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BACKGROUND: Systemic inflammation is common in obesity and is a key risk factor in the development and progression of type 2 diabetes. In vitro and animal studies suggest that vitamin D has anti-inflammatory functions, which are thought to occur via inhibition of the nuclear factor kappa-B (NFu03baB) pathway. However, existing clinical trials of vitamin D supplementation are limited by short durations, low doses of vitamin D, and variability in participantsu2019 vitamin D deficiency status, and no previous trials have investigated the effect of vitamin D supplementation on NFu03baB activity in vivo in humans. AIMS: We conducted a double-blind randomized placebo-controlled trial to investigate whether vitamin D supplementation, provided in a sufficient dose and duration to vitamin D-deficient individuals, would improve plasma inflammatory markers as well as reduce NFu03baB activity in peripheral blood mononuclear cells (PBMCs), compared to placebo.METHODS: Sixty-five overweight or obese (body mass index (BMI)u2265 25 kg/m2), vitamin D-deficient (25-hydroxyvitamin D (25(OH)D)u2264 50 nmol/l) adults were randomized to either a bolus oral dose of 100,000 IU followed by 4,000 IU daily of cholecalciferol, or matching placebo for 16 weeks. Before and after intervention, we measured anthropometry: BMI, waist-to-hip ratio (WHR) and % body fat by dual energy X-ray absorptiometry; serum 25-hydroxyvitamin D (25(OH)D) concentrations (chemiluminescent immunoassays); plasma inflammatory markers: high sensitivity C-reactive protein (hsCRP; rate turbidimetry), tumor necrosis factor-alpha (TNF-u03b1), monocyte chemoattractant protein-1 (MCP-1), and interleukins (IL)-1u03b2, -6, -8, -10, -12, -18, -23 and -33 (multiplex assay; flow cytometry); and NFu03baB activity in PBMCs (DNA-binding assays). Questionnaires were used to collect data on sun exposure habits and dietary vitamin D intake (3-day food record).RESULTS: Fifty-four participants completed the study (35 males/ 19 females; age= 31.9 u00b1 8.5 years; BMI= 30.9 u00b1 4.4 kg/m2 (mean u00b1 SD)). There were no differences in demographic, anthropometric, or biochemical parameters between vitamin D and placebo groups at baseline. Serum 25(OH)D concentrations increased with vitamin D supplementation compared with placebo (57.0 u00b1 21.3 versus 1.9 u00b1 15.1 nmol/l, p
While the skeletal effects of vitamin D are well-documented, the role and importance of vitamin D outside of bone health has not been well-established. Vitamin D receptors are located in nearly every tissue of the body, and low levels of vitamin D are associated with a range of various diseases. This book provides an in-depth examination of these extraskeletal effects of vitamin D and the associations between vitamin D deficiency and various disease states. Beginning with a review of the biochemistry and physiology of vitamin D, subsequent chapters investigate its relationship to autoimmune and infectious diseases, various forms of cancer, endocrine issues such as diabetes, obesity and reproductive function, cardiovascular disease and muscle weakness. Concluding chapters discuss the role of vitamin D in neurological disorders, including Alzheimer's Disease, and cognitive function. Focusing on extraskeletal effects only across a range of conditions, Extraskeletal Effects of Vitamin D will be an important resource for clinical endocrinologists and primary care physicians.
Obesity accounts for $168 billion in annual medical expenses and increases the risk of cardiovascular disease, cancer, and type-2 diabetes, three diseases responsible for over 50% of deaths in the United States. It is well established that the pattern of adiposity is an important factor in the relationship with disease risk and that visceral adiposity, which favors hypertrophy (characterized by enlarged cells) is more dangerous than subcutaneous adiposity, which tends to be hyperplastic (characterized by an increase in cell number). Hypertrophy is associated with inflammation and insulin resistance, and hyperplasia (adipogenesis, i.e., the formation of new adipocytes), is associated with improved insulin sensitivity. Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine that activates a nuclear factor-kappa B (NFKB) intracellular pathway that is an important mediator of obesity-associated insulin resistance and increased risk of type-2 diabetes. Interestingly, obesity has been positively associated with both low vitamin D status and elevated levels of TNF-alpha. Our studies focused on examining the influence of the active vitamin D hormone, 1,25-dihydroxyvitamin D, and TNF-alpha on adipogenesis and inflammation in human primary adipocytes and determining whether the balance of these two factors influences the extent to which adipocytes accumulate lipid or express pro-inflammatory cytokines. We found no effect of 1,25-dihydroxyvitamin D on adipogenesis or pro-adipogenic gene expression despite a clear upregulation of a vitamin D responsive gene, 24-hydroxylase, in response to treatment with 1,25-dihydroxyvitamin D. TNF-alpha clearly inhibited adipogenesis and expression of PPAR-gamma and C/EBP-alpha and enhanced expression of the pro-inflammatory cytokines IL-6 and MCP-1, but not IL-8. There was a trend towards a dose-dependent downregulation of MCP-1 by 1,25-dihydroxyvitamin D in three individuals; however, this effect was not statistically significant. While we found no interaction between TNF-alpha and 1,25-dihydroxyvitamin D on adipogenesis, there is a potential anti-inflammatory action of 1,25-dihydroxyvitamin D in human primary adipocytes. Future studies into this potential are warranted in light of the growing obesity epidemic and the interest in finding nutritionally modifiable treatment or prevention strategies to mitigate the negative consequences of obesity.
