Association of Vitamin D with Severity and Outcome of COVID-19: Clinical and Experimental Evidence.

INTRODUCTION: The role of vitamin in COVID-19 remains controversial. We investigated the association between endogenous vitamin D and the severity of COVID-19 as well as the mechanisms of action of vitamin D supplementation. METHODS: 25(OH)D3 in serum was associated with disease severity and outcome in 190 COVID-19 patients. In a COVID-19 animal model using intravenous injection of plasma from patients with COVID-19 acute respiratory distress syndrome into C57/BL6 mice, mice were treated with 0.25 µg human 1,25(OH)D3 or vehicle. Mice were sacrificed on day 4. Cytokines and myeloperoxidase (MPO) in tissues were measured. Changes in gene expression after vitamin D supplementation were measured. RESULTS: Vitamin D deficiency and insufficiency were associated with increased severity and unfavorable outcome after 28 days. Vitamin D levels were negatively associated with biomarkers of COVID-19 severity. Vitamin D supplementation after challenge of mice with COVID-19 plasma led to reduced levels of TNFα, IL-6, IFNγ, and MPO in the lung, as well as down-regulation of pro-inflammatory pathways. CONCLUSION: Normal levels of endogenous vitamin D are associated with reduced severity and risk of unfavorable outcome in COVID-19, possibly through attenuation of tissue-specific hyperinflammation.

Compromised NHE8 Expression Is Responsible for Vitamin D-Deficiency Induced Intestinal Barrier Dysfunction.

Objectives: Vitamin D (VitD) and Vitamin D receptor (VDR) are suggested to play protective roles in the intestinal barrier in ulcerative colitis (UC). However, the underlying mechanisms remain elusive. Evidence demonstrates that Na+/H+ exchanger isoform 8 (NHE8, SLC9A8) is essential in maintaining intestinal homeostasis, regarded as a promising target for UC therapy. Thus, this study aims to investigate the effects of VitD/VDR on NHE8 in intestinal protection. Methods: VitD-deficient mice, VDR-/- mice and NHE8-/- mice were employed in this study. Colitis mice were established by supplementing DSS-containing water. Caco-2 cells and 3D-enteroids were used for in vitro studies. VDR siRNA (siVDR), VDR over-expression plasmid (pVDR), TNF-α and NF-κb p65 inhibitor QNZ were used for mechanical studies. The expression of interested proteins was detected by multiple techniques. Results: In colitis mice, paricalcitol upregulated NHE8 expression was accompanied by restoring colonic mucosal injury. In VitD-deficient and VDR-/- colitis mice, NHE8 expression was compromised with more serious mucosal damage. Noteworthily, paricalcitol could not prevent intestinal barrier dysfunction and histological destruction in NHE8-/- mice. In Caco-2 cells and enteroids, siVDR downregulated NHE8 expression, further promoted TNF-α-induced NHE8 downregulation and stimulated TNF-α-induced NF-κb p65 phosphorylation. Conversely, QNZ blocked TNF-α-induced NHE8 downregulation in the absence or presence of siVDR. Conclusions: Our study indicates depressed NHE8 expression is responsible for VitD-deficient-induced colitis aggravation. These findings provide novel insights into the molecular mechanisms of VitD/VDR in intestine protection in UC.

The Role of Vitamin D and Its Molecular Bases in Insulin Resistance, Diabetes, Metabolic Syndrome, and Cardiovascular Disease: State of the Art.

In the last decade, an increasing awareness was directed to the role of Vitamin D in non-skeletal and preventive roles for chronic diseases. Vitamin D is an essential hormone in regulating calcium/phosphorous balance and in the pathogenesis of inflammation, insulin resistance, and obesity. The main forms of vitamin D, Cholecalciferol (Vitamin D3) and Ergocalciferol (Vitamin D2) are converted into the active form (1,25-dihydroxyvitamin D) thanks to two hydroxylations in the liver, kidney, pancreas, and immune cells. Some anti-inflammatory cytokines are produced at higher levels by vitamin D, while some pro-inflammatory cytokines are released at lower levels. Toll-Like Receptor (TLR) expression is increased, and a pro-inflammatory state is also linked to low levels of vitamin D. Regardless of how it affects inflammation, various pathways suggest that vitamin D directly improves insulin sensitivity and secretion. The level of vitamin D in the body may change the ratio of pro- to anti-inflammatory cytokines, which would impact insulin action, lipid metabolism, and the development and function of adipose tissue. Many studies have demonstrated an inverse relationship between vitamin D concentrations and pro-inflammatory markers, insulin resistance, glucose intolerance, metabolic syndrome, obesity, and cardiovascular disease. It is interesting to note that several long-term studies also revealed an inverse correlation between vitamin D levels and the occurrence of diabetes mellitus. Vitamin D supplementation in people has controversial effects. While some studies demonstrated improvements in insulin sensitivity, glucose, and lipid metabolism, others revealed no significant effect on glycemic homeostasis and inflammation. This review aims to provide insight into the molecular basis of the relationship between vitamin D, insulin resistance, metabolic syndrome, type 1 and 2 diabetes, gestational diabetes, and cardiovascular diseases.

