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SUPPLEMENT

White Vegetables: A Forgotten Source of Nutrients

Magnesium in Disease Prevention and Overall Health 1,2

Stella Lucia Volpe*

Department of Nutrition Sciences, Center for Integrated Nutrition & Perf ormance College of Nursing and Heal th Professions Dre xel University, Philadelphia, PA

ABSTRACT

ABSTRACT

Magnesium is the fourth most abundant mineral and the second most ab undant intracellular divalent cation and has been recognized as a cofactor for >300 metabolic reactions in the body. Some of the proce sses in which magnesium is a cofactor include, but are not limited to, protein synthesis, cellular energy production and storage, reproduc tion, DNA and RNA synthesis, and stab ilizing mitochondrial membranes. Magnesium also plays a critical role in nerve transmission, cardiac excit ability, neuromuscular conduction, muscular contraction, vasomotor tone, blood pressure, and glucose and in sulin metabolism. Because of magnesium s many functions within the body, it plays a major role in disease prevention and overall health. Low levels of magnesium have been associated with a numbe r of chronic diseases including migraine headaches, Alzheimer s disease, cerebrovascular accident (stroke), hypertension, cardiovascular disease, and type 2 diabetes mellitus. Good food sources of magnesium include unrefined (whole) grains, spinach, nuts, legumes, and white potatoes (tubers). This review presents recent research in the areas of magnesium and chronic disease, with the goal of emphasizing magnesiums role in disease prevention and overall health. Adv. Nutr. 4: 378S383S, 2013.

Introduction

Magnesium is the fourth most abundant mineral and the second most abundant intracellular divalent cation and has been recognized as a cofactor for >300 metabolic reac- tions in the body (1,2). Approximately 50% of magnesium is in the bone, 50% is in the tissues and organs, and 1% is in the blood (1,2). Some of the processes in which magnesium is a cofactor include, but are not limited to, protein synthesis, cellular energy production and storage, reproduction, DNA and RNA synthesis, and stabilizing mitochondrial membranes (36). Magnesium also plays a critical role in maintaining nor- mal nerve and muscle function, cardiac excitability (normal

1 Published in a supplement to Advances in Nutrition . Presented at the Purdue University Roundtable on “White Vegetables: A Forgotten Source of Nutrients” held June 18–19, 2012 in Chicago, IL. The roundtable was sponsored by Purdue University. The roundtable and supplement publication were supported by an unrestricted grant from the Alliance for Potato Research and Education. All roundtable speakers received travel funding and an honorarium for participation in the meeting and manuscript preparation. The views expressed are those of the authors. The supplement coordinator was Catherine Nnoka, a paid consultant to the Alliance for Potato Research and Education. Guest editor Connie Weaver received compensation from the Alliance for Potato Research and Education for travel expenses, manuscript preparation, and editorial services for the supplement publication. Guest editor Cheryl Anderson received compensation from the Alliance for Potato Research and Education for editorial services. 2 Author disclosures: S. L. Volpe, no conflicts of interest. * To whom correspondence should be addressed. E-mail: Stella.L.Volpe@drexel.edu

heart rhythm), neuromuscular conduction, muscular contrac- tion, vasomotor tone, normal blood pressure, bone integrity, and glucose and insulin metabolism (3 16). In this regard, magnesium deficiency has been associated with a number of chronic diseases, including migraine headaches, Alz- heimer s diseases, cerebrovascular accident (stroke), hy- pertension, cardiovascular disease, and type 2 diabetes mellitus (17 22). The Dietary Reference Intake for magnesium for adults is 310 420 mg/d; magnesium intake is often below these rec- ommendations, particularly as people age (23). Although magnesium content is high in whole grains and dark, leafy green vegetables, magnesium is also high in white vegetables such as white potatoes (24 26). The purpose of this review is to present research in the area of magnesium and disease. The goal of this paper is to demonstrate the importance of magnesiums role in dis- ease prevention and overall health.

