Magnesium Intake and the Metabolic Syndrome: Epidemiologic Evidence to Date
Ka He, MD, ScD, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 North Lake Shore Drive, Suite 1102, Chicago, IL 60611 E-mail: firstname.lastname@example.org
The importance of magnesium intake in relation to the metabolic syndrome has been increasingly recognized. Magnesium is an essential mineral, critical for a number of metabolic functions in the human body. The major dietary sources of magnesium intake include whole grains, legumes, nuts, and green leafy vegetables. Animal studies indicate a pivotal role of magnesium in glucose homeostasis and insulin secretion and action. Experimental and clinical studies suggest that magnesium intake may be inversely related to the risk of hypertension and type 2 diabetes mellitus, and may decrease blood triglyceride and increase high-density lipoprotein cholesterol levels. The purpose of this brief review is to summarize the epidemiologic data relating magnesium to the metabolic syndrome and to discuss the potential mechanisms.
The metabolic syndrome is a cluster of metabolic risk factors: abdominal obesity, hyperglycemia and/or hyperinsulinemia, dyslipidemia (high triglyceride and low high-density lipoprotein [HDL] cholesterol levels), and elevated blood pressure.1 This syndrome has become a worldwide health disorder that leads to increased risk of cardiovascular disease and diabetes mellitus.2
Magnesium, a cofactor for hundreds of enzymes, is an essential mineral that is critical for a number of metabolic functions in the human body. The major dietary sources of magnesium intake include whole grains, legumes, nuts, and green leafy vegetables (Table I).3 Magnesium content tends to be lost substantially during the refining and processing of foods. A survey in a representative sample of US adults indicates that the average magnesium intake in the United States is below the daily reference intakes (Table II).3,4 Magnesium status in the human body is a result of interactions among dietary intake, intestinal absorption, renal excretion, and exchange from bone.5
Table I. Major Dietary Sources of Magnesium
|Pumpkin seeds, roasted||1/4 cup||303|
|Soy nuts||1/2 cup||196|
|Tofu, firm||1/2 cup||128|
|Chili with beans||1 cup||115|
|Wheat germ, toasted||2 Tbsp||90|
|Unsweetened chocolate||1 oz||88|
|Sunflower seeds||1/4 cup||82|
|Halibut, baked||3 oz||78|
|Swiss chard, cooked||1/2 cup||75|
|Spinach, cooked||1/2 cup||66|
|Black beans||1/2 cup||60|
|Oatmeal, cooked||1 cup||56|
|Peanut butter||2 Tbsp||51|
|Baked potato with skin||1||55|
|Cereal, raisin bran||1 oz||48|
|Low fat yogurt||1 cup||43|
|Milk, fat free||1 cup||28|
|Green peas, cooked||1/2 cup||23|
|Tbsp indicates tablespoon.|
Table II. Magnesium Requirements: Daily Reference Intakes by Life Stage
Dietary Magnesium Intake and the Metabolic Syndrome
Magnesium intake has been observed to be associated with all features of the metabolic syndrome. Evidence that magnesium favorably affects individual components of the metabolic syndrome, though not entirely consistent, has led some researchers to hypothesize that magnesium intake is related to a lower risk of metabolic syndrome as an entity. Data directly relating dietary magnesium intake to metabolic syndrome are sparse (Table III).