Correlation of CYP2R1 gene promoter methylation with circulating vitamin D levels among healthy adults.

Background & objectives: Despite being a tropical country, vitamin D deficiency is highly prevalent in India with studies indicating 40-99 per cent prevalence. Apart from calcium and phosphate metabolism, vitamin D is involved in cell cycle regulation, cardiovascular, hepatoprotection. The metabolism of vitamin D is regulated by vitamin D tool genes (CYP2R1/CYP27B1/CYP24A1/VDR). The promoter regions of some of these genes have CpG islands, making them prone to methylation induced gene silencing, which may cause a reduction in circulating vitamin D levels. Epigenetic basis of vitamin D deficiency is yet to be studied in India, and hence, this pilot study was aimed to analyze whether methylation levels of CYP2R1 gene were correlated with the levels of 25(OH)D in healthy, adult individuals in Indian population. Methods: In this cross-sectional study, healthy adults of 18-45 yr of age with no history of malabsorption, thyroidectomy, chronic illness or therapeutic vitamin D supplementation were recruited. DNA methylation analysis was carried out by methylation specific quantitative PCR. Serum calcium, phosphate and vitamin D levels were also quantified. Statistical analysis was done by R 4.0.5 software. Results: A total of 61 apparently healthy adults were analyzed. The serum vitamin D levels did not correlate with CYP2R1 methylation levels in our study population. Significant positive correlation was observed between age and serum vitamin D levels. Significant association of gender was found with CYP2R1 methylation levels. Interpretation & conclusions: This study found no significant correlation between levels of CYP2R1 methylation and circulating 25(OH)D deficiency. Further studies on the Indian population having a larger sample size including entire vitamin D tool genes, among different ethnic groups may be conducted to elucidate molecular etiology of circulating 25(OH)D deficiency. The high prevalence of normal serum calcium and phosphate levels among vitamin D deficient subjects in this study coupled with the strikingly high prevalence of the deficiency at the national level, may suggest the need to revise the cut-off criteria for vitamin D deficiency in the Indian population.

Pregnancy, Breastfeeding, and Vitamin D.

Exclusive breastfeeding is considered the ideal food in the first six months of life; however, paradoxically, vitamin D content in human breast milk is clearly low and insufficient to obtain the recommended intake of 400 IU daily. This article summarizes the extraordinary metabolism of vitamin D during pregnancy and its content in human breast milk. The prevalence of hypovitaminosis D in pregnant women and/or nursing mothers and its potential maternal-fetal consequences are analyzed. The current guidelines for vitamin D supplementation in pregnant women, nursing mothers, and infants to prevent hypovitaminosis D in breastfed infants are detailed. Low vitamin D content in human breast milk is probably related to active changes in human lifestyle habits (reduced sunlight exposure).

Prenatal vitamin D supplementation mitigates inflammation-related alveolar remodeling in neonatal mice.

