The Role of Vitamin D Binding Protein, Total and Free 25-Hydroxyvitamin D in Diabetes

Vitamin D is important for bone health, but may also have extra-skeletal effects. Vitamin D and its binding protein DBP have immunological effects and may therefore be important in the development of type 1 diabetes (T1DM), and low serum levels of 25-hydroxyvitamin D (25(OH)D) are associated with later development of type 2 diabetes (T2DM). However, it has so far been difficult to convincingly show an effect of vitamin D supplementation on prevention or treatment of diabetes. The serum level of 25(OH)D has traditionally been used as a marker of a subject's vitamin D status. This measurement includes both 25(OH)D bound to DBP and albumin as well as the free from of 25(OH)D. However, according to the free hormone hypothesis, the free form is the biologically active. Previously the free form of 25(OH)D had to be calculated based on measurements of 25(OH)D, DBP, and albumin, but recently a method for direct measurement of free 25(OH)D has become commercially available. This is important in clinical conditions where the amount of DBP is affected, and has caused a renewed interest in which vitamin D metabolite to measure in clinical situations. In the present review the relations between DBP, total and free 25(OH)D in T1DM and T2DM are described

Lost relation between blood pressure and serum 25-hydroxyvitamin D

Background: Low serum 25-hydroxyvitamin D (25(OH)D) levels have consistently been associated with hypertension. During the last decades there has been an unexplained reduction in blood pressure (BP) in Western countries. We therefore examined the relation between serum 25(OH)D and BP in the 7th survey of the Tromsø study 2015/2016. Methods: Blood pressure and serum 25(OH)D were measured and life-style factors registered in 15,951 subjects not using BP medication. Results: In unadjusted analyses there was a significant negative association between serum 25(OH)D and systolic and diastolic BP that disappeared after adjusting for relevant confounders. This finding is in contrast to our previous reports on 25(OH)D and BP. We therefore cross-sectionally re-analyzed non-smoking (due to interference by smoking in the 25(OH)D assay) subjects not using BP medication from the 4th survey in 1994/1995 (n ¼ 4108), 6th survey in 2007/ 2008 (n ¼ 7553) and 7th survey 2015/2016 (n ¼ 13,413). Adjusting for age and BMI, there were significant inverse relations between BP and 25(OH)D in the 4th, to a lesser degree in the 6th, and none in the 7th survey. For males the age- and BMI-adjusted differences in systolic BP between those with serum 25(OH)D 100 nmol/L were 6.2 mmHg, 4.1 mmHg and 0.1 mmHg, for the 4th, 6th and 7th surveys, respectively. Conclusions: Concomitant with a substantial reduction in BP from 1994 to 2015, there has been a loss of relation between 25(OH)D and BP which is hard to explain

The effect of high-dose vitamin D supplementation on muscular function and quality of life in postmenopausal women—A randomized controlled trial

Objective: Observational studies have suggested positive associations between serum 25-hydroxyvitamin D (25(OH)D) levels and muscular strength, balance and quality of life. Our aim was to examine whether high-dose vitamin D supplementation would improve these measures as compared to standard-dose vitamin D, as well as the possible muscular effects of single nucleotide polymorphisms (SNPs) in genes encoding vitamin D-related enzymes. Design: A 12-month randomized, double-blind, controlled trial where the participants received daily elemental calcium (1000 mg) plus vitamin D3 (800 IU). In addition, the participants were randomized to receive either capsules with vitamin D3 (20 000 IU) or matching placebos to be taken twice a week. Patients: A total of 297 postmenopausal women with osteopenia or osteoporosis. Measurements: Muscle strength (handgrip and knee extensor strength), balance (tandem test) and quality of life (EQ-5D) were measured at baseline and after 12 months. The subjects were genotyped for SNPs related to vitamin D metabolism. Results: Of the 297 included women, 275 completed the study. Mean serum 25(OH)D levels dramatically increased in the high-dose group (from 64.7 to 164.1 nmol/L; P<.01), while a more moderate increased was observed in the standard-dose group (from 64.1 to 81.8 nmol/L; P<.01). There was no significant difference between the groups in change in muscular strength, balance or quality of life over the intervention period. Polymorphisms in rs3829251 (located in the 7-dehydrocholesterol reductase gene) were associated with muscle strength and treatment effects. Conclusion: One-year treatment with high-dose vitamin D had no effect on muscular strength, balance or quality of life in postmenopausal women with osteopenia or osteoporosis as compared to standard dose. The association between rs3829251 and muscle strength needs confirmation in other populations

Response to Letter to the Editor from Dalan: "Vitamin D Supplementation for Prevention of Type 2 Diabetes Mellitus: To D or Not to D?"

