Effect of magnesium treatment on vitamin D resistance

描述(由申请人提供)：在对一组有结直肠腺瘤病史的患者进行的临床试验中，我们建议评估补充镁(Mg)对血清维生素D代谢物水平的影响。尽管食物强化和饮食补充，维生素D缺乏/缺乏在美国仍然相对普遍。许多流行病学研究一直发现，维生素D水平低与患包括结直肠癌(CRC)在内的非骨骼慢性疾病的风险增加有关。然而，随机临床试验产生了不一致的结果。一个引人注目的观察是，血清25-羟基维生素D(25(OH)D)水平的很大一部分人与人之间的差异是无法解释的。此外，补充相同剂量的维生素D后，血清25(OH)D的水平存在显著的个体差异。镁在维生素D的合成和代谢中起着关键作用，决定25(OH)D水平的3种关键酶的活性可能依赖于镁。此外，镁缺乏与“镁依赖型维生素D抗性软骨病”有关，补充镁可显著逆转对维生素D治疗的耐药性。最近，我们发现镁的摄入量与维生素D的摄入量显著地相互作用，这与维生素D缺乏和不足的风险有关。此外，我们发现血清25(OH)D与死亡率的关系，包括结直肠癌的死亡率，可能会被镁摄入量改变，而与高血清25(OH)D浓度相关的风险降低主要出现在镁摄入量中值的人群中。我们对镁-维生素D相互作用的新发现可以解释25(OH)D水平的一些变化，并可能提供另一种可能的解释来解释以前的不一致。最近，一项动物研究发现，缺乏镁的饮食显著降低了主要将25(OH)D转化为其活性形式的酶1，25-二羟基维生素D(1，25(OH)D)的mRNA，并显著增加了主要将25(OH)D转化为24，25-二羟基维生素D(24，25(OH)D)的酶的mRNA表达。此外，一项补充维生素D的随机临床试验观察到维生素D代谢物转化率的变化，其中25(OH)D的转化率显著增加到24，25(OH)D，但血清24，25(OH)D与血清25(OH)D的比率仅受到维生素D补充的短暂和轻微的影响。此外，最初的比率预测了维生素D治疗的疗效(即 25(OH)D)。基于这些发现，我们假设补充镁降低了24，25(OH)D和24，25(OH)D/25(OH)D的比值(这是镁缺乏的两个标志)，从而提高了对维生素D的抵抗力，降低了结直肠癌的风险。为了验证假设，我们建议在180人(90 mg治疗组和90个安慰剂组)进行为期12周的镁干预之前和结束时，测量血清中24，25(OH)D、25(OH)D和1，25(OH)D的水平。这项研究将首次评估补充镁对维生素D抵抗的影响，并将为未来的预防试验奠定基础。

DESCRIPTION (provided by applicant): In the setting of an on-going clinical trial in a population of patients with a history of colorectal adenoma, we are proposing to evaluate the effect of magnesium (Mg) supplementation on serum levels of vitamin D metabolites. Despite food fortification and dietary supplementation, vitamin D insufficiency/deficiency is still relativly common in the US. Many epidemiologic studies consistently found that low vitamin D status was associated with increased risks of non-skeletal chronic diseases including colorectal cancer (CRC). However, randomized clinical trials generated inconsistent results. One striking observation is that a large portion of the inter-person variation in serum 25- hydroxyvitamin D (25(OH)D) levels is unexplained. Further, there is a substantial inter-individual variation in serum 25(OH)D in response to the same dose of vitamin D supplementation. Mg plays a critical role in the synthesis and metabolism of vitamin D. The activities of 3 key enzymes determining 25(OH)D level may be Mg-dependent. Further, Mg deficiency has been implicated in "Mg-dependent vitamin-D-resistant rickets" and Mg supplementation substantially reversed resistance to vitamin D treatment. Very recently, we found intake of Mg significantly interacted with intake of vitamin D in relation to risks of vitamin D deficiency and insufficiency. Furthermore, we found the associations of serum 25(OH)D with mortality, including mortality due to CRC, may be modified by Mg intake, and the reduction in risk associated with high serum concentrations of 25(OH)D appeared primarily among those with Mg intake e median. Our novel finding of Mg-vitamin D interaction may explain some of the variability in 25(OH)D levels and may provide another possible interpretation to explain previous inconsistencies. Very recently, an animal study found the Mg-deficient diet significantly reduced the mRNA of the enzyme that primarily converts 25(OH)D to its active form, 1,25-dihydroxyvitamin D (1,25(OH)D), and significantly increased mRNA expression of the enzyme which mainly converts 25(OH)D to 24,25- dihydroxyvitamin D (24,25(OH)D). Further, a randomized clinical trial of vitamin D supplementation observed changes in vitamin D metabolite conversion with a significant increase in conversion of 25(OH)D to 24,25(OH)D. However, the ratio of serum 24,25(OH)D to serum 25(OH)D was only temporarily and slightly affected by vitamin D supplementation. Furthermore, the initial ratio predicted the efficacy of vitamin D treatment (i.e. rise in 25(OH)D). Based on these findings, we hypothesize that Mg supplementation reduces 24,25(OH)D and the ratio of 24,25(OH)D/ 25(OH)D (two markers of Mg deficiency), and, thus, improves resistance to vitamin D and reduces risk of CRC. To test hypothesis, we propose to measure serum levels of 24,25(OH)D, 25(OH)D, and 1,25 (OH)D in samples collected prior to and at the conclusion of a 12-week Mg intervention in 180 individuals (90 Mg-treatment and 90 placebo). This study will be the first to evaluate the effect of Mg supplementation on resistance to vitamin D and will lay the foundation for future prevention trials.