The development of chronic lung disease in the neonate, also known as bronchopulmonary dysplasia (BPD), is the most common long-term complication in prematurely born infants. In BPD, the disease-characteristic inflammatory response culminates in nonreversible remodeling of the developing gas exchange area, provoked by the impact of postnatal treatments such as mechanical ventilation (MV) and oxygen treatment. To evaluate the potential of prenatal treatment regimens to modulate this inflammatory response and thereby impact the vulnerability of the lung toward postnatal injury, we designed a multilayered preclinical mouse model. After administration of either prenatal vitamin D-enriched (VitD+; 1,500 IU/g food) or -deprived (VitD-; <10 IU/kg) food during gestation in C57B6 mice (the onset of mating until birth), neonatal mice were exposed to hyperoxia (FiO2 = 0.4) with or without MV for 8 h at days 5-7 of life, whereas controls spontaneously breathed room air. Prenatal vitamin D supplementation resulted in a decreased number of monocytes/macrophages in the neonatal lung undergoing postnatal injury together with reduced TGF-ß pathway activation. In consequence, neonatal mice that received a VitD+ diet during gestation demonstrated less extracellular matrix (ECM) remodeling upon lung injury, reflected by the reduction of pulmonary α-smooth muscle actin-positive fibroblasts, decreased collagen and elastin deposition, and lower amounts of interstitial tissue in the lung periphery. In conclusion, our findings support strategies that attempt to prevent vitamin D insufficiency during pregnancy as they could impact lung health in the offspring by mitigating inflammatory changes in neonatal lung injury and ameliorating subsequent remodeling of the developing gas exchange area.NEW & NOTEWORTHY Vitamin D-enriched diet during gestation resulted in reduced lung inflammation and matrix remodeling in neonatal mice exposed to clinically relevant, postnatal injury. The results underscore the need to monitor the subclinical effects of vitamin D insufficiency that impact health in the offspring when other risk factors come into play.

Determination of vitamin D3 conjugated metabolites: a complementary view on hydroxylated metabolites.

Experts typically define vitamin D deficiency levels by the determination of a circulating 25-hydroxyvitamin D3-calcifediol prohormone. A large part of the population is characterized by deficient vitamin D levels (calcifediol < 20 ng mL-1) despite individuals not being affected by any disorder. Cholecalciferol (vitamin D3) and/or calcifediol supplementation is a common practice for vitamin D-deficient individuals as recommended by international scientific societies and official agencies. In the last few years, several studies have reported the presence of conjugated vitamin D3 metabolites, mainly glucuronidation and sulfation derivatives, although simultaneous quantitative measurements involving phase I and II vitamin D metabolites have not been carried out. A quantitative method based on tandem mass spectrometry detection is proposed here for the combined determination of phase I and phase II vitamin D3 metabolites in human serum. As phase I and phase II metabolites are preferentially ionized in different modes, a switching polarity mode was adopted to determine both groups of compounds in serum at high sensitivity levels (pg mL-1). The validation of this proposal was successfully accomplished by following the Center for Drug Evaluation and Research (CDER) guidelines. Its applicability was tested in a cohort of volunteers with mostly deficient baseline levels. Considering the sulfated form of calcifediol, the sum of its concentrations showed sufficient baseline vitamin D levels in all individuals, suggesting that this could be a novel strategy for vitamin D deficiency definition. Therefore, phase II metabolites are proposed to be included when evaluating the vitamin D status since they provide more information about the overall status of the vitamin D endocrine system. Nevertheless, further studies are required to confirm the biological activity of these conjugated metabolites and the suitability of this strategy for the description of vitamin D deficiency.

Effects of Vitamin D supplementation or deficiency on metabolic phenotypes in mice of different sexes.

Vitamin D is a steroid hormone precursor that was initially recognized for its important roles in calcium-phosphate homeostasis and bone health. However, the resent prevalence of vitamin D deficiency has highlighted its non-skeletal function, such as its important role in regulating endogenous metabolism. The aim of the present study was to examine the roles of vitamin D supplementation or deficiency on metabolic phenotypes in both male and female mice by using targeted metabolomics analysis. Six weeks old C57BL/6 mice of different sexes were fed with standard chow diet (1000 IU/kg vitamin D3 contained), vitamin D deficient diet (0 IU/kg vitamin D3 contained), or vitamin D enriched diet (10,000 IU/kg vitamin D3 contained) for a total of 14 weeks. Liver pathological analysis showed that vitamin D deficiency caused significant fat deposition in both male and female mice. While vitamin D supplementation was found to improve the accumulation of fat in the liver tissue. Metabolomics analysis indicated that metabolic perturbation related to vitamin D regulation in male mice mainly involved in tricarboxylic acid cycle, fatty acylcarnitine and fatty acid metabolism, sugar metabolism, glutathione metabolism, steroid hormone and pyrimidine metabolism. Based on the criteria of VIP> 1 in OPLS-DA analysis and P < 0.05 in hypothesis test, a total of 62 metabolites and 78 metabolites were found to be significantly changed in VD-deficiency group and VD-supplement group compared with the control group, respectively. While for female mice, the metabolites disturbance mainly involved in fatty acylcarnitine and fatty acid metabolism, TCA, sugar metabolism, folate cycle, methionine cycle, and purine metabolism. A total of 38 and 57 metabolites were found to be significantly changed (VIP>1 and P < 0.05) in VD-deficiency group and VD-supplement group compared with the control group, respectively. Energy metabolism was the most relevant metabolic pathway for vitamin D regulation in both male and female mice. Sex-specific changes of fatty acyl carnitines and dehydroepiandrosterone were observed in the vitamin D supplementation groups. However, most of the energy metabolism related compounds exhibited the same trend in vitamin D supplementation groups of different sexes. Pearson's correlation analysis indicated that vitamin D was significantly correlated (P < 0.05) with the levels of D-fructose 6-phosphate, D-glucose 1-phosphate, D-glucose 6-phosphate, DL-pyroglutamic acid, 2-oxoglutarate, L-glutamic acid, and fumarate, which were all involved in the sugar metabolism pathway. The results achieved in this study demonstrated that vitamin D significantly regulated the metabolism of lipid and sugar, and the regulation showed a certain sex specificity.

