Effects of a 1-year supplementation with cholecalciferol on interleukin-6, tumor necrosis factor-alpha and insulin resistance in overweight and obese subjects.

Insufficient vitamin D status has been linked to autoimmune diseases, cancer and metabolic disorders, like obesity and insulin resistance. In vitro and animal studies suggest that vitamin D may play a crucial role in immune activation and inflammation. The relation between vitamin D and pro-inflammatory cytokines is not completely established. Furthermore, it is not known if the effect of vitamin D on entities of metabolic syndrome is mediated through its effect on cytokines or other biomarkers. The objectives of this study were to investigate if there is a relationship between vitamin D status and such pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and high sensitive C-reactive protein (hs-CRP) in patients with overweigh and obesity. We also proposed that the intervention with high dose of cholecalciferol may have effect on the cytokine levels and result in corresponding changes in the measures of insulin resistance (HOMA-IR and QUICKI). Serum levels of IL-6, TNF-α and hs-CRP were measured in 332 overweight and obese subjects who completed a 1-year randomised intervention with either 40,000 IU vitamin D (cholecalciferol) per week or 20,000 IU vitamin D per week, or placebo. We found significant associations between IL-6, TNF-α, vitamin D and insulin resistance indices at baseline. One year intervention with vitamin D decreased serum IL-6 levels; however hs-CRP levels were significantly increased. Neither measures of insulin resistance, nor TNF-α were influenced by a 1-year vitamin D supplementation.

Macular Layer Thickness and Effect of BMI, Body Fat, and Traditional Cardiovascular Risk Factors: The Tromsø Study.

Purpose: The purpose of this study was to investigate associations between cardiovascular risk factors and the thickness of retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), and outer retina layers (ORL). Methods: In this population-based study, we included participants from the Tromsø Study: Tromsø6 (2007 to 2008) and Tromsø7 (2015 to 2016). Persons with diabetes and/or diagnosed glaucoma were excluded from this study. Retinal thickness was measured on optical coherence tomography (Cirrus HD-OCT) macula-scans, segmented on RNFL, GCIPL, and ORL and associations were analyzed cross-sectionally (N = 8288) and longitudinally (N = 2595). We used directed acyclic graphs (DAGs) for model selection, and linear regression to adjust for confounders and mediators in models assessing direct effects. Factors examined were age, sex, blood pressure, daily smoking, serum lipids, glycated hemoglobin, body mass index (BMI), total body fat percentage (BFP), and the adjustment variables refraction and height. Results: The explained variance of cardiovascular risk factors was highest in GCIPL (0.126). GCIPL had a strong negative association with age. Women had thicker GCIPL than men at higher age and thinner ORL at all ages (P < 0.001). Systolic blood pressure was negatively associated with RNFL/GCIPL (P = 0.001/0.004), with indication of a U-shaped relationship with GCIPL in women. The negative association with BMI was strongest in men, with significant effect for RNFL/GCIPL/ORL (P = 0.001/<0.001/0.019) and in women for GCIPL/ORL (P = 0.030/0.037). BFP was negatively associated with GCIPL (P = 0.01). Higher baseline BMI was associated with a reduction in GCIPL over 8 years (P = 0.03). Conclusions: Cardiovascular risk factors explained 12.6% of the variance in GCIPL, with weight and blood pressure the most important modifiable factors.

Tracking of serum 25-hydroxyvitamin D levels during 14 years in a population-based study and during 12 months in an intervention study.

Low serum 25-hydroxyvitamin D (25(OH)D) levels are associated with risk factors for cardiovascular disease, and they also appear to predict later development of type 2 diabetes, cancer, and an increased mortality rate. These predictions are all based on a single 25(OH)D measurement, but so far there are no known reports on tracking of serum 25(OH)D levels. In the present Norwegian study, serum 25(OH)D levels were measured 1) in 2,668 subjects in the 1994 and 2008 Tromsø surveys and 2) every third month for 1 year in 94 subjects randomly assigned to placebo in a vitamin D intervention study. There was a marked seasonal variation in 25(OH)D, and, depending on the method of adjusting for season, the correlation coefficient between serum 25(OH)D measurements from 1994 and 2008 ranged from 0.42 to 0.52. In the 1-year intervention study, the correlation between baseline and 12-month values was 0.80. Apart from the effect of season, changes in weight, intake of vitamin D, and physical activity were related to change in serum 25(OH)D levels. Tracking of serum 25(OH)D appears similar to that for blood pressure and serum lipids, and it provides some support for the use of a single 25(OH)D measurement to predict future health outcomes.