We thank Rinkoo Dalan for the comments on our paper (1, 2). We agree that although the reduction in diabetes risk with vitamin D supplementation among people at high risk for diabetes appears to be moderate (~ 12% relative risk reduction compared to placebo) (3), certain individuals may derive a higher (or lower) benefit based on certain characteristics. For example, in the simplest demonstration of such heterogeneity, vitamin D supplementation reduced diabetes risk by 62% among participants in the Vitamin D and Type 2 Diabetes (D2d) study who had a baseline serum 25-hydroxyvitamin D (25[OH]D) level of less than 12 ng/mL (30 mmol/L) (2). Consistent with the focus of the scientific community on precision nutrition, we agree that we need to better understand responsiveness to vitamin D supplementation for specific outcomes of interest. The vitamin D response index is an interesting concept that reflects activation of the vitamin D receptor, and it is determined on the basis of measuring vitamin D–triggered changes in the expression of 24 target genes in peripheral blood mononuclear cells and 12 clinical and biochemical parameters (4). There are at least 2 limitations: 1) Although such an index may reflect vitamin D–induced changes in specific response parameters, these changes may not necessarily translate to clinically meaningful outcomes, such as lowering diabetes risk. 2) Low-, mid-, and high-responders are determined with statistical means within a specific cohort but that can be calculated only retrospectively; specific cutoffs to define degree of response need to be established for use in real time in research or in the clinical setting. The author also suggests that daily, steady exposure to vitamin D is preferred over intermittent exposure for optimal benefit, and we agree. In a secondary analysis from the D2d study, we reported that participants who received the active intervention (100 mcg [4000 units] of vitamin D3 daily) and maintained high 25(OH)D levels that were stable throughout the trial period had the lowest risk of diabetes, whereas participants in the placebo group who maintained similar overall 25(OH)D levels that fluctuated during follow-up did not derive significant benefit (5)

Associations of serum 25-hydroxyvitamin D and subjective sleep measures in an arctic population: Insights from the population-based Tromsø Study

Objective - To investigate the relation between serum 25-hydroxyvitamin D (s-25(OH)D) and subjective sleep measures in an Arctic population (69°N). Methods - Cross-sectional data was collected from 21,083 individuals (aged ≥40 years) participating in the population based Tromsø Study: Tromsø7 (2015–2016). The present study included 20,438 participants, after having excluded respondents missing data on s-25(OH)D (n = 161) and/or subjective sleep measures (including sleep duration, insomnia, and daytime sleepiness)(n = 490). Based on s-25(OH)D (assessed using LC-MS/MS), participants were grouped as deficient (75 nmol/L). Sleep duration was grouped as inadequate (ISD) if Results - In both men and women, s-25(OH)D was positively associated with sleep duration, and compared to the sufficient s-25(OH)D group, the insufficient s-25(OH)D group reported significantly shorter sleep duration in both sexes. There was an increased odds of ISD in both men and women but adjusted for confounding factors this was only significant in women (1.16 [1.03, 1.32], p = .017). In men, there were no significant associations between s-25(OH)D and the remaining sleep measures. Women in the high s-25(OH)D group had lower ESS-scores (−0.28 [-0.47, −0.08], p = .006), but higher odds of insomnia (1.16 [1.01, 1.33], p = .036) compared to women in the sufficient group. Conclusions - In this Arctic population, a tenuous association was found between s-25(OH)D and subjective sleep measures, predominantly in women

Effect of Vitamin D Supplementation on Psoriasis Severity in Patients With Lower-Range Serum 25-Hydroxyvitamin D Levels A Randomized Clinical Trial