Vitamin D status modulates mitochondrial oxidative capacities in skeletal muscle: role in sarcopenia.

Skeletal muscle mitochondrial function is the biggest component of whole-body energy output. Mitochondrial energy production during exercise is impaired in vitamin D-deficient subjects. In cultured myotubes, loss of vitamin D receptor (VDR) function decreases mitochondrial respiration rate and ATP production from oxidative phosphorylation. We aimed to examine the effects of vitamin D deficiency and supplementation on whole-body energy expenditure and muscle mitochondrial function in old rats, old mice, and human subjects. To gain further insight into the mechanisms involved, we used C2C12 and human muscle cells and transgenic mice with muscle-specific VDR tamoxifen-inducible deficiency. We observed that in vivo and in vitro vitamin D fluctuations changed mitochondrial biogenesis and oxidative activity in skeletal muscle. Vitamin D supplementation initiated in older people improved muscle mass and strength. We hypothesize that vitamin D supplementation is likely to help prevent not only sarcopenia but also sarcopenic obesity in vitamin D-deficient subjects.

Relevance of Vitamin D and Its Deficiency for the Ovarian Follicle and the Oocyte: An Update.

For many years, vitamin D (VD) has been known to be an essential micronutrient with important relevance not only for the skeletal system, but also for numerous other mammalian organ systems. Low levels of VD result in a VD deficiency, which is a global health problem. Moreover, VD deficiencies are linked to several pathologies, for instance, diseases of the cardiovascular system, diabetes mellitus, or sub- and infertility. In the past two decades, an increasing body of evidence has shown that adequate physiological levels of VD are crucial for the female gamete and its microenvironment, and VD deficiency has been associated with decreased live birth rates among women undergoing in vitro fertilization (IVF). With regard to the female reproductive tract, VD receptors (VDRs) have been detected in the ovary, endometrium, and the placenta. Although it has been reported that VD seems to be relevant for both calcium-dependent and independent pathways, its relevance for the oocyte's developmental competence and life span remains elusive. Therefore, herein, we aim to provide an update on the importance of VD and VD deficiency for the oocyte and the follicular microenvironment.

Immunohistochemical Expression of Vitamin D Receptor in Uterine Fibroids.

One of the many factors involved in the development of uterine fibroids is vitamin D deficiency. One aspect of this deficiency is decreased serum concentration of calcidiol-25(OH)D, a metabolite of D3 vitamin. The active form of vitamin D3, which arises after numerous enzymatic reactions, is calcitriol-1,25(OH)2D3; this compound is transported to various body tissues. Vitamin D possesses extra-genomic effects due to its influence on various signaling pathways, i.e., through activating tyrosine kinases and by genomic effects via binding to a specific nuclear receptor, vitamin D receptor (VDR). The vitamin D/VDR complex regulates the expression of genes and is involved in the pathogenesis of fibroids. Numerous studies have shown that vitamin D supplementation reduces fibroid size. It has also been shown that the expression of VDR in myoma tissue is significantly lower than in the uterine muscle tissue at the tumor periphery. However, the expression of VDR in non-myoma uterine muscle has not previously been investigated. Our VDR expression studies were performed immunohistochemically with tissue microarrays (TMA) in three tissue groups: 98 uterine myoma tissues, 98 uterine tissues (tumor margin), and 12 tissues of normal uterine muscle (i.e., without fibroids). A statistical analysis showed significantly lower VDR expression in uterine muscle at the periphery of the fibroid than in healthy uterine muscle. Lower expression of VDR at the periphery of the myoma compared to that in normal uterine muscle may indicate potential for new myomas. This observation and the described reduction in the size of fibroids after vitamin D supplementation supports the hypothesis of causal development of uterine fibroids and may be useful for the prevention of re-development in the event of their excision from the uterus.