Vitamin D deficiency is a worldwide problem linked to numerous diseases affecting men, women, and children of all ages. Enormous progress in the study of vitamin D has been made since the first edition of this highly-acclaimed book was published nearly 20 years ago, and current research continues to draw headlines. Feldman and Pike’s Vitamin D, Fifth Edition continues to build on the successful formula from previous editions, taking the reader from the basic elements of fundamental research to the most sophisticated concepts in therapeutics. The two comprehensive volumes provide investigators, clinicians, and students with a comprehensive, definitive, and up-to-date compendium of the diverse scientific and clinical aspects of vitamin D, where each area is covered by both basic and clinical experts in the field. In Volume I: Biochemistry, Physiology and Diagnostics, international experts in endocrinology, bone biology, and human physiology take readers through the basic research of vitamin D. This impressive reference presents a comprehensive review of the multi-faceted actions of vitamin D relating both to skeletal and extra-skeletal action. Researchers from all areas of vitamin D will gain insight into how clinical observations and practices can feed back into the research cycle and will, therefore, be able to develop more targeted genomic and proteomic insights into the mechanisms of disease. Volume II: Health, Disease and Therapy authoritatively covers the evidence for new roles of vitamin D, ranging from organ transplantation to cancer, diabetes, inflammatory bowel disease, multiple sclerosis, and renal disease. The coverage is appropriately broad, drawing on aspects of internal medicine, pediatrics, nutrition, orthopedics, oncology, neurology, obstetrics and gynecology, and immunology, as well as, new areas for vitamin D including sports medicine, opthalmology, veterinary medicine and ICU care – including COVID-19. Clinical researchers will gain a strong understanding of the molecular basis for a particular disease and better understand future directions for research in this still-growing field. A comprehensive reference ranging from basic biochemistry, cell biology, and physiology principles to the clinical diagnostic and management implications of vitamin D Saves researchers and clinicians time in quickly accessing the very latest details on the diverse scientific and clinical aspects of vitamin D, as opposed to searching through thousands of journal articles Chapters written by the most prominent and well-published names in the field
BACKGROUND: Chronic low-grade inflammation is common in obesity and related chronic conditions, including type 2 diabetes. Vitamin D has been proposed to have anti-inflammatory properties; however the effect of vitamin D supplementation on inflammation in type 2 diabetes has not been established. AIM: We conducted a systematic review and meta-analysis to examine the effect of vitamin D supplementation on inflammatory markers compared to placebo or usual care in patients with type 2 diabetes, and to identify relevant knowledge gaps. METHODS: Medline, CINAHL, EMBASE and All EBM were systematically searched (from inception to 25 January 2017) for randomized controlled trials (RCTs) investigating the effects of vitamin D supplementation on inflammatory markers in type 2 diabetes patients. Two independent reviewers screened all full text articles (no date or language limits) for RCTs of vitamin D supplementation (any form, route, duration, and co-supplementation) compared to placebo or usual care on all inflammatory marker outcomes in patients with type 2 diabetes (on any treatment regimen and with or without comorbidities). Meta-analyses and meta-regression were conducted using random-effects models to calculate standardized mean differences (SMD) and 95%CIs. Two independent reviewers extracted data and assessed risk of bias and quality using the grading of recommendations, assessment, development and evaluation (GRADE) approach.RESULTS: Twenty-nine RCTs (n=1,780) met the inclusion criteria, 20 of which had available data for pooling. In meta-analyses of 20 RCTs (n=1,270), vitamin D-supplemented groups had lower follow-up levels of C-reactive protein (SMD: -0.23 mg/L (-0.37,-0.09); p=0.002), tumor necrosis factor-alpha (SMD: -0.49 pg/ml (-0.84,-0.15); p=0.005), and erythrocyte sedimentation rate (SMD: -0.47 mm/hr (-0.89,-0.05); p=0.03), and higher levels of leptin (SMD: 0.42 u00b5g/L (0.04, 0.81); p=0.03), compared to placebo. No differences were observed for adiponectin, interleukin-6, or E-selectin (all p>0.05). In meta-regression and subgroup analyses, age, sex, BMI, diabetes duration, baseline vitamin D status, and supplementation dose and duration did not alter the results. There was no evidence of heterogeneity (p>0.1) or publication bias (p>0.1) and most studies were low to moderate risk of bias. CONCLUSIONS: Our meta-analysis provides level one evidence that vitamin D supplementation may improve chronic low-grade inflammation in patients with type 2 diabetes. Further studies are needed to establish whether improved inflammation following vitamin D supplementation would translate into improved health outcomes for patients with type 2 diabetes. PROSPERO registration number: CRD42016047755.