Table III. Studies of Dietary Magnesium Intake and the Metabolic Syndrome
|Study design||Cross-sectional||Cross-sectional||Prospective cohort; 15-year follow-up|
|Men, %||0||No information||46.2|
|Magnesium measurement||Semiquantitative food frequency questionnaire||Single dietary 24-h recall||Interviewer-administered quantitative food frequency questionnaire|
|Definition of metabolic syndrome||ATP III definition; fasting glucose levels were not available||ATP III definition||ATP III definition|
|Main findings||Odds ratio for top quintile, 0.73 (95% CI, 0.60–0.88)*; P for trend, .0008||Odds ratio for top quintile, 0.52 (95% CI, 0.30–0.89)*; P for trend, .04||Hazard ratio for top quartile, 0.69 (95% CI, 0.52–0.91)*; P for trend, <.01|
|Conclusion||Magnesium intake was inversely related to the prevalence of the metabolic syndrome and systemic inflammation.||Dietary magnesium intake was inversely related to the prevalence of the metabolic syndrome.||Magnesium intake was inversely associated with incidence of the metabolic syndrome and its components.|
|NHANES III indicates Third National Health and Nutrition Examination Survey; CARDIA, Coronary Artery Risk Development in Young Adults; ATP III, Adult Treatment Panel III; and CI, confidence interval.|
Song et al6 first reported an inverse relation between dietary intake of magnesium and the prevalence of metabolic syndrome among 11,686 apparently healthy American women in the Women's Health Study. Compared with those in the lowest quintile of magnesium intake, women in the highest quintile of intake had 27% lower risk of the metabolic syndrome defined according to the National Cholesterol Education Program Adult Treatment Panel III report (ATP III) criteria (odds ratio [OR], 0.73; 95% confidence interval [CI], 0.60–0.88; P for trend, <.001). Also, the investigators found a significant inverse association between magnesium intake and plasma concentrations of C-reactive protein. This inverse association appeared to be more pronounced among women who were overweight and those who ever smoked. The authors suggested that a possible beneficial effect of magnesium intake on diabetes and cardiovascular disease might be related to its roles in ameliorating systemic inflammation and/or the development of the metabolic syndrome. Of note, data on fasting glucose levels were not available in this study. The investigators used the diagnosis of incident type 2 diabetes as an alternate measure of baseline abnormal glucose metabolism.
Using data from the Third National Health and Nutrition Examination Survey (NHANES III), Ford et al7 examined the cross-sectional associations between dietary intake of magnesium and the prevalence of the metabolic syndrome. This study provides additional evidence that magnesium intake is inversely associated with the prevalence of the metabolic syndrome. The multivariable OR of having the metabolic syndrome (defined using the criteria of the ATP III) for participants in the highest quintile of magnesium intake was 0.52 (95% CI, 0.30–0.89; P for trend, .04) compared with those in the lowest quintile of intake. The results remained after excluding vitamin or mineral supplement users. In this study, however, magnesium intake was not significantly related to any of the components of the metabolic syndrome after adjustment for other covariates.
Recently, He et al8 conducted a longitudinal study and prospectively examined the relations between magnesium intake and incident metabolic syndrome and its components (defined by the ATP III criteria) in young adult Americans. During the 15 years of follow-up, the investigators documented 608 incident cases of the metabolic syndrome among 4637 Americans, aged 18–30 years, who were free from the metabolic syndrome and diabetes at baseline. After adjustment for potential confounders and baseline status of each component of the metabolic syndrome, magnesium intake was inversely associated with incidence of the metabolic syndrome. The multivariable hazard ratio of metabolic syndrome for participants in the highest quartile was 0.69 (95% CI, 0.52–0.91; P for trend, <.01) compared with those in the lowest quartile of magnesium intake. The inverse associations were not appreciably modified by sex and race (Caucasian and African American). Also, magnesium intake was inversely related to individual components of the metabolic syndrome. Specifically, significant inverse relations were observed between magnesium intake and fasting glucose level, waist circumference, and HDL cholesterol level. In addition, the investigators examined the cross-sectional associations between magnesium intake and fasting insulin levels.8 A consistent inverse correlation between magnesium intake and fasting insulin level was observed in both magnesium supplement users and nonusers. This study provides strong prospective evidence that higher magnesium intake or a diet rich in magnesium may be important to maintaining good metabolic health. Furthermore, a major advantage of this study is that it was conducted in young adults, whose dietary decisions are not as likely as those of older adults to be dictated by current health status and risk of disease development. People who are middle-aged or older are more likely to have already experienced the onset of disease. Consequently, their lifestyle choices and health conditions may be affected by perceived ill health or treatment for existing disease that relates to individual components of the metabolic syndrome.