Vitamin D and the Kidney: Two Players, One Console.

Vitamin D belongs to the group of liposoluble steroids mainly involved in bone metabolism by modulating calcium and phosphorus absorption or reabsorption at various levels, as well as parathyroid hormone production. Recent evidence has shown the extra-bone effects of vitamin D, including glucose homeostasis, cardiovascular protection, and anti-inflammatory and antiproliferative effects. This narrative review provides an overall view of vitamin D's role in different settings, with a special focus on chronic kidney disease and kidney transplant.

Elimination of Vitamin D Signaling Causes Increased Mortality in a Model of Overactivation of the Insulin Receptor: Role of Lipid Metabolism.

Vitamin D (VD) deficiency has been associated with cancer and diabetes. Insulin signaling through the insulin receptor (IR) stimulates cellular responses by activating the PI3K/AKT pathway. PTEN is a tumor suppressor and a negative regulator of the pathway. Its absence enhances insulin signaling leading to hypoglycemia, a dangerous complication found after insulin overdose. We analyzed the effect of VD signaling in a model of overactivation of the IR. We generated inducible double KO (DKO) mice for the VD receptor (VDR) and PTEN. DKO mice showed severe hypoglycemia, lower total cholesterol and increased mortality. No macroscopic tumors were detected. Analysis of the glucose metabolism did not show clear differences that would explain the increased mortality. Glucose supplementation, either systemically or directly into the brain, did not enhance DKO survival. Lipidic liver metabolism was altered as there was a delay in the activation of genes related to ß-oxidation and a decrease in lipogenesis in DKO mice. High-fat diet administration in DKO significantly improved its life span. Lack of vitamin D signaling increases mortality in a model of overactivation of the IR by impairing lipid metabolism. Clinically, these results reveal the importance of adequate Vitamin D levels in T1D patients.

Jiangzhi granule attenuates non-alcoholic steatohepatitis through modulating bile acid in mice fed high-fat vitamin D deficiency diet.

Vitamin D deficiency is a common phenomenon in non-alcoholic fatty liver disease (NAFLD) and the progressive non-alcoholic steatohepatitis (NASH). Jiangzhi Granule (JZG) formula is a Traditional Chinese medicine prescription, and has been found effective against NAFLD/NASH. Here we showed that vitamin D deficiency could accelerate NASH development, and reduce vitamin D receptor (VDR) expression. JZG treatment alleviated high-fat vitamin D deficient (HF-VDD) diet-induced NASH in C57BL/6 J mice, and up-regulated both the liver and intestinal VDR expression independent of 1,25-dihydroxy-vitamin D3 level. We analyzed the fecal BA profile using liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQMS) -based metabolomics, and found that JZG modulated fecal BA profile, predominantly increased the ratio of secondary BA species, as well as the expression of tight junction proteins Zona occludens 1(ZO-1) and occludin in the colon. In vitro experiment further confirmed the representative secondary BA species lithocholic acid (LCA) and keto-LCA upregulated the expression of and ZO-1 through VDR in LPS-stressed Caco-2 cells. Our results identified the endogenous VDR activation by JZG through modulating BA species in vitamin D deficiency-related NASH mice, thus providing evidence for the clinical application of JZG in treating NASH.

Effects of repeated infections with non-typeable Haemophilus influenzae on lung in vitamin D deficient and smoking mice.