Background: Low vitamin D status, high inflammation, and excess weight have been shown to be associated with adverse physical and mental health effects. The association among young otherwise healthy overweight and obese adults has not been thoroughly investigated.
Background: Obesity is an epidemic in the United States, and it is associated with the pathogenesis of many chronic diseases. Individuals who are overweight or obese (Owt/Ob) are at a higher risk of developing cardiometabolic diseases and have a higher prevalence of micronutrient deficiencies when compared to individuals with a healthy weight. Vitamin D and magnesium are two micronutrients that are commonly found to be deficient in the Owt/Ob population, and deficiencies in both nutrients are independently associated with poor cardiometabolic health. Furthermore, magnesium is an essential cofactor that aids in vitamin D metabolism. We theorized that a poor magnesium status may lead to improper vitamin D metabolism, and therefore, leading to an increase of parathyroid hormone (PTH), a hormone that is an independent predictor for elevated systemic inflammation, hypertension, and cardiovascular disease. Parathyroid hormone and vitamin D exhibit a negative relationship in healthy weight individuals. However, this expected negative relationship between vitamin D and parathyroid hormone can potentially be altered in Owt/Ob individuals with magnesium deficiency. This dissertation focused on investigating the role magnesium plays in vitamin D metabolism and the effects of a combined vitamin D and magnesium treatment in the Owt/Ob population and its effect on protecting cardiometabolic health. Methods: A cross-sectional study was first conducted to determine the relationship between magnesium status, serum 25-hydroxyvitamin D (25OHD) concentrations, and serum PTH concentrations. Secondly, we conducted a 12-week double-blinded controlled supplementation trial to determine whether a combined magnesium and vitamin D would increase serum concentrations of 25OHD, and lower serum concentrations of PTH, markers of inflammation and blood pressure. This study had three treatment arms - magnesium + vitamin D (MagD) group, vitamin D only (VitD) group, and a placebo group. Participants in the MagD Group received 360 mg magnesium glycinate + 1000 IU vitamin D3 daily, VitD Group received 1000 IU vitamin D3 daily, and Placebo Group received 10 mg of cellulose. Information such as body composition measurements was collected using Dual-energy X-ray Absorptiometry, systolic and diastolic blood pressures were collected using the American Heart Association In-clinic Guideline for Blood Pressure Measurements, blood biomarkers (serum concentrations of 25-hydroxyvitamin D, parathyroid hormone, markers of inflammation) were assessed through fasting blood samples analyses. Additional information such as anthropometry measurements and diet records were also collected. Results: In our cross-sectional study, a total of 57 Owt/Ob participants were divided into three groups according to dietary magnesium intake percentiles (Low Mg Group = 33 percentile, Medium Mg Group = 33 to 66 percentile, High Mg Group = 66 percentile). Higher serum concentrations of 25OHD were negatively associated with lower serum concentrations of PTH only in the High Mg Intake group (r=-0.472, p=0.041), but not in other groups. For the 12-week double-blinded supplementation trial, a total of 83 Owt/Ob participants were randomized into one of the three study arms. Participants in the MagD Group had a greater increase in serum 25OHD compared to participants in VitD Group, but only for those whose baseline 25OHD were less than 23.49 ng/mL. There were no statistically significant effects on PTH concentrations and markers of inflammation between and within groups. Conclusion: A low dietary magnesium intake may alter PTH response to 25OHD. Furthermore, a combined magnesium and vitamin D treatment may be more effective in raising serum 25OHD concentrations compared to vitamin D supplements alone for individuals whose 25OHD level were insufficient at baseline. However, increase in serum 25OHD concentrations may not influence systemic inflammation and blood pressure.