Importance - Topical vitamin D analogues are routine treatment for psoriasis, but the effect of oral supplementation has not been established. Objective - To examine the effect of vitamin D supplementation on psoriasis severity throughout the winter. Design, Setting, and Participants - This randomized, double-blind placebo-controlled clinical trial with 2 parallel groups was performed through 2 winter seasons (2017 to 2018 and 2018 to 2019). Randomization was computer generated. All participants, health care clinicians, and outcome assessors were masked to group assignment. Each participant was followed for 4 months. The presented analyses were conducted in May 2022. The trial was conducted at the clinical research unit of the University Hospital of North Norway (Tromsø; Norway). Adults from the general population in Tromsø with active plaque psoriasis and 25-hydroxyvitamin D (25[OH]D) levels of less than 24 ng/mL (to convert to nmol/L, multiply by 2.496) were included. Intervention - Vitamin D (cholecalciferol, 100 000 IU, loading dose, followed by 20 000 IU/week) or placebo for 4 months. Main outcomes and Measures - Psoriasis Area Severity Index (PASI) (primary outcome), Physician Global Assessment, self-administered PASI, and Dermatology Life Quality Index scores (secondary outcomes). Results - A total of 122 participants (46 women [37.7%]; mean [SD] age, 53.6 [10.0] years; mean [SD] PASI score, 3.1 [2.0]; mean [SD] serum 25(OH)D, 14.9 [3.9] ng/mL) were included. Of these, 60 (49.2%) were randomized to the vitamin D group and 62 (50.8%) to the placebo group. A total of 120 participants (59 vitamin D [49.2%]/61 placebo [51.8%]) completed the study. By completion, mean (SD) 25(OH)D levels were 29.7 (5.2) ng/mL (vitamin D) and 12.0 (3.8) ng/mL (placebo). There was no significant difference in change in PASI score between the groups (adjusted difference, 0.11; 95% CI, −0.23 to 0.45). There was no significant difference in change in Physician Global Assessment score (adjusted odds ratio, 0.66; 95% CI, 0.27-1.63), self-administered PASI (adjusted difference, −0.60; 95% CI, −1.76 to 0.55) or Dermatology Life Quality Index (adjusted difference, −0.86; 95% CI, −1.9 to 0.19) between the groups. No adverse effects of the intervention were registered. Conclusion and Relevance - The results of this randomized clinical trial showed that vitamin D supplementation did not affect psoriasis severity. Low baseline severity scores may explain the lack of measurable effect. Levels of 25(OH)D in the intervention group increased to a less-than-expected degree based on previous experimental data from the same source population, and this may have affected the results

Persistent Organic Pollutants and the Association with Maternal and Infant Thyroid Homeostasis: A Multipollutant Assessment

Source: doi: 10.1289/EHP152.Reproduced with permission from Environmental Health Perspectives.Background:Disruption of thyroid homeostasis has been indicated in human studies targeting effects of persistent organic pollutants (POPs). Influence on the maternal thyroid system by POPs is of special interest during pregnancy because such effects could impair infant thyroid homeostasis. Objectives:We investigated the association between POPs and thyroid-stimulating hormone (TSH) and thyroid hormones (THs) in mother and child pairs from the Northern Norway Motherand- Child Contaminant Cohort Study (MISA). Methods:Nineteen POPs and 10 thyroid parameters were analyzed in serum from 391 pregnant women in their second trimester. In addition, TSH concentrations in heel-prick samples from the infants were analyzed by the Norwegian Newborn Screening program. Association studies with a multipollutant approach were performed using multivariate analyses; partial least squares (PLS) regression, hierarchical clustering, and principal component analysis (PCA). Results:Several POPs were significantly associated with TSH and THs: a) PFOS was positively associated with TSH; b) PCBs, HCB, and nonachlors were inversely associated with T3, T4, and FT4; and, c) PFDA and PFUnDA were inversely associated with T3 and FT3. After mutual adjustments for the other contaminants, only PFDA and PFUnDA remained significantly associated with T3 and FT3, respectively. Infants born to mothers within the highest TSH quartile had 10% higher mean concentrations of TSH compared with children born to mothers in the lowest TSH quartile. Conclusion:The present results suggest that background exposures to POPs can alter maternal thyroid homeostasis. This research contributes to the understanding of multipollutant exposures using multivariate statistical approaches and highlights the complexity of investigating environmental concentrations and mixtures in regard to maternal and infant thyroid function

Longitudinal changes in vitamin D concentrations and the association with type 2 diabetes mellitus: the Tromsø Study

