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Journal of Endocrinology & Metabolism

Original Article

Volume 6, Number 3, June 2016, pages 80-89

Hypovitaminosis D Is Associated With Visceral Adiposity, High Levels of Low-Density Lipoprotein and Triglycerides in Alternating Shift Workers

Vitamin D comprises a group of secosteroid molecules, classically acting on bone metabolism and calcium homeostasis. Calcidiol (25(OH)D) is the biochemical marker that best reflects vitamin D status, and the active metabolite, calcitriol (1,25(OH)₂D₃), acts as a hormone steroid [1]. This exerts its biological effect via the nuclear receptor (VDR), which is widely distributed in tissues, and provides a range of physiological effects in the body [2]. Humans get vitamin D through the skin by exposure to solar ultraviolet B rays (UVB) and dietary intake, which meets only 10-20% of the body’s needs [3].

Observational studies suggest there is a strong vitamin D deficiency associated with cardiovascular disease (CVD) and its risk factors (RFs), such as dyslipidemia and adiposity. Several authors [4-8] observed that the low levels of vitamin D increases the risk of CVD and its FRs, but the mechanisms that explain this association are still being explored. Clinical and experimental studies are needed to determine an appropriate vitamin D status that could contribute to the prevention of CVD.

According to Ding et al (2012) [9], the connection of vitamin D with adipose tissue is due to signaling through the VDR, which inhibits adipogenic transcription factors and lipid accumulation during adipocyte differentiation. The association between increased adiposity and reduced serum calcidiol has been reported for more than three decades, suggesting, as the primary hypothesis, the facility to be stored in adipose tissue due to lipid solubility [10]. Thus, the low bioavailability of calcidiol compromises the function of adipose tissue.

Hypovitaminosis D (25(OH)D < 30 ng/mL or 75 nmol/L) is a recent public health problem, which has been reaching different populations in different age groups around the world [11]. Advanced age, female gender, higher latitude, air pollution, winter season, darker skin pigmentation, less sunlight exposure, dietary habits, and the absence of vitamin D fortification in foods are the main factors that are significantly associated with low levels of 25(OH)D [12].

A study by Ward et al (2011) was the first to draw attention to the risk of vitamin D deficiency according to some occupational standards, such as night shifts and long hour shifts [13]. Hypovitaminosis D primarily accompanies individuals who have changes in one or more components of the lipid profile [14-16], and are overweight or obese [17]. However, among the studies of shift workers that evaluated the association with cardiovascular RFs, few paid attention to the relationship of vitamin D with changes in the levels of dyslipidemia components and high adiposity affecting this occupational group.

Although studies show the association of shift work with an increased risk for CVD [18, 19], the pathways that could explain the development of these RFs are not yet fully known and little is known about their manifestations in alternating shift workers in the mining area. Therefore, this study aimed to assess whether hypovitaminosis D is an additional mechanism to explain lipid profile disorders and excess abdominal adiposity, represented by the volume of visceral fat presented by alternating shift workers of a mining company operating in the Inconfidentes region, located in the state Minas Gerais, in southeastern Brazil.

A cross-sectional study was carried out with 391 adult men, off-road truck drivers operating at four mines in a mining company located in the region of Inconfidentes, Mariana and Ouro Preto municipalities, in the State of Minas Gerais, Brazil. Men with kidney disease or chronic liver disease and using statin and/or vitamin D supplements were excluded. The drivers work under conditions of alternating shifts, with clockwise rotation (morning/afternoon/evening), including 6 and 12 h of rest.

The socio-demographic characteristics were obtained by means of a semi-structured self-administered questionnaire. Skin color was self-reported. To determine alcohol consumption, we used the “Alcohol Use Disorders Identification Test - AUDIT” (WHO, 1992) [20] with individuals classified as low-risk consumption and risk drinking. Smoking was evaluated by “Fagerstrom Nicotine Dependence Test - FTND” [21] with individuals classified as smokers and non-smokers. The level of physical activity was measured by version 8 of the “International Physical Activity Questionnaire - IPAQ” [22].

Three blood pressure measurements were performed with automatic digital blood pressure monitor HEM - 705CP^® device (Omron). The worker sat with the cuff pressure firmly set and adjusted and kept at heart level. The interval between measurements was 1 - 2 min. At the end of the measurements, the lower value blood pressure measurement was considered. Systolic blood pressure (SBP) ≥ 140 mm Hg and/or diastolic blood pressure (DBP) ≥ 90 mm Hg and/or use of antihypertensive medication were classified as arterial hypertension [23]. Alternatively, we adopted a lower cut-off point to classify blood pressure as “changed”, for those with SBP ≥ 130 mm Hg or DBP ≥ 85 mm Hg or use of antihypertensive.