Current status of knowledge

Dietary Reference Intakes for magnesium The Dietary Reference Intakes for magnesium has been established as the RDA. They range from 80 mg/d for chil- dren 13 y of age to 130 mg/d for children 48 y of age. For older males, the RDA for magnesium ranges from as

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ã2013 American Society for Nutrition. Adv. Nutr. 4: 378S–383S, 2013; doi:10.3945/an.112.003483.

low as 240 mg/d (range, 9 13 y of age) and increases to 420 mg/d for males 31 to 70 y of age and older. For females, the RDA for magnesium ranges from 240 mg/d (913 y of age) to 360 mg/d for females 14 18 y of age. The RDA for females 31 to 70 y of age and older is 320 mg/d (23). It has been reported that ~60% of adults in the United States do not consume the RDA for magnesium (27). The lower intake of magnesium from a larger proportion of the U.S. population may be related to the increased rate of chronic disease. Nonetheless, increased diseases attributed to magne- sium deciency have not yet been reported, perhaps because they have not been explored in the medical community and/or because they may be related to a magnesium insufciency and not an overt magnesium de ciency. It has been reported, however, that low magnesium status has been associated with chronic in ammatory stress conditions (27). In humans, de cient magnesium intakes are mostly con- sidered marginal to moderate, i.e., between 50% and 90% of the RDA and may be related to chronic in ammatory re- sponse conditions (27). This in ammatory response could play a role in obesity in humans because obesity has been characterized as having a chronic low-grade in ammation component and an increased incidence of a low magnesium status (27). It is this marginal to moderate magnesium de - ciency through aggravating chronic in ammatory stress that may be contributing signi cantly to the occurrence of ather- osclerosis, hypertension, osteoporosis, type 2 diabetes melli- tus, and certain types of cancer (27). Furthermore, certain medications prescribed for such diseases, such as loop and thiazide diuretics (often prescribed for hypertension and/or congestive heart failure), can further exacerbate magnesium loss, typically through the urine (28).

Food sources of magnesium Although magnesium is a rather ubiquitous mineral, there is no major food that provides an extremely high amount of magnesium. The foods highest in magnesium include unre- ned (whole) grains, spinach, nuts, legumes, and potatoes (tubers) (26). Freedman and Keast (25) evaluated the contri- bution of white potatoes, oven-baked potatoes, and French fries to the nutrient needs in children and adolescents. They reported that these vegetables provided at least 5% of the magnesium intake. Thus, white vegetables that are prepared healthfully need to be taken into consideration when educating individuals on healthy nutrition options for magnesium intake. Table 1 provides examples of the amount of magnesium in some foods. More recently, Freedman and Keast (29) evaluated 24-h dietary recall data from NHANES 20032006 to establish nu- trient contributions from white potatoes. They reported that, among all groups of consumers, white potatoes (prepared in various ways) contributed to w 10% of the total daily intake of various vitamins and minerals, including magnesium (29).

Magnesium status Magnesium status can be measured via serum total magne- sium concentrations, ionized magnesium levels, red blood

Table 1. Foods high in magnesium 1

Food

Magnesium, mg

1/4 cup of wheat bran (57 g)

89

1

oz of dry roasted almonds (28.4 g)

80

1/2 cup of frozen, cooked spinach (14.2 g)

78

1

oz of mixed, dry roasted nuts (28.4 g)

64

3/4 cup of bran flakes cereal (170 g)

64

2 tbsp of smooth peanut butter (32 g)

49

1 medium baked potato with skin

48

1/2 cup of cooked pinto beans (113 g)

43

1/2 cup of brown, long-grained cooked rice (113 g)

42

1/2 cup of mature seeds, cooked lentils, (113 g)

36

1 cup of low-fat chocolate milk (234 mL)

33

1 medium banana

32

8

fluid oz of low-fat fruit yogurt (234 mL)

32

1.5 oz of milk chocolate candy bar (43 g)

