Chapter 5 104 Glucocorticoids are essential formaintenance of vascular tone.Findings from (pre)clinical studies have shown that 11β-HSDs are expressed in the vascular wall, presumably in vascular smooth muscle cells 29,30. In fact, a study of Hadoke et al. have demonstrated that mice with 11β-HSD type 2 knock-out developed endothelial dysfunction 31. The authors concluded that 11β-HSD type 2, rather than 11β-HSD type 1, influences vascular tone in mice. Thus, targeting this enzyme likely reduce cortisol action and may contribute to a lower CVD risk 10. Indeed, patients with Cushing’s syndrome show an increased risk of the metabolic syndrome32, which is in turn associated with increased risk of CVD 9. Alterations in the vascular system may underlie these associations. Baykan et al. showed that endothelial function in patients with Cushing’s syndrome was impaired 6. Another study observed increased arterial stiffness in these patients, which was independent of blood pressure elevation 33. Emerging evidence suggests that increasing dietary magnesium intake could be an important dietary approach to reduce the risk of CVD 1. Indeed, we previously showed a clinically relevant improvement on arterial stiffness, measured with carotid-to-femoral pulse wave velocity, after long-term magnesium supplementation2. In the current study, we found that oral magnesium supplementation significantly increased 11β-HSD type 2 activity in overweight and slightly obese adults, which may provide a mechanistic link between dietary magnesium intake and cardiovascular health benefits. It is well known that glucocorticoids contribute to insulin resistance 34. Interestingly, accumulating evidence suggest a beneficial role of magnesium in insulin sensitivity 35. Thus, it might be possible that magnesium improves glucocorticoid metabolism, thereby affecting insulin sensitivity, which in turn reduces the risk of CVD. It should be noted that in our previous study, we did not observe an effect of oral magnesium supplementation on insulin sensitivity 36. The lack of effect could be explained by the fact that the participants had baseline serum magnesium levels within the normal range. In fact, subgroup analyses of a meta-analysis that summarized the effects of oral magnesium supplementation on fasting glucose, insulin and the HOMA-IR index revealed that greater reductions of the HOMA-IR index were found in subjects with hypomagnesaemia at baseline 37. Major strengths of the present study include the double-blinded placebo-controlled design, as well as the long duration of the intervention trial. Another strength includes the use of 24-h urinary cortisol and cortisone excretion and measurements of their metabolites, which allowed us to study underlying mechanisms. Specifically, the
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