Long-term magnesium supplementation improves glucocorticoid metabolism 103 5 Discussion In this post-hoc analysis of a randomized, controlled trial with overweight and slightly obese adults, we observed a reduction in 24-h urinary cortisol excretion after 24-wk of daily supplementation with 350 mg magnesium. Also, changes in THFs/THE and cortisol/cortisone ratios were observed, which reflects an increased kidney 11β-HSD type 2 activity. These novel findings indicate an increased inactivation of cortisol by the 11β-HSD type 2 enzyme that may be another potential mechanism by which increased dietary magnesium intake lowers CVD risk. To the best of our knowledge, this is the first human intervention trial that addressed the effect of oral magnesium supplementation on glucocorticoid metabolism, as assessed by 24-h urinary measurements of cortisol, cortisone, and their metabolites. Effects of magnesium on glucocorticoid metabolism have been previously reported by preclinical studies. A magnesium deficient diet has been shown to affect glucocorticoid metabolism in rats 15,16. The latter study showed that in rats receiving a magnesium deficient diet, corticosterone concentrations were elevated. Also, the expression of the gene encoding the enzyme 11β-HSD type 1 was increased,whereas the expression of the gene encoding the enzyme 11β-HSD type 2 was decreased. The mechanism underlying the effect of dietary magnesium restriction on altered 11β-HSD activity is unknown. Previous studies showed that 11β-HSDs are regulated by several cytokines and growth factors, including insulin-like growth factor 1 (IGF-1), as well as by gonadal steroids19–21 . Interestingly, a magnesium deficient diet in rats has been associated with reductions in serum IGF-1 22. Thus, it might be possible that the potential effects of magnesium restriction on IGF-1 underlie the effects on altered 11β-HSD activity. A limited number of clinical studies observed beneficial effects of oral magnesium supplementation on circulating cortisol concentrations 23–26. Although evidence regarding the mechanism by which magnesium lowers circulating cortisol levels is somewhat controversial, it might be that the effect is mediated by changes in the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is an endocrine feedback system in which corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the anterior pituitary to produce adrenocorticotropic hormone (ACTH), while ACTH stimulates the adrenal cortex to produce cortisol. Indeed, a previous study in mice showed deregulation of the HPA axis induced by a magnesium deficient diet, as evident by an increased transcription of the CRH and increased plasma CRH concentrations 27. Another study conducted in healthy men found that after magnesium administration, secretion of ACTH was significantly reduced 28.
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