BACKGROUND: In chronic obstructive pulmonary disease (COPD), exacerbations cause acute inflammatory flare-ups and increase the risk for hospitalization and mortality. Exacerbations are common in all disease stages and are often caused by bacterial infections e.g., non-typeable Heamophilus influenzae (NTHi). Accumulating evidence also associates vitamin D deficiency with the severity of COPD and exacerbation frequency. However, it is still unclear whether vitamin D deficiency when combined with cigarette smoking would worsen and prolong exacerbations caused by repeated infections with the same bacterial strain. METHODS: Vitamin D sufficient (VDS) and deficient (VDD) mice were exposed to nose-only cigarette smoke (CS) for 14 weeks and oropharyngeally instilled with NTHi at week 6, 10 and 14. Three days after the last instillation, mice were assessed for lung function, tissue remodeling, inflammation and immunity. The impact of VDD and CS on inflammatory cells and immunoglobulin (Ig) production was also assessed in non-infected animals while serum Ig production against NTHi and dsDNA was measured in COPD patients before and 1 year after supplementation with Vitamin D3. RESULTS: VDD enhanced NTHi eradication, independently of CS and complete eradication was reflected by decreased anti-NTHi Ig's within the lung. In addition, VDD led to an increase in total lung capacity (TLC), lung compliance (Cchord), MMP12/TIMP1 ratio with a rise in serum Ig titers and anti-dsDNA Ig's. Interestingly, in non-infected animals, VDD exacerbated the CS-induced anti-NTHi Ig's, anti-dsDNA Ig's and inflammatory cells within the lung. In COPD patients, serum Ig production was not affected by vitamin D status but anti-NTHi IgG increased after vitamin D3 supplementation in patients who were Vitamin D insufficient before treatment. CONCLUSION: During repeated infections, VDD facilitated NTHi eradication and resolution of local lung inflammation through production of anti-NTHi Ig, independently of CS whilst it also promoted autoantibodies. In COPD patients, vitamin D supplementation could be protective against NTHi infections in vitamin D insufficient patients. Future research is needed to decipher the determinants of dual effects of VDD on adaptive immunity. TRAIL REGISTRATION: ClinicalTrials, NCT00666367. Registered 23 April 2008, https://www.clinicaltrials.gov/ct2/show/study/NCT00666367 .

Vitamin D/VDR in the pathogenesis of intervertebral disc degeneration: Does autophagy play a role?

To date, the underlying mechanisms involved intervertebral disc degeneration (IDD) remain unclear, which has hindered the development of molecular biological therapy for IDD. Autophagy is vital for intracellular quality control and metabolic balance in intervertebral disc cells. Hence, autophagy homeostasis is important. Emerging evidence has implicated vitamin D (VD) and the vitamin D receptor (VDR) in IDD progression because of their effects on different autophagy steps. However, the results of clinical trials in which VD supplementation was assessed as a treatment for IDD are controversial. Furthermore, experimental studies on the interplay between VD/VDR and autophagy are still in their infancy. In view of the significance of the crosstalk between VD/VDR and autophagy components, this review focuses on the latest research on VD/VDR modulation in autophagy and investigates the possible regulatory mechanisms. This article will deepen our understanding of the relationship between VD/VDR and autophagy and suggests novel strategies for IDD prevention and treatment.

Vitamin D in Neurological Diseases.

Vitamin D may have multiple effects on the nervous system and its deficiency can represent a possible risk factor for the development of many neurological diseases. Recent studies are also trying to clarify the different effects of vitamin D supplementation over the course of progressive neurological diseases. In this narrative review, we summarise vitamin D chemistry, metabolism, mechanisms of action, and the recommended daily intake. The role of vitamin D on gene transcription and the immune response is also reviewed. Finally, we discuss the scientific evidence that links low 25-hydroxyvitamin D concentrations to the onset and progression of severe neurological diseases, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, migraine, diabetic neuropathy and amyotrophic lateral sclerosis. Completed and ongoing clinical trials on vitamin D supplementation in neurological diseases are listed.

The role of vitamin D in metabolic and reproductive disturbances of polycystic ovary syndrome: A narrative mini-review.

