary magnesium.


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  		Table 5. Effect of Magnesium Depletion and Repletion on Blood Magnesium Variables Determined the Last Five Weeks in Each Dietary Period for Each Subject

 

Figure 2
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  		Fig. 2. Plasma magnesium concentrations. *Value does not contain two subjects that began magnesium repletion after 42 and 52 days of magnesium depletion. +Value does not contain four subjects that began magnesium repletion after 42, 52 and 64 days of magnesium depletion.

 
Table 6 indicates that the high iron supplementation of the diet prevented a marked change in iron status. Hemoglobin, red blood cell number, and plasma iron concentration were not significantly different during the last 5 weeks of magnesium depletion and repletion. Both hematocrit and serum ferritin were decreased slightly, but the ferritin values were not in the deficient range. Both MCH and MCHC were significantly higher during magnesium repletion than depletion; this finding probably reflects the significant decrease in MCV during magnesium repletion.


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  		Table 6. Effect of Magnesium Depletion and Repletion on Red Blood Cell and Iron Variables Determined the Last Five Weeks of Each Dietary Period for Each Subject

 
Fig. 3 shows that serum total cholesterol declined slightly during the magnesium deprivation period. Twenty days after magnesium repletion started, serum cholesterol increased and remained rather constant until the end of the study. Table 7 shows that the mean serum total cholesterol the last five weeks of depletion was significantly lower than in the similar period of magnesium repletion. Most of the change was in the LDL-cholesterol fraction. Magnesium depletion slightly decreased the serum triglyceride concentration also. Table 7 also shows that erythrocyte superoxide dismutase (ESOD) was higher during the last weeks of magnesium repletion than depletion. The time course of the change in ESOD is shown in Fig. 4.


Figure 3
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  		Fig. 3. Serum total cholesterol concentrations. *Value does not contain two subjects that began magnesium repletion after 42 and 52 days of magnesium depletion. +Value does not contain four subjects that began magnesium repletion after 42, 52 and 64 days of magnesium depletion.

 

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  		Table 7. Effect of Magnesium Depletion and Repletion on Serum Total Cholesterol, Cholesterol Fractions, Triglycerides, and Erythrocyte Superoxide Dismutase (ESOD) Determined the Last Five Weeks of Each Dietary Period for Each Subject

 
Dietary magnesium did not significantly affect serum aldosterone, sodium and potassium concentrations, and urine calcium concentration (Table 8). However, based on 24-h urine determinations, both urinary sodium and potassium were significantly lower during magnesium depletion than repletion.


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  		Table 8. Effect of Magnesium Depletion and Repletion on Urinary and Serum Sodium, Potassium and Aldosterone Determined the Last Five Weeks of Each Dietary Period for Each Subject

 
The glucose, insulin and glucagon responses to the glucose tolerance test are shown in Figs. 5–7. These figures show that fasting serum glucose was higher during magnesium depletion than repletion. In the IVGTT test during magnesium depletion, serum glucose rose to a higher concentration and remained higher until the end of the test than during the magnesium repletion (Fig. 5). Thus, the area under the curve for glucose was significantly greater (p < 0.006) during magnesium depletion than repletion. However, the rate of glucose decrease in the IVGTT test was not significantly affected by magnesium deprivation, nor was the insulin response (Fig. 6). At the start of the IVGTT test, basal serum glucagon concentration was not different during the two dietary periods. A few minutes after glucose infusion, plasma glucagon decreased in the magnesium depletion dietary period, and increased in the magnesium repletion period such that average glucagon concentration was significantly lower (p < 0.02) during magnesium deprivation.


Figure 5
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  		Fig. 5. Serum glucose concentrations of 10 volunteers from which blood was collected for each time period in and IVGTT test during magnesium depletion and repletion. The area under the curve was significantly different (p < 0.006), but the glucose disappearance rate was not significantly different, between the magnesium depletion and repletion periods.