28

1

slice of whole-wheat bread,

23

commercially prepared 1/2 cup of avocado cubed (113 g)

22

1 Adapted from (26) with permission.

cell magnesium, and urinary magnesium levels using the magnesium loading test. Of these, serum magnesium con- centrations have been shown to be the least sensitive to mag- nesium status unless there is a severe magnesium de ciency already present (30); although ionized magnesium concen- trations and the magnesium loading test have been shown to be more accurate, there is still debate among researchers. Although the magnesium loading test is still considered the gold standard, it cannot be used in individuals with kidney disease (30). Despite the fact that serum magnesium levels are not sensitive to magnesium status, most researchers con- tinue to use serum magnesium concentrations, but more re- searchers are using ionized magnesium concentrations. If possible, researchers should consider using 2 markers of magnesium status to ensure reliable results.

Magnesium and migraine headaches It has been reported that magnesium may be an effective complementary treatment for migraine headaches (31). Mi- graine headaches more than likely have a genetic basis. These types of headache disorders stimulate a mechanism deep in the brain that releases inammatory products in the region of the blood vessels and nerves of the brain. Migraines can last anywhere from hours to days, with many individuals unable to function normally during an attack. Attacks can be as infrequent as once a year to as frequent as once a week, with nausea being the most common symptom. Although the cause of migraine headaches is unknown (31). Mauskop (32) stated that the efficacy of some non- pharmacologic therapies appears to approach that of most drugs used for the prevention of migraine and tension- type headaches.Therapies such as magnesium supplemen- tation result in minimal to no side effects and are generally low in cost (32). In a comprehensive search strategy, Pringsheim et al. (33) evaluated randomized, double-blind, controlled trials of treatments for migraine prophylaxis. They graded the re- search articles based on the criteria developed by the U.S.

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Preventive Services Task Force. Based on the research that they evaluated, Pringsheim et al. (33) strongly recommended magnesium citrate, among a number of other medications and supplements, for use as prophylaxis for migraines. Nonetheless, they stated that prophylactic drug selection should be based on a variety of issues, including migraine clinical characteristics, other disorders/diseases, side effects, and effectiveness. In a randomized, placebo-controlled clinical trial, Tar- ighat Esfaniani et al. (34) evaluated the effects of magnesium on migraine symptoms. A total of 133 patients, with history of migraine headaches, were randomly assigned to 1 of 4 groups: 1) 500 mg/d of magnesium oxide, 2) 500 mg/d of L-carnitine, 3) 500 mg/d of magnesium oxide plus 500 mg/d of L-carnitine, 4) control group. Participants remained on this regimen for 12 wk. The migraine indicators used were number of attacks per month, number of days per month, and headache severity. Although there was a signif- icant decrease in migraine indicators in all groups, it was found that magnesium supplementation had a significant effect on all migraine indicators (34). Data from trials conducted for as long as 12 wk suggest that magnesium is an effective therapy for migraine head- aches. Longer term trials with a greater number of partici- pants are required to further evaluate the effects of magnesium on migraine headaches.

Magnesium and Alzheimer s disease Alzheimers disease is the most widespread reason for de- mentia (35). Alzheimer s disease is the sixth leading cause of death in the United States, with >79,000 deaths per year (35). Barbagallo et al. (22) examined magnesium bal- ance in patients with mild to moderate Alzheimers disease. Their study population included 101 older patients (73.4 6 0.8 y of age; 42 men, 59 women) who were evaluated for both serum total magnesium and serum ionized magnesium concentrations and were administered the Mini-Mental State Examination. Ionized magnesium concentrations were significantly lower in the group with Alzheimers disease com- pared with their age-matched controls without Alzheimers disease (0.50 6 0.01 mmol/L vs. 0.53 6 0.01 mmol/L; P < 0.01); no significant differences existed between groups with respect to serum magnesium concentrations. The ion- ized magnesium concentrations were significantly related to cognitive function and not physical function. Individuals with Alzheimers disease had significantly lower Mini- Mental State Examination scores (20.5 6 0.7 vs. 27.9 6 0.2; P < 0.001) and significantly lower scores for the physical function tests. This study demonstrates an association be- tween ionized magnesium concentrations and individuals who have mild to moderate Alzheimers disease (22). Ozawa et al. (36) examined whether a diet high in potas- sium, calcium, and magnesium would reduce the risk of de- mentia in 1081 community-dwelling Japanese men and women, 60 y of age and older who did not have diagnosed dementia. At the 17-y follow-up, 303 participants had a diagnosis of dementia, 98 vascular dementia, and 166

