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      Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data

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          Abstract

          Background

          A large number of observational studies have reported harmful effects of low 25-hydroxyvitamin D (25OHD) levels on non-skeletal outcomes. We performed a systematic quantitative review on characteristics of randomized clinical trials (RCTs) included in meta-analyses (MAs) on non-skeletal effects of vitamin D supplementation.

          Methods and findings

          We identified systematic reviews (SR) reporting summary data in terms of MAs of RCTs on selected non-skeletal outcomes. For each outcome, we summarized the results from available SRs and scrutinized included RCTs for a number of predefined characteristics. We identified 54 SRs including data from 210 RCTs. Most MAs as well as the individual RCTs reported null-findings on risk of cardiovascular diseases, type 2 diabetes, weight-loss, and malignant diseases. Beneficial effects of vitamin D supplementation was reported in 1 of 4 MAs on depression, 2 of 9 MAs on blood pressure, 3 of 7 MAs on respiratory tract infections, and 8 of 12 MAs on mortality. Most RCTs have primarily been performed to determine skeletal outcomes, whereas non-skeletal effects have been assessed as secondary outcomes. Only one-third of the RCTs had low level of 25OHD as a criterion for inclusion and a mean baseline 25OHD level below 50 nmol/L was only present in less than half of the analyses.

          Conclusions

          Published RCTs have mostly been performed in populations without low 25OHD levels. The fact that most MAs on results from RCTs did not show a beneficial effect does not disprove the hypothesis suggested by observational findings on adverse health outcomes of low 25OHD levels.

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          Most cited references209

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          The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis.

          Altered vitamin D and calcium homeostasis may play a role in the development of type 2 diabetes mellitus (type 2 DM). EVIDENCE ACQUISITION AND ANALYSES: MEDLINE review was conducted through January 2007 for observational studies and clinical trials in adults with outcomes related to glucose homeostasis. When data were available to combine, meta-analyses were performed, and summary odds ratios (OR) are presented. Observational studies show a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalent type 2 DM or metabolic syndrome [OR (95% confidence interval): type 2 DM prevalence, 0.36 (0.16-0.80) among nonblacks for highest vs. lowest 25-hydroxyvitamin D; metabolic syndrome prevalence, 0.71 (0.57-0.89) for highest vs. lowest dairy intake]. There are also inverse associations with incident type 2 DM or metabolic syndrome [OR (95% confidence interval): type 2 DM incidence, 0.82 (0.72-0.93) for highest vs. lowest combined vitamin D and calcium intake; 0.86 (0.79-0.93) for highest vs. lowest dairy intake]. Evidence from trials with vitamin D and/or calcium supplementation suggests that combined vitamin D and calcium supplementation may have a role in the prevention of type 2 DM only in populations at high risk (i.e. glucose intolerance). The available evidence is limited because most observational studies are cross-sectional and did not adjust for important confounders, whereas intervention studies were short in duration, included few subjects, used a variety of formulations of vitamin D and calcium, or did post hoc analyses. Vitamin D and calcium insufficiency may negatively influence glycemia, whereas combined supplementation with both nutrients may be beneficial in optimizing glucose metabolism.
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            Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain.

            Despite a growing body of evidence that Vitamin D is involved in mammalian brain functioning, there has been a lack of direct evidence about its role in the human brain. This paper reports, for the first time, the distribution of the 1,25-dihydroxyvitamin D3 receptor (VDR), and 1alpha-hydroxylase (1alpha-OHase), the enzyme responsible for the formation of the active vitamin in the human brain. The receptor and the enzyme were found in both neurons and glial cells in a regional and layer-specific pattern. The VDR was restricted to the nucleus whilst 1alpha-OHase was distributed throughout the cytoplasm. The distribution of the VDR in human brain was strikingly similar to that reported in rodents. Many regions contained equivalent amounts of both the VDR and 1alpha-OHase, however the macrocellular cells within the nucleus basalis of Meynert (NBM) and the Purkinje cells in the cerebellum expressed 1alpha-OHase in the absence of VDR. The strongest immunohistochemical staining for both the receptor and enzyme was in the hypothalamus and in the large (presumably dopaminergic) neurons within the substantia nigra. The observed distribution of the VDR is consistent with the proposal that Vitamin D operates in a similar fashion to the known neurosteroids. The widespread distribution of 1alpha-OHase and the VDR suggests that Vitamin D may have autocrine/paracrine properties in the human brain.
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              Visceral fat adipokine secretion is associated with systemic inflammation in obese humans.

              Although excess visceral fat is associated with noninfectious inflammation, it is not clear whether visceral fat is simply associated with or actually causes metabolic disease in humans. To evaluate the hypothesis that visceral fat promotes systemic inflammation by secreting inflammatory adipokines into the portal circulation that drains visceral fat, we determined adipokine arteriovenous concentration differences across visceral fat, by obtaining portal vein and radial artery blood samples, in 25 extremely obese subjects (mean +/- SD BMI 54.7 +/- 12.6 kg/m(2)) during gastric bypass surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Mean plasma interleukin (IL)-6 concentration was approximately 50% greater in the portal vein than in the radial artery in obese subjects (P = 0.007). Portal vein IL-6 concentration correlated directly with systemic C-reactive protein concentrations (r = 0.544, P = 0.005). Mean plasma leptin concentration was approximately 20% lower in the portal vein than in the radial artery in obese subjects (P = 0.0002). Plasma tumor necrosis factor-alpha, resistin, macrophage chemoattractant protein-1, and adiponectin concentrations were similar in the portal vein and radial artery in obese subjects. These data suggest that visceral fat is an important site for IL-6 secretion and provide a potential mechanistic link between visceral fat and systemic inflammation in people with abdominal obesity.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                7 July 2017
                2017
                : 12
                : 7
                : e0180512
                Affiliations
                [1 ]Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
                [2 ]Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork, Ireland
                [3 ]Icelandic Heart Association, Kopavogur, Iceland
                [4 ]Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
                [5 ]Swiss Cardiovascular Centre Bern, Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
                [6 ]Tromsø Endocrine Research Group, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway
                [7 ]Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
                [8 ]Department of Internal Medicine, Section of Endocrinology, Vrije University Medical Center, Amsterdam, Netherlands
                [9 ]Amsterdam Public Health Research Institute, Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, Netherlands
                University of Alabama at Birmingham, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-2152-4247
                Article
                PONE-D-17-18246
                10.1371/journal.pone.0180512
                5501555
                28686645
                8fa6f001-f3df-42f3-988f-5c3239d0b8cf
                © 2017 Rejnmark et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 14 May 2017
                : 18 June 2017
                Page count
                Figures: 1, Tables: 1, Pages: 39
                Funding
                Funded by: European Community’s Seventh Framework Programme (FP7/2007-2013)
                Award ID: 613977
                Award Recipient :
                This project has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 613977 for the ODIN Integrated Project [Food-based solutions for optimal vitamin D nutrition and health through the life cycle, http://www.odin-vitd.eu/].
                Categories
                Research Article
                Physical sciences
                Chemistry
                Chemical compounds
                Organic compounds
                Vitamins
                Vitamin D
                Physical sciences
                Chemistry
                Organic chemistry
                Organic compounds
                Vitamins
                Vitamin D
                Research and Analysis Methods
                Research Design
                Observational Studies
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Vitamins
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Vitamins
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Birth Weight
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Birth Weight
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Mood Disorders
                Depression
                Medicine and Health Sciences
                Cardiovascular Medicine
                Cardiovascular Diseases
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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