No effect of supplementation with cholecalciferol on cytokines and markers of inflammation in overweight and obese subjects.

Epidemiological studies indicate a relation between vitamin D status and autoimmune diseases, and in vitro studies demonstrate an effect of 1,25-dihydroxyvitamin D on immune activation. However, the relation between serum levels of 25-hydroxyvitamin D (25(OH)D) and the effect of vitamin D supplementation on serum levels of cytokines are not settled. In the present study interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, intercellular adhesion molecule-1, interferon-gamma, monocyte chemotactic protein-1, and high sensitivity C-reactive protein, were measured in 437 overweight subjects and 324 completed a one year intervention with 40,000 IU vitamin D per week (group DD), 20,000 IU vitamin D per week (group DP), or placebo (group PP). No consistent relations between serum levels of the cytokines and 25(OH)D were found at baseline. In the intervention study, there was no difference in delta values (value at end of study minus value at inclusion) between the three groups regarding the individual cytokines measured, nor was there any indication of a polarization of the T cells towards a Th2 dominant type. In conclusion, we were not able to demonstrate with certainty any significant relation between serum levels of 25(OH)D levels and a number of cytokines and markers of inflammation.

Cross-sectional and longitudinal relation between serum 25-hydroxyvitamin D and body mass index: the Tromsø study.

PURPOSE: The serum 25-hydroxyvitamin D (25(OH)D) levels are lower in obese than lean subjects. The present study examines the cross-sectional and longitudinal relations between body mass index (BMI) and serum 25(OH)D, and the serum 25(OH)D response to vitamin D supplementation in relation to BMI. METHODS: The Tromsø study is a longitudinal population-based multipurpose study. The fourth survey was conducted in 1994 and the sixth in 2008. The intervention study was a 1-year placebo-controlled randomized intervention trial, where the results from the 93 subjects given 40,000 IU per week are presented. RESULTS: A total of 10,229 subjects were included in the 2008 cross-sectional study. There was a significant negative association between serum 25(OH)D levels and BMI which was also present during the winter months. Serum 25(OH)D levels varied through seasons, but not BMI. In the longitudinal study from 1994 to 2008 which included 2,656 subjects, change in BMI was a significant negative predictor of change in 25(OH)D. In the intervention study, there was a significant and negative correlation between BMI and serum 25(OH)D both at baseline and at the end of the study. The increase in serum 25(OH)D after 1 year was significantly and inversely related to baseline BMI. CONCLUSIONS: We have confirmed the strong association between serum 25(OH)D and BMI. The very obese need higher vitamin D doses than lean subjects to achieve the same serum 25(OH)D levels.

No significant effect on bone mineral density by high doses of vitamin D3 given to overweight subjects for one year.

BACKGROUND: In meta-analyses supplementation with vitamin D appears to reduce incidence of fractures, and in cross-sectional studies there is a positive association between serum 25-hydroxyvitamin D (25(OH)D) levels and bone mineral density (BMD). However, the effect of supplementation with high doses of vitamin D on BMD is more uncertain and could in theory have both positive and negative effects. METHODS: The study was a one year, double blind placebo-controlled intervention trial performed at the University Hospital of North Norway. 421 subjects, 21 - 70 years old, were included and 312 completed the study. The subjects were randomized to vitamin D3 40.000 IU per week (DD group), vitamin D3 20.000 IU per week (DP group), or placebo (PP group). All subjects were given 500 mg calcium daily. Serum 25(OH)D, osteoprotegrin (OPG), receptoractivator of nuclear factor-kappaB ligand (RANKL), and BMD at the lumbar spine and the hip were measured before and at the end of the study. RESULTS: At baseline the mean serum 25(OH)D levels were 58 nmol/L (all subjects) and increased to 141 and 100 nmol/L in the DD and DP groups, respectively. After one year, no significant differences were found between the three groups regarding change in BMD, serum OPG or RANKL. CONCLUSIONS: Supplementation with high doses of vitamin D for one year does not appear to have a negative effect on BMD in healthy subjects. In order to disclose a positive effect, subjects with low BMD and/or low serum 25(OH)D levels need to be studied. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT00243256).