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Alzheimers disease. Ozawa et al. (36) reported a significant inverse association between potassium, calcium, and mag- nesium intake and all-cause dementia and vascular demen- tia; the lower the intakes were, the greater the rates of dementia. This same association was not observed with Alzheimers disease. The strength of this study was the num- ber of participants and the length of follow-up; however, no causal effect can be determined for magnesium alone or any of the other minerals because it was an observational study and other confounding factors could have played a role.

Magnesium and cerebrovascular accident (stroke) Cerebrovascular accidents (strokes) can lead to paralysis, in- ability to speak and/or swallow normally (and thus lead to malnutrition), or death. Strokes are the fourth leading cause of death in the United States, with >128,000 deaths per year (35). Strokes are typically a result of uncontrolled hyperten- sion. Because of magnesiums role in blood pressure control, it has also been studied in relation to strokes. Larsson et al. (37) conducted a meta-analysis to summarize the associa- tion between magnesium intake and stroke risk. The criteria the researchers chose for their meta-analysis were the fol- lowing: 1) the study had to be a prospective design, 2) the exposure of interest was magnesium intake, 3) the main outcome measure was stroke, 4) the researchers reported RRs with 95% CIs for 3 quantitative categories of magne- sium intake, and 5) the RRs had to be adjusted for age and sex (37). Of the 163 peer-reviewed journal articles screened, Larsson et al. (37) found that 7 prospective studies quali ed based on their criteria. These studies were published be- tween 1998 and 2011. There were 6477 cases of stroke and 241,378 participants. Four of the studies were conducted in the United States, 2 were conducted in Europe, and 1 was conducted in Taiwan. The median magnesium intakes were 242 mg/d in men and women in the United States and 471 mg/d in Finnish men (37). The 7 prospective studies reviewed by Larsson et al. (37) provided risk estimates that were adjusted for age, smoking, and BMI. Most researchers controlled or adjusted for phys- ical activity (6 studies), diabetes mellitus (6 studies), his- tory of hypertension or measured blood pressure (6 studies), alcohol consumption (6 studies), and other nutrients (3 studies). Larsson et al. (37) reported a statistically signi cant in- verse association between magnesium intake and risk of stroke. They found that an intake increment of 100 mg/d of magnesium was associated with an 8% reduction in the risk of stroke. Magnesium intake was inversely associated with the risk of ischemic stroke, not hemorrhagic stroke. Once again, a causal relationship was not reported, although the strength of this meta-analysis was the strict inclusion cri- teria for the studies included.

Magnesium and hypertension Magnesium is involved in blood pressure regulation (7). In- tracellular magnesium hinders the calcium depolarization