Aim We aimed to investigate the relationship between pre- and post-diagnostic 25-hydroxyvitamin D (25(OH)D) concentrations and type 2 diabetes (T2DM) over a period of 30 years in individuals who developed T2DM compared to healthy controls. Methods This case–control study included 254 participants with blood samples collected at fve diferent time-points (T1–T5) between 1986 and 2016. Of the 254 participants, 116 were diagnosed with T2DM between T3 and T4, and were considered cases; the remaining 138 were controls. Linear mixed regression models were used to examine pre- and post-diagnostic changes in 25(OH)D concentrations, and logistic regression was used to examine associations between these concentrations and T2DM at each time-point. Results 25(OH)D concentrations at diferent time-points and the longitudinal change in concentrations difered between cases and controls, and by sex. For women, each 5-nmol/l increase in 25(OH)D concentrations was inversely associated with T2DM at T3 (odds-ratio, OR, 0.79), whereas for men, this same increase was positively associated with T2DM at T1 (OR 1.12). Cases experienced a signifcant decrease in pre-diagnostic 25(OH)D concentrations (p value <0.01 for women, p value =0.02 for men) and a signifcant increase in post-diagnostic 25(OH)D concentrations (p value <0.01 for women, p value =0.01 for men). As such, each 1-unit increase in month-specifc z-score change between T1 and T3 was signifcantly inversely associated with T2DM (OR 0.51 for women, OR 0.52 for men), and each such increase between T3 and T5 was signifcantly positively associated with T2DM in women (OR 2.48). Conclusions 25(OH)D concentrations seem to be afected by disease progression and type 2 diabetes diagnosis

Effects of vitamin D supplementation on bone turnover markers and other bone-related substances in subjects with vitamin D deficiency

In observational studies, vitamin D deficiency is a risk factor for low bone density and future fractures, whereas a causal relation has been difficult to show in randomized controlled trials (RCTs). Similarly, vitamin D deficiency has been associated with increased bone turnover, but RCTs with vitamin D have not shown conclusive effects. This could be due to inclusion of vitamin D sufficient subjects and low vitamin D doses. In the present study 399 subjects with mean baseline serum 25-hydroxyvitamin D (25(OH)D) 34.0 nmol/L completed a four months intervention with vitamin D3 20,000 IU per week versus placebo. Mean serum 25(OH)D increased to 89.0 nmol/L in the vitamin D group and decreased slightly in the placebo group. A small, but significant, decrease in the bone formation marker procollagen of type 1 amino-terminal propeptide (P1NP) was seen in the vitamin D group as compared to the placebo group (mean delta P1NP -1.2 pg/mL and 1.5 ng/mL, respectively, P  6.5 pmol/L and post-intervention decrease in PTH, the decrease in P1NP was more pronounced, they also exhibited significantly reduced serum CTX-1 and increased serum sclerostin. In conclusion, supplementation with vitamin D appears to suppress bone turnover, possibly mediated by PTH reduction. Our findings need to be confirmed in even larger cohorts with vitamin D insufficient subjects

Assessing the relationship between perfluoroalkyl substances, thyroid hormones and binding proteins in pregnant women; a longitudinal mixed effects approach

Accepted manuscript version. Published version available at https://doi.org/10.1016/j.envint.2015.01.007. Accepted manuscript version, licensed CC BY-NC-ND 4.0.The mechanisms involved in thyroid homeostasis are complex, and perfluoroalkyl substances (PFASs) have been indicated to interfere at several levels in this endocrine system. Disruption of the maternal thyroid homeostasis during early pregnancy is of particular concern, where subclinical changes in maternal thyroid hormones (THs) may affect embryonic and foetal development. The present study investigated associations between THs, thyroid binding proteins (TH-BPs) and PFAS concentrations in pregnant women from Northern Norway. Women participating in The Northern Norway Mother-and-Child contaminant Cohort Study (MISA) donated a blood sample at three visits related to their pregnancy and postpartum period (during the second trimester, 3 days and 6 weeks after delivery) in the period 2007–2009. Participants were assigned to quartiles according to PFAS concentrations during the second trimester and mixed effects linear models were used to investigate potential associations between PFASs and repeated measurements of THs, TH-BPs, thyroxin binding capacity and thyroid peroxidase antibodies (anti-TPOs). Women within the highest perfluorooctane sulfonate (PFOS) quartile had 24% higher mean concentrations of thyroid stimulating hormone (TSH) compared to the first quartile at all sampling points. Women within the highest quartiles of perfluorodecanoate (PFDA) had 4% lower mean concentrations of triiodothyronine (T3) and women within the highest quartile of perfluoroundecanoate (PFUnDA) had 3% lower mean concentrations of free triiodothyronine (FT3). Further, the difference in concentrations and the changes between three time points were the same for the PFAS quartiles. Thyroxin binding capacity was associated with all the THs and TH-BPs, and was selected as a holistic adjustment for individual changes in TH homeostasis during pregnancy. Finally, adjusting for maternal iodine status did not influence the model predictions. Findings in the present study suggest modifications of TH homeostasis by PFASs in a background exposed maternal population. The variation in levels of THs between PFAS quartiles was within normal reference ranges and may not be of clinical significance in the pregnant woman. However, subtle individual changes in maternal THs may have significant consequences for foetal health