 

Figure 7
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  		Fig. 7. Serum glucagon concentrations of 10 volunteers from which blood was collected for each time period in an IVGTT test during magnesium depletion and repletion. The mean glucagon concentration was higher during magnesium repletion than depletion (p < 0.02).

 

Figure 6
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  		Fig. 6. Serum insulin concentrations of 10 volunteers from which blood was collected for each time period in and IVGTT test during magnesium depletion and repletion.

 

   DISCUSSION
 
Although the analyzed magnesium content of the basal diet at the beginning of the study was 4.16 mmol/8.4 MJ (101 mg/2000 kcal), different caloric intakes by the volunteers to maintain weight at admission weight ± 2% resulted in mean magnesium intakes between 4.28 and 4.44 mmol (104 and 108 mg)/day during the depletion period. The range of magnesium intakes was 3.00 to 5.88 mmol (73 to 143 mg)/d. The mean magnesium intake during the repletion period was generally near 12.67 mmol (308 mg)/d, but was somewhat higher for a few weeks because two volunteers were supplemented with an additional 4.12 mmol (100 mg) Mg/day to assure that heart rhythm changes were reversed to baseline. Based on the amount found in the feces, about 50% of the 12.67 to 13.13 mmol (308 to 319 mg) Mg/day intake was absorbed; this is consistent with reports indicating that approximately 30% to 50% of the 8.23 to 14.40 (200 to 350 mg) magnesium provided by the average American diet daily is absorbed [28,29]. When the magnesium intake was only 4.28 to 4.44 mmol (104 to 108 mg)/day, the fecal magnesium content indicated a similar percent absorption rate. Thus, retention in the body and the ability of the kidney to prevent loss in the urine are major factors in whether balance is positive or not. Urinary magnesium excretion was significantly decreased by the magnesium restriction, but this homeostatic response was not adequate to prevent a non-positive magnesium balance and a magnesium-deficient status in the postmenopausal women when the dietary magnesium intake was 4.16 mmol/8.4 MJ (101 mg Mg/2000 kcal)/d. When the diet was supplemented with magnesium so that daily intake was over 12.35 mmol (300 mg)/day, all subjects showed an immediate change from a non-positive magnesium balance during the last collection of the magnesium depletion period to a marked positive magnesium balance (ranged from 2.14 to 6.58 mmol [52 to 160 mg]/day the first 6 days after repletion started). The last five weeks, all subjects except one had positive balances ranging from 1.60 mmol (39 mg) for two women aged 47 and 67 years to 3.12 mmol (75 mg)/day for one woman aged 75 years; the one exception (aged 55 years) had a positive balance of only 0.21 mmol (5 mg)/day. Thus, age apparently did not markedly affect the ability to achieve positive magnesium balance after a period of magnesium deprivation. If one considers the highly positive magnesium balance during magnesium repletion an indication of magnesium retention similar to that expected with a magnesium load test, the balance data indicate that the subjects were magnesium deficient when the magnesium repletion began. Additional evidence that the magnesium status of the women declined when dietary magnesium was low was provided by the decrease in red blood cell membrane magnesium concentration during the depletion period and the increase during magnesium repletion. Thus, the biochemical and functional changes found in the women during the magnesium depletion period compared to the magnesium repletion period most likely were the result of a primary magnesium deficiency induced by a diet whose menu would not be considered atypical.

Based on the results presented, the concentration of magnesium in serum or its albumin and macroglobulin fractions are not suitable variables for ascertaining whether a person is becoming magnesium deficient under experimental conditions. Fig. 2 suggests, depending upon the length of time of magnesium deprivation, a decrease, increase, or no change in serum magnesium concentration may be seen during experimental magnesium deprivation. The initial response to magnesium deprivation may be a decrease in the concentration of serum magnesium. However, in this study the concentration increased as magnesium depletion progressed. This increase may have been the result of increased mobilization from internal magnesium stores in muscle [30] and bone. The reason magnesium repletion did not significantly increase the serum concentration of magnesium may have been that magnesium was being removed from the blood to restore muscle and bone magnesium concentrations.