that leads to muscle contraction, leading to vascular relaxa- tion and thus decreased blood pressure (7). Dickinson et al. (38) evaluated the effects of magnesium supplementation for the treatment of hypertension. This was a meta-analysis using the following inclusion criteria for studies: 1 ) randomized, controlled trials of a parallel or crossover design that compared oral magnesium supple- mentation with usual care, placebo, or no treatment; 2 ) the treatment and follow-up had to be $ 8 wk in duration, 3) the participants in the studies had to be at least 18 y of age with a systolic blood pressure $ 140 mm Hg, and 4) the researchers had to have reported both systolic and dia- stolic blood pressure at the end of the follow-up period (38). The researchers found 12 randomized, controlled trials that met their criteria, with a total sample size of 545 participants. When all trials were combined, there was no significant decrease in systolic blood pressure between mag- nesium supplementation and controls; however, diastolic blood pressure was significantly decreased. Dickinson et al. (38) concluded that [i]n view of the poor quality of in- cluded trials and the heterogeneity between trials, the evi- dence in favor of a causal association between magnesium supplementation and blood pressure reduction is weak and is probably due to bias. This is because poor quality studies generally tend to over-estimate the effects of treat- ment. Larger, longer duration and better quality double- blind placebo controlled trials are needed to assess the effect of magnesium supplementation on blood pressure and car- diovascular outcomes.More recently, Kass et al. (39) conducted a meta-analysis to assess effect of magnesium supplementation on blood pressure. They also wanted to establish the characteristics of trials showing the largest effect size. The primary outcome measures were systolic blood pressure and diastolic blood pressure. Of the 141 peer-reviewed articles they identi ed, 22 trials with 23 sets of data and a total sample size of 1173 were used. The studies ranged from 3 to 24 wk of follow-up, and all were published before July 2010. The sup- plemental magnesium dose ranged from 120 to 973 mg/d, with a mean dose of 410 mg/d used. When Kass et al. (39) combined their data, the overall ef- fect was 0.32 for systolic blood pressure (95% CI: 0.23, 0.41) and 0.36 for diastolic blood pressure (95% CI: 0.27, 0.44). A greater effect was found for interventions in crossover trials:

0.51 for systolic blood pressure and 0.47 for diastolic blood pressure (39). In general, Kass et al. (39) reported that higher doses of magnesium led to greater reductions in blood pressure. Not all trials that they examined demonstrated a signi cant decrease in blood pressure; however, combining all trials, there was a 3- to 4-mm Hg decrease in systolic blood pres- sure and a 2- to 3-mm Hg decrease in diastolic blood pres- sure. Based on the results of this single meta-analysis (40), magnesium supplementation appears to achieve a small, clinically signi cant reduction in blood pressure. Dickinson et al. (39) did not report signi cant effects of magnesium on blood pressure, perhaps because their study

was published in 2006, and Kass et al. (40) reported their study in 2012 and included larger trials. However, the crite- ria that each group of researchers used to include in their meta-analyses were different, which ultimately could have caused the differences in results.

Cardiovascular disease Cardiovascular disease is a chronic disease that remains the leading cause of death, with ~599,413 deaths per year in the United States (35). In animal studies, magnesium de ciency has been shown to accelerate atherosclerosis, but magne- sium supplementation has been shown to be preventive. For humans, it is possible that individuals who consume more dietary magnesium are more health conscious. None- theless, the daily dietary intake of magnesium has decreased from w 500 mg/d in the 1900s to w 175 mg/d. This is likely a result of an increased consumption of processed foods

(40,41).

The mechanisms proposed for potential cardiovascular bene ts of magnesium intake include improvement of glu- cose and insulin homeostasis or lipid metabolism; its actions as an antihypertensive, antidysrhythmic, anti-inammatory, or anticoagulant agent; its antiplatelet effects; its effect on re- duced vascular contractility, and/or increasing endothelium- dependent vasodilation. Magnesium might lower blood pressure by acting as a calcium antagonist on smooth muscle tone, causing vasorelaxation (40 46).