Bone mineral density at the hip in Norwegian women and men--prevalence of osteoporosis depends on chosen references: the Tromsø Study.

This study describes bone mineral density (BMD) and the prevalence of osteoporosis in women and men between 30-89 years in an unselected population. BMD was measured in g/cm(2) at total hip and femoral neck by dual-energy-X-ray absorptiometry in 3,094 women and 2,132 men in the 2001 Tromsø Study. BMD levels were significantly explained by age and declined progressively in both sexes from middle into old age, with highest decline in women. With osteoporosis defined as a T-score of two and a half standard deviation below the young adult mean BMD, the prevalence at the total hip in subjects above 70 years was 6.9% in men and 15.3% in women, respectively, using the Lunar reference material for T-score calculations. The prevalence increased significantly to 7.3% in men and 19.5% in women, when T-scores were calculated on basis of the young adult mean BMD (age group 30-39 years) in the study population. At the femoral neck, prevalence of osteoporosis increased from 13.5 to 18.5% in men, and from 20.4 to 35.2% in women above 70 years, respectively, depending on how T-scores were calculated. The study highlights the challenges with fixed diagnostic levels when measuring normally distributed physiologic parameters. Although BMD only partly explains fracture risk, future studies should evaluate which calculations give optimal fracture prediction.

Supplementation with High Doses of Vitamin D to Subjects without Vitamin D Deficiency May Have Negative Effects: Pooled Data from Four Intervention Trials in Tromsø.

Data were pooled from four randomized clinical trials with vitamin D performed in Tromsø with weight reduction, insulin sensitivity, bone density, and depression scores as endpoints. Serum lipids, glycated hemoglobin (HbA1c), and high sensitivity C-Reactive Protein, (HS-CRP) were measured at baseline and after 6-12 months of supplementation with vitamin D 20 000 IU-40 000 IU per week versus placebo. A total of 928 subjects who completed the interventions were included. At baseline the mean serum 25-hydroxyvitamin D (25(OH)D) level in those given vitamin D was 55.9 (20.9) nmol/L and the mean increase was 82.4 (40.1) nmol/L. Compared with the placebo group there was in the vitamin D group at the end of the studies a slight, but significant, increase in HbA1c of 0.04%, an increase in HS-CRP of 0.07 mg/L in those with serum 25(OH)D < 50 nmol/L, and in those with low baseline HDL-C and serum 25(OH)D < 50 nmol/L a slight decrease serum HDL-C of 0.08 mmol/L (P < 0.05). No serious side-effects were seen. In conclusion, in subjects without vitamin D deficiency, there is no improvement in serum lipids, HbA1c, or HS-CRP with high dose vitamin D supplementation. If anything, the effect is negative.

Parameters of the thrombogram are associated with serum 25-hydroxyvitamin D levels at baseline, but not affected during supplementation with vitamin D.

