背景:身体已经进化出稳态机制,以将Ca2和1,25-二羟基维生素D[1,25(OH)2D]的游离水平维持在狭窄的生理范围内。临床指南强调PTH在维持这种稳态方面的重要贡献。
目的:研究维生素D(VitD)代谢的稳态调节机制,并应用机制见解改善VitD状态的临床评估。
方法:交叉临床试验研究参与者在补充VitD3之前和之后。
方法:社区。
方法:11名维生素D缺乏(25-羟维生素D[25(OH)D]≤20ng/mL)的健康个体。
方法:VitD3-补充剂(根据BMI,每周一次或两次50,000IU,持续4-6周),以达到25(OH)D≥30ng/mL。
结果:补充VitD3可显着增加平均25(OH)D2.7倍和24,25-二羟基维生素D[24,25(OH)2D]4.3倍。相比之下,PTH的平均水平,FGF23和1,25(OH)2D没有变化。数学模型表明,24-羟化酶活性在25(OH)D≥50ng/mL时达到最大,在25(OH)D<10-20ng/mL时达到最低(~90%抑制)。与总血浆25(OH)D(ρ=0.51;p=0.01)相比,1,25(OH)2D/24,25(OH)2D比率更好地预测了建模的24-羟化酶活性(h)(ρ=-0.85;p=0.001)和24,25(OH)2D/25(OH)D比率(ρ=0.37;p=0.3)。
结论:抑制24-羟化酶通过降低1,25(OH)2D的代谢清除,为有症状的VitD缺乏症提供了第一道防线。1,25(OH)2D/24,25(OH)2D比率提供了VitD状态的有用指数,因为它包含24,25(OH)2D水平,因此,提供了对24-羟化酶活性的洞察。当VitD可用性有限时,这抑制了24-羟化酶活性-从而降低了24,25(OH)2D的水平并增加了1,25(OH)2D/24,25(OH)2D的比率。因此,增加的1,25(OH)2D/24,25(OH)2D比率表示触发稳态调节,发生在VitD缺乏症的早期阶段。
BACKGROUND: The body has evolved homeostatic mechanisms to maintain free levels of Ca+2 and 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis.
OBJECTIVE: To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status.
METHODS: Crossover clinical trial studying participants before and after VitD3-supplementation.
METHODS: Community.
METHODS: 11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL).
METHODS: VitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D≥30 ng/mL.
RESULTS: VitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)2D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)2D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D≥50 ng/mL and achieved a minimum (∼90% suppression) with 25(OH)D<10-20 ng/mL. The 1,25(OH)2D/24,25(OH)2D ratio better predicted modeled 24-hydroxylase activity (h) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH)2D/25(OH)D ratio (ρ=0.37; p=0.3).
CONCLUSIONS: Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)2D. The 1,25(OH)2D/24,25(OH)2D ratio provides a useful index of VitD status since it incorporates 24,25(OH)2D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity - thereby decreasing the level of 24,25(OH)2D and increasing the 1,25(OH)2D/24,25(OH)2D ratio. Thus, an increased 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.