Body weight, body fat percentage (BF%), and the visceral fat area (VFA) were obtained by bioimpedance (BIA), the segmented body composition monitor InBody model 720^® (Biospace Co. Ltd. Factory) and height was measured in centimeters by Estadiometer digital HM-210 model D^® (Charder). The body mass index (BMI) was calculated using the formula weight (kg)/height² (m) and classified into pre-obese (BMI: 25 - 29.9 kg/m²) and obesity (BMI ≥ 30 kg/m²) according to the World Health Organization (2000) [24]. Waist circumference (WC), hip circumference (HC) and circumference neck (NC) were obtained with a simple, inelastic tape measure [25]. The waist/hip ratio (WHR) was calculated by the WC_(cm)/HC_(cm) ratio and the waist/height ratio (WHER) was calculated by the WC_(cm)/height_(m) ratio. Blood collection was performed after fasting for 12 h and held in the collection tube S-Monovette^® (Sarstedt) of 7.5 mL without anticoagulant to obtain serum for biochemical analysis and S-Monovette^® tube (Sarstedt) 2.7 mL containing fluoride to obtain plasma for blood glucose level.

The concentration of vitamin D (25(OH)D) was determined in Liaison^® apparatus (DiaSorin), a chemiluminescence immune analyzer. The levels of parathyroid hormone intact molecule (iPTH) were determined by electrochemiluminescence in Cobas apparatus E 6000/601^® (Roche). Serum levels of vitamin D were classified according to Maeda et al (2014) [26] as sufficient (25(OH)D ≥ 30 ng/mL or 75 nmol/L) and low (25(OH)D < 30 ng/mL or 75 nmol/L). iPTH levels were ranked according to the respective kit manufacturer as normal (≤ 65pg/mL) and high (> 65pg/mL).

Dosages of triglycerides (TG), total cholesterol (TC), and high-density lipoprotein (HDL-c) fraction were determined by enzyme-colorimetric method (Human Brazil, Itabira, Brazil) in the Auto-Analyzer Chemwell R6^® (Technology Awareness). Low-density lipoprotein cholesterol (LDL-c) and very low-density lipoprotein cholesterol (VLDL-c) fractions were obtained by mathematical calculation using the Friedewald formula for triglyceride concentration less than or equal to 400 mg/dL [27]. The components of the lipid profile were classified according to the V Brazilian Guidelines for dyslipidemia and prevention of atherosclerosis [28]. Dyslipidemia was considered when one or more criteria were met according to NCPE/ATP III (2002) [29]: total cholesterol ≥ 200 mg/dL, LDL-c ≥ 130 mg/dL, HDL-c < 40 mg/dL, TG ≥ 150 mg/dL and VLDL-c ≥ 30 mg/dL.

Fasting blood glucose was determined by enzymatic colorimetric analysis (Bioclin, Belo Horizonte, Brazil) in CM20 apparatus (Wiener). Blood glucose was classified according to the IDF (2005) [30] as normal (< 100 mg/dL) and impaired (≥ 100 mg/dL).

Fasting insulin levels (pg/mL), adiponectin (pg/mL), and C-reactive protein (mg/L) (CRP) were determined by Milliplex^® Human Panel adipokine magnetic bead method. Insulin and adiponectin levels were classified according to the values below and above the 75th percentile and CRP levels were classified as low risk/moderate (< 3 mg/L) and high risk (≥ 3 mg/L) according to the American Society of Cardiology and the Centers for Disease Control and Prevention (CDC) [31].

Student’s t-test and analysis of variance (ANOVA) were used to estimate statistical significance between mean values of age and levels of lipid profile components, PTH, blood glucose, insulin, and adiponectin according to the categories of 25(OH)D. Univariate analysis was used to cross-classified the categories of 25(OH)D (< 30 ng/mL or < 75 nmol/L and ≥ 30 ng/mL or ≥ 75 nmol/L) with demographic and behavioral variables and biochemical, anthropometric, clinical and body composition characteristics to generate odds ratios (ORs) with 95% confidence intervals (CIs) to guide interpretation. Multiple logistic regression models (enter method) were performed using CVD RF variables significantly associated with the categories of 25(OH)D in univariate analysis. To adjust the models, only the variables with P ≤ 0.25, biological plausibility, and epidemiological relevance were considered. The significance level for all tests was set at 5% (P < 0.05). Statistical analyses were performed using SPSS software version 22.0.

This study was approved by the Ethics Committee on Research With Human of the Ouro Preto Federal University. Participation in the study was entirely voluntary: workers consent and signed informed consent of each participant were obtained prior to the study.