Background:Vitamin D supplementation has been proposed as a potential strategy for preventing type 2 diabetes and cardiovascular disease (CVD). Existing clinical trials are limited by short durations, low doses of vitamin D, variability in participantsu2019 vitamin D deficiency status, and use of surrogate measures of body composition, insulin sensitivity, and insulin secretion. Aims:To address existing knowledge gaps, we conducted a double-blind randomized placebo-controlled trial to investigate whether vitamin D supplementation, provided in a sufficient dose and duration to vitamin D-deficient individuals, would improve cardiometabolic risk factors including body fat, insulin sensitivity and secretion as measured by gold-standard methods, as well as blood pressure, serum lipids and high-sensitivity C-reactive protein (hsCRP) concentrations. We hypothesized that vitamin D supplementation would improve cardiometabolic risk factors, compared to placebo. Methods:Sixty-five overweight or obese (body mass index (BMI)u2265 25 kg/m2), vitamin D-deficient (25-hydroxyvitamin D (25OH)D)u2264 50 nmol/L) adults were randomized to either a bolus oral dose of 100,000 IU followed by 4,000 IU daily of cholecalciferol, or matching placebo for 16 weeks. Before and after intervention, participants had gold-standard assessment of body composition (% body fat by dual energy X-ray absorptiometry), insulin sensitivity (hyperinsulinemic-euglycemic clamps) and total, first phase, and second phase insulin secretion (intravenous glucose tolerance tests), as well as measurement of BMI, waist-to-hip ratio (WHR), blood pressure, pulse pressure (PP), mean arterial pressure (MAP), serum lipids (ELISA), and hsCRP (immunoturbidimetric assay). Multivariable regression was performed to assess differences between groups after adjustment for clinically relevant factors, and all analyses were adjusted for multiple testing using Bonferroni correction.Results:Fifty-four participants completed the study (35M/19F; age= 31.9 u00b1 8.5 years; BMI= 30.9 u00b1 4.4 kg/m2 (mean u00b1 SD)). Serum 25(OH)D increased with vitamin D supplementation compared to placebo (57.0 u00b1 21.3 versus 1.9 u00b1 15.1nmol/L, p=0.02). Vitamin D and placebo groups did not differ in change in anthropometric measures including BMI (0.003 u00b1 0.9 versus -0.1 u00b1 1.2, p= 0.9), WHR (-0.01 u00b1 0.04 versus 0.001 u00b1 0.01) or % body fat (-0.4 u00b1 1.6 versus -0.3 u00b1 1.7, p=0.9). There were no differences between vitamin D and placebo groups in markers of glucose metabolism, including fasting glucose (0.04 u00b1 0.5 versus 0.2 u00b1 0.4 mmol/l, p=0.9), fasting insulin (0.1 u00b1 5.9 versus 2.1 u00b1 6.3 mlU/L) insulin sensitivity (0.02 u00b1 2.0 versus -0.03 u00b1 2.8mg/kg/min, p=0.9) or total insulin secretory response (insulin area under the curve (AUC)) (-6.9 u00b1 843 versus 130 u00b1 1092 mlU/L, p=0.9), respectively. First phase insulin AUC (-21 u00b1 212 versus 24 u00b1 184 mlU/L, p=0.9) and second phase insulin AUC (13 u00b1 598 versus 124 u00b1 818 mlU/L, p=0.9) also did not differ between vitamin D and placebo groups, respectively. Cardiovascular parameters including systolic and diastolic blood pressure, PP, MAP, serum lipids (total, high-, and low- density lipoprotein cholesterol, or triglycerides) and hsCRP concentrations did not differ between groups (all p>0.1). Results remained non-significant in multivariable logistic regression models after adjustment for age, sex, and % body fat (all p>0.1), and after further adjustment for ethnicity, sun exposure, physical activity, and dietary vitamin D intake (all p>0.1).Discussion:Vitamin D supplementation does not improve cardiometabolic risk factors in vitamin D-deficient, overweight or obese adults, despite using high dose vitamin D supplementation and robust endpoint measures. It is therefore unlikely that vitamin D supplementation would be an effective strategy for reducing diabetes risk, even in vitamin D-deficient populations.
Obese adults are more susceptible to poor vitamin D status and response to supplementation than lean adults, but explanatory mechanisms remain unclear. Proposed hypotheses include increased degradation or adipose tissue sequestration of vitamin D. The purpose of this study was to investigate how plasma 25-hydroxyvitamin D3[25(OH)D3] concentrations respond to vitamin D repletion relative to changes in plasma vitamin D3 and the major degradation metabolite, 24,25-dihydroxyvitamin D3 [24,25(OH)2D3]. We also investigated how obesity and obesity-related adipose tissue inflammation affects vitamin D status. This was a randomized intervention pilot study that supplemented daily oral vitamin D3 doses of either 2,000 IU or 4,000 IU to fifteen vitamin D-deficient, overweight to obese adults for three months. At baseline and 3-month visits, we measured concentrations of vitamin D3, 25(OH)D3, and 24,25(OH)2D3 in plasma and adipose tissue using high performance liquid chromatography-tandem mass spectrometry. We also measured gene expression of the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF[alpha]), in adipose tissue. Plasma concentration of 25(OH)D3 significantly increased after supplementation (p