One sign of primary dietary magnesium deficiency most likely is heart arrhythmia. In this study, the arrhythmias that responded the best and quickest to magnesium repletion were atrial flutter and fibrillation (exhibited by three subjects). Increased VPDs during the magnesium depletion period did not respond quickly to magnesium repletion, but the number of VPDs decreased to baseline in one subject, near baseline in another, and below baseline in a third by the end of repletion. The suggestion that atrial flutter and fibrillation can result from dietary magnesium deficiency is supported by the finding that supplemental magnesium has been used to successfully convert atrial fibrillation to sinus rhythm [11]. Also, patients with atrial fibrillation have been found to have low erythrocyte magnesium concentrations [31].

Age may have influenced the appearance of heart arrhythmias with magnesium deprivation in the present experiment. Barbagallo et al [32] compared the concentrations of cytosolic free magnesium (Mgi) in erythrocytes from subjects older and younger than 65 years. They found that Mgi was lower in older than younger normal subjects. If the woman who exhibited supraventricular tachycardia during magnesium deprivation is included, four of the six women aged 65 or over showed heart rhythm changes. Only two of the seven women younger of than 65 years showed heart rhythm changes and one of these had a high BMI (34.4). Perhaps more of the women aged 65 years or older started the present study with a lower magnesium status than those younger than 65 years.

The heart arrhythmias also may have been related to the change in the urinary excretion of sodium and potassium. Feyertag et al [33] found that a magnesium supplement of 15 mmol magnesium citrate compared to a placebo for 3 weeks given to patients after myocardial infarction decreased ventricular extrasystoles. Urinary potassium and sodium excretion also increased in the magnesium supplemented patients. The increased excretion may be an indication that an electrolyte imbalance was present during the magnesium depletion period. Much evidence exists that magnesium has a regulatory role in Na+ and K+ transport, cellular distribution, and intracellular concentration. Magnesium activates the Na+, K+-ATPase pump that has a major role in regulating Na+ and K+ transport [34]. The finding of decreased urinary excretion of potassium during magnesium deprivation in the present study contrasts to that found with humans made severely magnesium deficient (6 to 10 mg/day); they had increased urinary potassium [35]. The increase was suggested to occur through a stimulation of aldosterone secretion that increases urinary potassium excretion [36]. Perhaps the severity of the magnesium deficiency was the reason for the contrasting results. This possibility is supported by the finding of no significant change in circulating aldosterone and blood pressure induced by the magnesium deficiency in the present experiment.

The finding that the concentration of total cholesterol was lower during magnesium depletion than repletion was surprising. Animal experiments suggested that magnesium deficiency should increase serum cholesterol. However, in order to show that magnesium deficiency affects serum cholesterol in rats, experiments had to be long-term, use pair-feeding techniques with severe deficiency, or required high dietary cholesterol [8]. No convincing reports have indicated that increased serum total cholesterol is a primary sign of magnesium deficiency in humans. Two other reports gave cholesterol findings that support our data showing that magnesium deprivation may decrease serum total cholesterol. Veiga et al [37] found that postmenopausal women with RBC magnesium concentrations lower than 44 mg (1.81 mmol)/L had lower plasma total and LDL-cholesterol than postmenopausal women with RBC magnesium concentrations higher than 44 mg. Nielsen [9] found that a diet supplying about 4.86 mmol (118 mg) magnesium/day compared to a diet supplying about 13.09 mmol (318 mg) magnesium/day resulted in decreased plasma total cholesterol in postmenopausal women. Perhaps the change in circulating cholesterol reflected a change in erythrocyte cellular membrane lipid composition. Lipid components of the erythrocyte membrane exchange rapidly with plasma lipoproteins, and erythrocyte cellular membrane composition and fluidity is altered by magnesium deficiency [8].