INTRODUCTION: In vitro studies indicate an anticoagulant effect of 1,25-dihydroxyvitamin D, and sun exposure may lower the risk of thrombotic events. Accordingly, an effect on haemostatic parameters could be expected after supplementation with vitamin D. MATERIALS AND METHODS: 158 obese or overweight subjects were included in a one year intervention study with supplementation with 40.000 IU vitamin D(3) per week or placebo. All subjects were given 500 mg calcium daily. Plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator antigen (tPA Ag), and tissue factor-induced thrombin generation over time in plasma assessed by the calibrated automated thrombogram (CAT) method as a parameter of over all thrombotic activity, were measured before and at the end of the study. RESULTS: Mean baseline serum 25(OH)D level was 61.8 nmol/L and increased in the vitamin D group to 145.6 nmol/L at the end of the study. At baseline there was a significant decrease in the CAT variables lag time and time to peak of the thrombogram across increasing serum 25(OH)D quartiles, whereas no significant associations between serum 25(OH)D and PAI-1 or tPA Ag were found. After one year, no significant differences were found between the vitamin D and placebo groups regarding change in any of the haemostatic parameters. CONCLUSIONS: The association between lag time and time to peak in the CAT assay and serum 25(OH)D levels could indicate a pro-thrombotic state in subjects with high serum 25(OH)D levels, whereas the lack of effect of high dose vitamin D supplementation questions the causality of this relation.

Effect of smoking on the serum levels of 25-hydroxyvitamin D depends on the assay employed.

OBJECTIVE: Because we found higher serum 25-hydroxyvitamin D (25(OH)D) levels among smokers than among non-smokers with analyses using an electrochemiluminescence immunoassay (ECLIA) from Roche, the purpose of the present study was to examine whether this difference between smokers and non-smokers was maintained using other serum 25(OH)D assays. DESIGN: A cross-sectional population-based study on 6932 participants from the Tromsø study, 1994-1995, and one validation study comparing six different serum 25(OH)D assays in 53 non-smokers and 54 smokers were performed. METHODS: The association between smoking, season and serum 25(OH)D as measured by ECLIA (Roche) was assessed in the population-based study using general linear models with multivariate adjustments. In the validation study, serum levels of 25(OH)D were analysed with liquid chromatography coupled with mass spectrometry assay from two different laboratories, RIA (DiaSorin), HPLC, RIA (IDS) and ECLIA (Roche). T-tests and linear mixed model analyses were performed to compare the serum 25(OH)D levels in smokers and non-smokers within and between the methods. RESULTS: In the population-based study, the serum levels of 25(OH)D using the ECLIA method were 51.9, 53.2 and 72.0 nmol/l in never, former and current smokers (P<0.01). In the validation study, the serum concentration of 25(OH)D was 10.3 nmol/l higher in smokers than in non-smokers (P<0.01) using the ECLIA (Roche), while non-significantly lower serum levels of 25(OH)D were found in smokers using the other five methods. CONCLUSIONS: These two studies indicate that the ECLIA (Roche) overestimates serum 25(OH)D levels in smokers by unknown mechanisms. If confirmed, this might have clinical consequences, and the issue needs further exploration.

The association between serum parathyroid hormone and bone mineral density, and the impact of smoking: the Tromso Study.

OBJECTIVE: To explore the relation between serum parathyroid hormone (PTH) and bone mineral density (BMD), adjusted for lifestyle factors including smoking. DESIGN: Cross-sectional study. METHODS: The Tromsø Study is a population-based study performed for the fifth time in 2001. Serum PTH was measured and the subjects filled in a questionnaire covering lifestyle factors. BMD at the hip, distal and ultradistal forearm was measured. RESULTS: Complete datasets were available in 1442 men and 1368 women. Age, body mass index and serum PTH were strong predictors of BMD level at the hip in both genders. No significant relation was seen between serum PTH and BMD at the distal or ultradistal forearm. When smokers and non-smokers were analysed separately, the relation between PTH and BMD at the hip was significant in current non-smokers only. In males, current non-smokers had significantly higher BMD at all three measurement sites compared with current smokers. Male former smokers had values in between current and never smokers. There was a significant and negative relation between number of years smoked and BMD at the hip. In male former smokers, there was an increase in BMD with increasing years since smoking cessation. CONCLUSION: Serum PTH is negatively associated with BMD at the hip, and the relation seems to be masked, or diminished, by smoking. Smoking reduces BMD at the hip, distal and ultradistal forearm in males, and the effect appears to be mainly time and not dose dependent.