Magnesium and type 2 diabetes mellitus Perhaps the most studied chronic disease with respect to magnesium is type 2 diabetes mellitus (and the metabolic syndrome). Magnesium plays a signi cant role in glucose and insulin metabolism, mainly through its impact on tyro- sine kinase activity, by transferring the phosphate from ATP to protein. Magnesium may also affect phosphorylase b kinase activity by releasing glucose-1-phosphate from glyco- gen. In addition, magnesium may directly affect glucose transporter protein activity 4 (GLUT4), and help to regulate glucose translocation into the cell. In a cross-sectional design, Guerrero-Romero and Rodríguez-Morán (16) compared 192 individuals with met- abolic syndrome with 384 healthy age- and sex-matched controls. The researchers reported hypomagnesemia in 126 and 19 individuals with and without the metabolic syn- drome, respectively ( P < 0.00001). Of all of the metabolic syndrome symptoms, hypomagnesemia was most closely related with dyslipidemia (OR: 2.8; 95% CI: 1.3, 2.9) and hy- pertension (OR: 1.9; 95% CI: 1.4, 2.8). The study of magne- siums role in type 2 diabetes mellitus, insulin resistance, and cardiovascular disease demonstrates magnesiums important role in health. In a 3-month prospective trial conducted by Guerrero- Romero et al. (47), 60 participants were randomly assigned in a double-blind fashion to either 300 mg/d of magnesium chloride or a placebo. Insulin resistance (homeostasis model assessment of insulin resistance index $3.0) was the major outcome. Hypomagnesemia was defined as serum magnesium

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concentrations #0.74 mmol/L (1.8 mg/dL). The researchers reported a significant increase in serum magnesium concen- trations from baseline to the end of intervention ( P < 0.0001), with no change in the placebo group ( P = 0.063). The researchers also reported significant improvements in insulin sensitivity in the magnesium-supplemented group from baseline to the end of the study ( P < 0.0001), with no change in the placebo group ( P = 0.087). Insulin sensitiv- ity, as measured by the homeostasis model assessment of in- sulin resistance index, was >4.0 at baseline and was <3.0 at the end of the study (47). If magnesium supplementation affects insulin sensitivity in participants with diabetes mellitus, it may also improve insulin sensitivity in obese individuals who are at risk of type 2 diabetes mellitus. Mooren et al. (48) examined the ef- fects of oral magnesium supplementation in overweight in- dividuals with normal serum magnesium levels who had insulin resistance, but not type 2 diabetes mellitus. Individ- uals were randomly assigned to receive either magnesium aspartate hydrochloride supplementation ( n = 27) or a pla- cebo ( n = 25) for 6 mo. Magnesium supplementation led to a significant improvement in fasting blood glucose concen- trations and some insulin sensitivity measures compared with the placebo group. The researchers emphasized the importance of consider- ing the use of magnesium supplementation to prevent type 2 diabetes mellitus in those individuals who are at risk (e.g., overweight individuals with insulin resistance) (48). It has been well established that cardiovascular disease, hypertension, and type 2 diabetes mellitus are interrelated. Because magnesium has been shown to directly in uence vascular tone and may release nitric oxide, leading to vaso- dilation, Barbagallo et al. (49) evaluated if oral magnesium would improve vascular function in older patients with type 2 diabetes mellitus. Sixty participants with type 2 dia- betes mellitus (71.1 6 6.1 y of age; 25 men, 25 women) were assigned to receive either 4.5 g/d of magnesium pico- late (368 mg/d of magnesium ion) ( n = 30) or a placebo ( n = 30). Patientsusual diabetes mellitus and hypertension care was not altered during the 1-mo trial. Magnesium sup- plementation significantly improved vascular tone, from 3.3% to 8.4% (measured using noninvasive flow-mediated dilation of the brachial artery) with no changes reported in the control group. By improving vascular tone, blood flow will improve, and blood pressure could be decreased.

Conclusions

This review highlights areas where magnesium has been shown to improve symptoms of migraine headaches, Alzheimers disease, cerebrovascular accident (stroke), hy- pertension, cardiovascular disease, and type 2 diabetes mellitus. Although not all researchers have reported im- provements or cause-and-effect relationships. there is good evidence to support the positive influence that magnesium has on overall health. More research is required, however, with larger sample sizes to further elucidate magnesiums effect on health. Longer term, prospective studies using

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similar amounts and types of magnesium supplementation are also needed to definitively establish a dose response ef- fect and the best type of magnesium to use.

Acknowledgments

The sole author had responsibility for all parts of the manuscript.

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