Recent studies suggest that magnesium deficiency can promote atherogenesis through mechanisms (e.g., LDL-cholesterol oxidation, formation of pro-inflammatory substances) other than by increasing circulating cholesterol [7,38]. The only indicator of reactive oxygen metabolism measured in this study was ESOD, which was significantly decreased by magnesium deprivation. This finding is similar to that found with rats. Kumar and Shivakumar [39] found that magnesium deficiency depressed the activity of superoxide dismutase in both plasma and heart in rats. Depressed ESOD may be an indicator that dietary magnesium deficiency may enhance the susceptibility of postmenopausal women to oxidative injury.

The response to the IVGTT indicates that dietary magnesium deficiency in humans impairs glucose homeostasis. The findings that fasting glucose was higher and rose to a higher concentration suggest impaired glucose disposal and possible decreased insulin sensitivity during magnesium deprivation. This would be in agreement with findings that indicate intracellular magnesium concentration modulates insulin action and oxidative glucose metabolism, and epidemiological studies showing that higher daily intakes of magnesium are associated with a lower incidence of noninsulin-dependent diabetes mellitus [40]. The reason for the apparent difference in the glucagon response during the IVGTT test is unclear. The difference may be reflecting a response to an acute rise is the circulating concentration of glucose because the fasting concentration was not significantly different during magnesium deprivation and repletion. The finding of no fasting difference is similar to that of Paolisso et al [41] who found that the plasma glucagon concentration did not increase with magnesium supplementation that increased erythrocyte magnesium in elderly diabetic patients. The major target organ for glucagon is the liver, where it stimulates glycogen breakdown to glucose. In the liver, glucagon also binds to specific receptors and increases both intracellular adenosine 3', 5'-monophosphate and calcium. Glucagon also is involved in magnesium conservation at the kidney level [42]. Perhaps glucose infusion induces a change in magnesium distribution, or the lack of magnesium results in a change in the cellular membrane response to glucagon that results in a different glucagon secretion with an acute rise in circulating glucose.


   CONCLUSION
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 CONCLUSION
ACKNOWLEDGMENTS
 REFERENCES
 
Findings were obtained that indicate magnesium balance may be a suitable method for determining whether subjects are being depleted of magnesium when fed a magnesium restricted diet under experimental conditions. If magnesium balance becomes non-positive upon feeding a diet low in magnesium, and persists for several weeks, it is likely that the subject will become magnesium deficient. A highly positive magnesium balance upon feeding a magnesium adequate diet after this magnesium deprivation would be confirmation of a low or deficient magnesium status. Thus, functional changes seen with such balance changes can be considered as signs of primary dietary magnesium deficiency. The present experiment suggests that signs of dietary magnesium deficiency may include heart arrhythmias, impaired glucose homeostasis, and altered lipid and oxidative metabolism. The study also establishes that an intake of 4.12 mmol Mg/8.4 MJ (100 mg Mg/2000 kcal) is inadequate for postmenopausal women. Because 10% of the elderly women in the United States consume less than 5.6 mmol (136 mg) Mg/d, magnesium deficiency may be a significant factor compromising cardiovascular health and glycemic control in this population.


   ACKNOWLEDGMENTS
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
REFERENCES
 
The author expresses gratitude to the members of the Grand Forks Human Nutrition Research Center clinical staff whose special talents and skills made this study possible: James Penland (psychology), Henry Lukaski (exercise physiology), Loanne Mullen and staff (dietary), Sandra Gallagher and staff (clinical chemistry), Betty Vetter and nursing staff (metabolic unit care), Donna Neese (protocol processing and scheduling), Nicholas Ralston, Rogers Sims and staff (mineral analysis), LuAnn Johnson (statistical analysis), and Christine Bogenreif (manuscript processing).


   FOOTNOTES
TOP
 FOOTNOTES
ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 
* Current Address: School of Medicine, University of North Dakota, Grand Forks, ND. Back

** Current address: PO Box 366, Gallatin Gateway, MT 59730. Back

Received June 7, 2005. Accepted May 4, 2006.


   REFERENCES
TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 CONCLUSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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