Vitamin D is a secosteroid hormone that plays a pivotal role in several metabolic and reproductive pathways in humans. Increasing evidence supports the role of vitamin D deficiency in metabolic disturbances and infertility in women with polycystic ovary syndrome (PCOS). Indeed, supplementation with vitamin D seems to have a beneficial role on insulin resistance (IR) and endometrial receptivity. On the other hand, exceedingly high levels of vitamin D appear to play a detrimental role on oocytes development and embryo quality. In the current review, we summarize the available evidence about the topic, aiming to suggest the best supplementation strategy in women with PCOS or, more generally, in those with metabolic disturbances and infertility. Based on the retrieved data, vitamin D seems to have a beneficial role on IR, insulin sensitivity and endometrial receptivity, but high levels and incorrect timing of administration seem to have a detrimental role on oocytes development and embryo quality. Therefore, we encourage a low dose supplementation (400-800 IU/day) particularly in vitamin D deficient women that present metabolic disturbances like PCOS. As far as the reproductive health, we advise vitamin D supplementation in selected populations, only during specific moments of the ovarian cycle, to support the luteal phase. However, ambiguities about dosage and timing of the supplementation still emerge from the clinical studies published to date and further studies are required.

Vitamin D Supplementation Improves Fasting Insulin Levels and HDL Cholesterol in Infertile Men.

CONTEXT: Vitamin D has been linked with glucose and lipid metabolism. Men with impaired gonadal function have a higher risk of metabolic syndrome and mortality, and vitamin D status may be a reversible modulator. OBJECTIVE: This work aimed to determine the effect of daily vitamin D and calcium supplementation for 150 days on glucose and lipid homeostasis in infertile men. METHODS: A single-center, double-blinded, randomized clinical trial (NCT01304927) was conducted. A total of 307 infertile men were randomly assigned (1:1) to a single dose of 300 000 IU cholecalciferol followed by 1400 IU cholecalciferol + 500 mg of calcium daily (n = 151) or placebo (n = 156) for 150 days. Reported metabolic parameters including fasting plasma glucose, glycated hemoglobin A1c, fasting serum insulin, homeostatic model assessment of insulin resistance (HOMA-IR), fasting plasma cholesterols, and triglycerides were secondary end points. The primary end point semen quality has previously been reported. RESULTS: Men receiving vitamin D supplementation improved their vitamin D status, whereas vitamin D status was aggravated in the placebo group characterized by higher serum parathyroid hormone. At the end of the trial, men receiving vitamin D supplementation had 13% lower fasting serum insulin concentrations compared with the placebo-treated group (65 vs 74 pmol/L, P = .018) and 19% lower HOMA-IR (2.2 vs 2.7, P = .025). Moreover, men in the vitamin D group had higher high-density lipoprotein (HDL) cholesterol levels (1.38 vs 1.32 mmol/L, P = .008) compared with the placebo group. CONCLUSION: High-dose vitamin D supplementation has beneficial effects on glucose homeostasis and HDL cholesterol levels in infertile men.

Effects of Vitamin D Supplementation on Insulin Sensitivity and Secretion in Prediabetes.

CONTEXT: Vitamin D regulates glucose homeostasis pathways, but effects of vitamin D supplementation on ß-cell function remain unclear. OBJECTIVE: To investigate the effects of vitamin D3 supplementation on insulin sensitivity and ß-cell function. METHODS: This is a prespecified secondary analysis of the Vitamin D and Type 2 Diabetes study. Overweight/obese adults at high risk for type 2 diabetes (prediabetes) were randomly treated with vitamin D3 4000 IU or matching placebo daily for 24 months. MAIN OUTCOME: Disposition index (DI), as an estimate of ß-cell function, was calculated as the product of Homeostasis Model Assessment 2 indices derived from C-peptide values (HOMA2%Scpep) and C-peptide response during the first 30 minutes of a 75-g oral glucose tolerance test (OGTT). RESULTS: Mean age was 60.5 ± 9.8 years and body mass index was 31.9 ± 4.4 kg/m2. Mean serum 25(OH)D level increased from 27.9 ± 10.3 ng/mL at baseline to 54.9 ng/mL at 2 years in the vitamin D group and was unchanged (28.5 ± 10.0 ng/mL) in the placebo group. The baseline DI predicted incident diabetes independent of the intervention. In the entire cohort, there were no significant differences in changes in DI, HOMA2%Scpep, or C-peptide response between the 2 groups. Among participants with baseline 25(OH)D level <12 ng/mL, the mean percent differences for DI between the vitamin D and placebo groups was 8.5 (95% CI, 0.2-16.8). CONCLUSIONS: Supplementation with vitamin D3 for 24 months did not improve an OGTT-derived index of ß-cell function in people with prediabetes not selected based on baseline vitamin D status; however, there was benefit among those with very low baseline vitamin D status.