Simona Bo, M.D., Department of Internal Medicine, University of Turin, Italy

Introduction

Magnesium is an essential cofactor in multiple enzymatic reactions, a direct antagonist of intracellular calcium, and could affect insulin action and carbohydrate metabolism. Insulin itself is an important regulator of intracellular magnesium [1]. Magnesium is essential for all energy-dependent transport systems, glycolysis, and oxidative energy metabolism. It participates in intracellular signaling systems, insulin receptor activity, phosphorylation and de-phosphorylation reactions, is considered a physiological calcium-blocker, and acts on platelet aggregation, vascular smooth muscle tone, as a relaxant, electrolyte homeostasis, and exerts anti-arrhythmic effects [1].

Magnesium and Metabolic Abnormalities

Reduced magnesium intake and serum concentrations are associated with type 2 diabetes, insulin resistance, hypertension, dyslipidemia, the metabolic syndrome, and cardiovascular diseases in adults [1-5]. Young adults with higher magnesium intake have lower risk of developing the metabolic syndrome [6]. In adolescents, an inverse relationship between serum and dietary magnesium and fasting insulin levels and indexes of insulin resistance was demonstrated [7]. A significant association between reduced magnesium intake and fasting glucose seems to be present even within the earlier childhood in pre-school children born pre-term with very low birth weight [8].

Magnesium supplementation prevents the development of diabetes in rats [9] and improves insulin sensitivity in type 2 diabetic patients [10]. A recent meta-analysis of nine randomized double-blind controlled trials evaluated the effects of oral magnesium supplementation on glycemic control in type 2 diabetic patients [11]. A 4-16 weeks supplementation was effective in reducing plasma fasting glucose values and raising HDL cholesterol. Finally, an inverse independent association between decreased serum magnesium values and nonalcoholic steatohepatitis was reported [12]. It has been hypothesized that by increasing the permeability of mitocondrial membranes, magnesium deficiency could decrease oxidation-phosphorylation coupling [13], involved in lipid peroxidation and cytokine induction, which are implicated in the pathogenesis of steatohepatitis.

Adjustments for Fiber Intake

There is, however, inconsistency in dietary intervention studies with magnesium: only a modest or inconsistent response was reported on glycemic control [5,14-16] and on hemoglobin levels [11]; magnesium supplements did not reduce diabetes risk [2]; the evidence in favor of a causal association between magnesium supplementation and blood pressure reduction is weak and is probably due to bias [17]. Furthermore, adjustments for fiber intake gave discordant results [4,18]. Dietary fibers are inversely correlated with metabolic abnormalities, and strongly related to dietary magnesium, as both are contained in the same foods. The major foods contributing to magnesium intake are in fact whole grain, nuts, fruits, and vegetables. Fiber intake might improve insulin sensitivity by a delayed rate of carbohydrate absorption; it prevents weight gain, by a longer feeling of satiety, and decreases inflammation and oxidative stress [19-21].

We have recently performed a cross-sectional study to investigate the association between dietary magnesium and fiber intake and metabolic variables, and high-sensitivity C-reactive protein (hs-CRP) values in Southern-European middle-aged healthy subjects from a population-based cohort [22]. Subjects within the lowest tertiles of magnesium and fiber intakes were 3-4 times more likely to have diabetes mellitus and the metabolic syndrome in a multiple logistic regression model, after multiple adjustments. After additional controlling for fiber intake, these associations were no longer significant. Magnesium intake was highly correlated with fiber consumption in the study population, due to the similarity in the foods containing both nutrients, but, no significant interaction between fiber and magnesium resulted from the analyses. Taking into account the limitation of a cross-sectional analysis and the difficulty for an observational study to identify the independent effect from a single nutrient, these results suggest a primary role for reduced fiber intake on metabolic abnormalities. The more favorable impact obtained with a high-fiber diet from whole grain might be due to its higher magnesium content, which might be additionally beneficial. Magnesium in fact is primarily found in bran and germ, most of which are removed in the refined grain.

Magnesium and Inflammation

Some recent studies [4,18] have reported an inverse association between serum and dietary magnesium and CRP, which represents both a marker of systemic inflammation and a well-known predictor of diabetes, the metabolic syndrome, and cardiovascular disease. However, adjustments for fiber intake either do not [4] or do [18] attenuate these associations.

We have found a significant inverse association between the lowest magnesium tertile and hs-CRP³3mg/l, after adjustments for multiple confounders and fiber intake (OR = 2.05; 95%CI 1.30-3.25). Values of hs-CRP could be affected by dysmetabolic disorders, such as overweight, obesity, or hypertension or other metabolic abnormalities. In order to minimize the potential effects of metabolic abnormalities on hs-CRP serum values, we have performed analyses in a healthy subgroup of subjects from the whole cohort, with normal BMI and without dysmetabolic disorders [22]. In these lean healthy subjects, hs-CRP values remained inversely associated with magnesium intake in a multivariate model (OR = 0.26; 95%CI 0.10-0.60; p = 0.002).

In rats magnesium deficiency induces a chronic impairment of redox status associated with inflammation, which could contribute to increased oxidized lipids, and promote hypertension and vascular disorders [23]. Magnesium deficiency inhibits endothelial growth and migration and stimulates the synthesis of nitric oxide and some inflammatory markers in vivo, thus directly modulating microvascular functions [24,25]. Finally, magnesium supplementation significantly affects endothelial function, and serum and dietary magnesium values are inversely associated with mean carotid wall thickness [3]. Therefore, low-grade inflammation might be a possible mediator in the associations found between cardiovascular diseases and dietary magnesium intake.

Conclusions

A still unresolved question is whether magnesium supplementation prevents people from developing diabetes, hypertension, and the metabolic syndrome. Further well-designed randomized trials are warranted, to avoid over-estimation and bias, and to determine long-term safety and benefits of magnesium supplementation.

References

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