Biomarkers of Magnesium Intake and the Metabolic Syndrome
Because of differences in bioavailability, results from studies with dietary magnesium measurement may not necessarily be consistent with those from studies using biomarkers of magnesium intake. Two studies related serum magnesium level to the metabolic syndrome and/or its components (Table IV). In 2002, Guerrero-Romero and Rodriguez-Moran9 conducted a cross-sectional population-based study of 192 individuals with the metabolic syndrome and 384 matched healthy control subjects. They found that low serum magnesium levels were associated with elevated risk of the metabolic syndrome. The OR of having the metabolic syndrome for those in the lowest quartile of serum magnesium level was 6.8 (95% CI, 4.2–10.9) compared with participants in higher quartiles. As for individual components of the metabolic syndrome, low serum magnesium concentration is a significant predicator of dyslipidemia and hypertension. Of note, the metabolic syndrome, in this study, was defined by modified criteria on the basis of the ATP III definition.1
Table IV. Studies of Biomarkers of Magnesium Intake and the Metabolic Syndrome
|Definition of metabolic syndrome||Modified definition based on the Adult Treatment Panel III criteria||Adult Treatment Panel III definition|
|Main findings||Odds ratio for low quartile: 6.8 (95% confidence interval [CI], 4.2–10.9); P<.00001||The study examined individual components of the metabolic syndrome. The association of magnesium and metabolic syndrome was not reported. Odds ratio for serum magnesium level <0.46 mmol/L was 4.71 (95% CI, 2.56–8.67) for triglycerides and 2.21 (95% CI, 1.21–x4.04) for waist circumference.|
|Conclusion||Low serum magnesium was related to increased risk of the metabolic syndrome.||High plasma triglycerides and waist circumference were independently correlated with low levels of magnesium.|
In another cross-sectional study, Corica et al10 evaluated circulating serum ionized magnesium concentrations in 290 type 2 diabetic patients and examined its associations with the components of the metabolic syndrome. They reported that the metabolic syndrome was associated with low serum magnesium in diabetic patients. Also, serum magnesium level was inversely related to triglycerides and waist circumference. For other components of the metabolic syndrome defined by the ATP III criteria, no statistically significant associations were observed; however, this study did not directly relate serum magnesium to the metabolic syndrome. In addition, it remains controversial whether serum magnesium levels can reflect long-term magnesium intake or total magnesium status in the human body.11 Serum magnesium did not appear to be well correlated with dietary magnesium intake and the intracellular magnesium pool, a biologically active portion of magnesium store.11,12
Although the underlying mechanisms for many of the pleiotropic effects of magnesium are not well understood, several pathways have been proposed to explain the beneficial effects of magnesium intake on metabolic disorders, including improvement of glucose and insulin homeostasis13 and lipid metabolism,14 as well as its antihypertensive,15 anti-inflammatory,6 and antioxidant functions.16 First, previous studies suggest that intracellular magnesium balance is important in maintaining peripheral glucose-mediated insulin action.17,18 Magnesium may preserve pancreatic β-cell function through its effects on cellular calcium homeostasis and/or oxidative stress.16 In fact, improvement in insulin sensitivity associated with increased magnesium intake has been reported in observational and clinical studies.19–21 Moreover, dietary magnesium intake was inversely correlated with fasting insulin level in diverse populations.22–25 Second, magnesium may affect lipid metabolism independent of its effects on insulin homeostasis. As a cofactor of many rate-limiting enzymes critical for lipid metabolism, magnesium has been shown to decrease low-density lipoprotein cholesterol and triglyceride levels and increase HDL cholesterol levels by inhibiting the activity of lecithin cholesterol acyl transferase26 and 3-hydroxy-3-methylglutaryl coenzyme A reductase, and stimulating lipoprotein lipase activity.27 The potential beneficial effects of magnesium on lipid metabolism have been supported by animal,14,28 epidemiologic,9,23 and clinical studies.26 Third, it has been suggested that magnesium has multiple functions critical for its antihypertensive effects, such as the inhibition of intracellular calcium mobilization as a calcium antagonist;15,29 attenuation of the adverse effect of sodium by stimulating activity of Na—K ATPase or increasing urinary excretion of sodium;15 decreased release of catecholamines;15,29 and improvement of myocardial contractility,29,30 systemic inflammation,6 and endothelium-dependent vasodilation.31,32 Data from experimental and observational studies on magnesium and blood pressure have been summarized elsewhere.15 Since the previous findings were not consistent, a meta-analysis pooled 20 randomized clinical trials including 1220 individuals and found a significant inverse association between magnesium supplementation and blood pressure.33 Fourth, in He et al,8 magnesium intake was inversely related to waist circumference. The mechanism for a possible beneficial effect of magnesium intake on body weight is, however, unknown. It has been suggested that magnesium may be involved in forming soaps with fatty acids in the intestine and may reduce the digestible energy content of the diet.34 Thus, magnesium intake may benefit weight maintenance. Further studies are warranted to better understand magnesium intake in relation to body weight.
