Dataset Information

Disassociation of Vitamin D's Calcemic Activity and Non-calcemic Genomic Activity and Individual Responsiveness: A Randomized Controlled Double-Blind Clinical Trial.

ABSTRACT: The aims of this randomized controlled double-blind clinical trial were to assess the impact of vitamin D supplementation on calcium metabolism and non-calcemic broad gene expression by relating them to the individual's responsiveness to varying doses of vitamin D3. Thirty healthy adults were randomized to receive 600, 4,000 or 10,000 IU/d of vitamin D3 for 6 months. Circulating parathyroid hormone (PTH), 25(OH)D, calcium and peripheral white blood cells broad gene expression were evaluated. We observed a dose-dependent increase in 25(OH)D concentrations, decreased PTH and no change in serum calcium. A plateau in PTH levels was achieved at 16 weeks in the 4000 and 10,000 IU/d groups. There was a dose-dependent 25(OH)D alteration in broad gene expression with 162, 320 and 1289 genes up- or down-regulated in their white blood cells, respectively. Our results clearly indicated that there is an individual's responsiveness on broad gene expression to varying doses of vitamin D3. Vitamin D3 supplementation at 10,000 IU/d produced genomic alterations several fold higher than 4,000 IU/d even without further changes in PTH levels. Our findings may help explain why there are some inconsistency in the results of different vitamin D's clinical trials.

SUBMITTER: Shirvani A

PROVIDER: S-EPMC6881448 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Disassociation of Vitamin D's Calcemic Activity and Non-calcemic Genomic Activity and Individual Responsiveness: A Randomized Controlled Double-Blind Clinical Trial.

Shirvani Arash A Kalajian Tyler Arek TA Song Anjeli A Holick Michael F MF

Scientific reports 20191127 1

The aims of this randomized controlled double-blind clinical trial were to assess the impact of vitamin D supplementation on calcium metabolism and non-calcemic broad gene expression by relating them to the individual's responsiveness to varying doses of vitamin D<sub>3</sub>. Thirty healthy adults were randomized to receive 600, 4,000 or 10,000 IU/d of vitamin D<sub>3</sub> for 6 months. Circulating parathyroid hormone (PTH), 25(OH)D, calcium and peripheral white blood cells broad gene expressi ...[more]

PMID: 31776371

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Project description:Vitamin D is a precursor for secosteroidal hormones, which demonstrate pleiotropic biological activities, including the regulation of growth and the differentiation of normal and malignant cells. Our previous studies have indicated that the inhibition of melanoma proliferation by a short side-chain, low calcemic analog of vitamin D-21(OH)pD is not fully dependent on the expression of vitamin D receptor (VDR). We have examined the effects of classic vitamin D metabolites, 1,25(OH)?D? and 25(OH)D?, and two low calcemic vitamin D analogs, (21(OH)pD and calcipotriol), on proliferation, mRNA expression and vitamin D receptor (VDR) translocation in three human melanoma cell lines: WM98, A375 and SK-MEL-188b (subline b of SK-MEL-188, which lost responsiveness to 1,25(OH)?D? and became VDR-/-CYP27B1-/-). All tested compounds efficiently inhibited the proliferation of WM98 and A375 melanoma cells except SK-MEL-188b, in which only the short side-chain vitamin D analog-21(OH)pD was effective. Overall, 21(OH)pD was the most potent compound in all three melanoma cell lines in the study. The lack of responsiveness of SK-MEL-188b to 1,25(OH)?D?, 25(OH)D? and calcipotriol is explained by a lack of characteristic transcripts for the VDR, its splicing variants as well as for vitamin D-activating enzyme CYP27B1. On the other hand, the expression of VDR and its splicing variants and other vitamin D related genes (RXR, PDIA3, CYP3A4, CYP2R1, CYP27B1, CYP24A1 and CYP11A1) was detected in WM98 and A375 melanomas with the transcript levels being modulated by vitamin D analogs. The expression of VDR isoforms in WM98 cells was stimulated strongly by calcipotriol. The antiproliferative activities of 21(OH)pD appear not to require VDR translocation to the nucleus, which explains the high efficacy of this noncalcemic pregnacalciferol analog in SK-MEL-188b melanoma, that is, VDR-/-. Therefore, we propose that 21(OH)pD is a good candidate for melanoma therapy, although the mechanism of its action remains to be defined.

Project description:BackgroundVitamin D deficiency is associated with obesity; whether repletion supports weight loss and changes obesity-related biomarkers is unknown.ObjectiveWe compared 12 mo of vitamin D3 supplementation with placebo on weight, body composition, insulin, and C-reactive protein (CRP) in postmenopausal women in a weight-loss intervention.DesignA total of 218 overweight/obese women (50-75 y of age) with serum 25-hydroxyvitamin D [25(OH)D] ≥10 ng/mL but <32 ng/mL were randomly assigned to weight loss + 2000 IU oral vitamin D3/d or weight loss + daily placebo. The weight-loss intervention included a reduced-calorie diet (10% weight loss goal) and 225 min/wk of moderate-to-vigorous aerobic activity. Mean 12-mo changes in weight, body composition, serum insulin, CRP, and 25(OH)D were compared between groups (intent-to-treat) by using generalized estimating equations.ResultsA total of 86% of participants completed the 12-mo measurements. The mean (95% CI) change in 25(OH)D was 13.6 (11.6, 15.4) ng/mL in the vitamin D3 arm compared with -1.3 (-2.6, -0.3) ng/mL in the placebo arm (P < 0.0001). Changes in weight [-7.1 (-8.7, -5.7) compared with -7.4 (-8.1, -5.4) kg], body mass index (in kg/m(2): both -2.8), waist circumference [-4.9 (-6.7, -2.9) compared with -4.5 (-5.6, -2.6) cm], percentage body fat [-4.1 (-4.9, -2.9) compared with -3.5 (-4.5, -2.5)], trunk fat [-4.1 (-4.7, -3.0) compared with -3.7 (-4.3, -2.9) kg], insulin [-2.5 (-3.4, -1.7) compared with -2.4 (-3.3, -1.4) μU/mL], and CRP [-0.9 (-1.2, -0.6) compared with -0.79 (-0.9, -0.4) mg/L] [corrected] were similar between groups (all P > 0.05). Compared with women who achieved 25(OH)D <32 ng/mL, women randomly assigned to vitamin D who became replete (ie, 25(OH)D ≥32 ng/mL) lost more weight [-8.8 (-11.1, -6.9) compared with -5.6 (-7.2, -5.0) kg; P = 0.05], waist circumference [-6.6 (-9.3, -4.3) compared with -2.5 (-4.6, -2.0) cm; P = 0.02], and percentage body fat [-4.7 (-6.1, -3.5) compared with -2.6 (-3.9, -2.2); P = 0.04]. Among women with complete pill counts (97% adherence), the mean decrease in CRP was 1.18 mg/mL (46%) in the vitamin D arm compared with 0.46 mg/mL (25%) in the placebo arm (P = 0.03).ConclusionsVitamin D3 supplementation during weight loss did not increase weight loss or associated factors compared with placebo; however, women who became replete experienced greater improvements. This trial was registered at clinicaltrials.gov as NCT01240213.

Dataset Information

Disassociation of Vitamin D's Calcemic Activity and Non-calcemic Genomic Activity and Individual Responsiveness: A Randomized Controlled Double-Blind Clinical Trial.

Publications

Disassociation of Vitamin D's Calcemic Activity and Non-calcemic Genomic Activity and Individual Responsiveness: A Randomized Controlled Double-Blind Clinical Trial.

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