Potential Confounders and Methodologic Issues
Previous studies have also shown that magnesium intake is inversely associated with many other correlated metabolic components that are not incorporated into the metabolic syndrome definitions used,35 such as systemic inflammation,6 endothelial dysfunction,36 oxidative stress,31 and impaired fibrinolysis.37,38 Although epidemiologic studies have examined the association between magnesium intake and the metabolic syndrome, most of them focused on the metabolic syndrome defined based on the ATP III criteria, and there are no data available addressing similar issues using other diagnosis criteria, such as those of the World Health Organization (WHO),39 the European Group on Insulin Resistance (EGIR), the American Association of Clinical Endocrinologists (AACE),41 or the International Diabetes Federation (IDF).42
In addition, several methodologic issues in epidemiologic studies deserve consideration, especially when longitudinal data regarding the association between magnesium intake and the development of metabolic profiles are sparse. The available evidence derived from cross-sectional studies is prone to be confounded by various aspects of diet, lifestyle, or socioeconomic factors. A large-scale prospective cohort study is considered optimal to study the temporal relation between diet/nutrient and disease; however, as in any observational study, it is always difficult to completely separate the independent effect of magnesium from other dietary nutrients such as fiber, calcium, and potassium that may also have antihypertensive effects. Also, measurement errors in the dietary assessment, including potential dietary change over the course of follow-up and residual confounding from either poorly measured or unmeasured variables, may substantially limit the ability of large cohort studies to elucidate the causality of nutrient—disease relation. The best approach to confirm a cause-and-effect relation is to perform a double-blinded and placebo-controlled randomized trial. Data on magnesium and the metabolic syndrome from randomized trials are not available. Previous trials on magnesium supplementation and metabolic disorders are limited in that small sample size; incomplete randomization; the lack of blinded design; variable durations of follow-up; high rates of noncompliance; and differences in magnesium treatment protocols, magnesium formulation and dose, and study populations may obscure the link between magnesium and the metabolic syndrome. Thus, future large-scale, well-designed randomized trials are necessary to unravel the direct effect of magnesium supplements.
In summary, accumulated epidemiologic evidence has shown consistently inverse associations of magnesium intake with the metabolic syndrome and its components as conventionally defined by the ATP III criteria. The results indicate that a diet rich in magnesium may be important in maintaining good metabolic health. The findings from epidemiologic studies are supported by experimental data showing the biologic effects of magnesium as a critical cofactor in metabolic functions within the human body. Because of the limitations of observational study, randomized clinical trials are needed to establish a causal relationship between magnesium and the metabolic syndrome. Nevertheless, the collective epidemiologic evidence regarding the potential benefits of magnesium intake is consistent with prevailing dietary recommendation for selecting a diet rich in vegetables, whole grains, legumes, and nuts that may protect against multiple risk factors of diabetes and cardiovascular disease in the general population.
Disclosure: This work was supported by National Institutes of Health research grant No. 1R01HL081572.