The average age of the 391 study participants was 36.1 ± 7.3 years (ranging from 20 to 57), and most of them with more than 8 years of education (90%). Among workers, 51% had more than 5 years of work shift, and the majority were non-smokers and non-alcoholic (83.7% and 84.7%). The study population was largely sedentary, where only 22.3% reported doing physical activities outdoors for 10 min or more for a minimum of three times a week, but only 22.7% had excess visceral fat. The prevalence of hypertension and dyslipidemia was 30.8% and 74.2%, respectively, and the prevalence of hypovitaminosis D (serum 25(OH)D below 30 ng/mL or 75 nmol/L) in this population was high (73%). The prevalence of overweight (BMI: 25 - 29.9 kg/m²) and obesity (BMI ≥ 30 kg/m²) was 48.4% and 17.2%, respectively.

Table 1 shows the distribution of the categories of demographic and behavioral variables according to vitamin D levels observed among these workers. Workers whose blood had been collected in the summer (29.7 ± 8.1 ng/mL or 74.2 nmol/L) had significantly higher vitamin D levels (P < 0.0001) than that collected in the spring (24.5 ± 7.2 ng/mL or 61.2 nmol/L).

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Table 1. Distribution of Categories of Demographic and Behavioral Variables According to the Levels of 25(OH)D

Table 2 shows the biochemical, anthropometric, clinical and body composition characteristics according to levels of 25(OH)D regarded as insufficient and sufficient in this population. All anthropometric variables were significant enough for the insufficient vitamin D group (< 30 ng/mL or 75 nmol/L), highlighting the waist/height ratio that had the highest value of OR 2.38 (95% CI: 1.46 - 3.88). For body composition variables, visceral fat was significant with an OR of 2.9 (95% CI: 1.46 - 5.75). Dyslipidemia had significantly lower vitamin D levels (OR: 2.7, 95% CI: 1.6 - 4.3) than individuals with normal cholesterol levels and fractions, and triglycerides. Between the cholesterol fractions, only the HDL was not significant when comparing the sufficient and insufficient groups. Hyperglycemic workers had significantly lower levels of vitamin D than euglycemic workers (P < 0.05).

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Table 2. Biochemical Characteristics, Anthropometric, and Clinical Body Composition According to Levels of 25(OH)D

The concentrations of biochemical variables were distributed in quartiles of 25(OH)D and there was a significant difference for all variables except for HDL-c and adiponectin (Table 3). Among the biochemical variables, as the levels of 25(OH)D increased, the levels of triglycerides, total cholesterol, LDL-c and VLDL-c fractions, fasting glucose, fasting insulin, and PTH decreased. The same pattern was seen in the VFA, BMI, and systolic and diastolic blood pressure. Conversely, the HDL-c fraction followed a pattern increasing from quartiles 1 through 4.

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Table 3. Distribution of Serum Levels of Lipid Profile Components, PTH, Blood Glucose, Insulin, and Adiponectin According to the Quartile of 25(OH)D in the Group of Alternating Shift Workers in the Inconfidentes Region, Minas Gerais

A binary logistic regression model was created using the anthropometric, body composition, and biochemical variables adjusted for age and seasonality. The variables that remained significant were visceral fat, LDL-c, and triglycerides (Table 4). In relation to workers with sufficient levels of vitamin D, those with insufficient levels most often presented with excess visceral fat in the range 11 - 20 cm³ (OR: 2.4; 95% CI: 1.1 - 5.2) with excess LDL-c above 160 mg/dL (OR: 5.9; 95% CI: 1.3 - 25.7), and excess triglycerides above 150 mg/dL (OR: 2.3; 95% CI: 1.3 - 4.0).

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Table 4. Risk Factors Adjusted for Age and Seasonality for Hypovitaminosis D (25(OH)D < 30 ng/mL or 75 nmol/L) in Alternating Shift Workers, Minas Gerais, Brazil

Table 5 shows the modification of risk analysis adjusted for age and seasonality for the insufficient and sufficient groups with regard to the TG levels and VFA. Considering TG levels < 150 mg/dL and VFA ≤ 10 cm³ as the reference group, the risk of vitamin D insufficiency was 2.2 times higher (95% CI: 1.23 - 3.83) in the presence of only TG ≥ 150 mg/dL and 2.0 times higher (95% CI: 0.80 - 4.89) in the presence of only VFA > 10 cm³. The risk was 8.23 (95% CI: 2.38 - 28.51) in the presence of both factors. Risk modification analysis was adjusted for age and seasonality for the insufficient and sufficient groups for TG and LDL-c levels. Considering TG levels < 150 mg/dL and LDL-c < 160 mg/dL as the reference group, the risk of vitamin D insufficiency was 2.1 times higher (95% CI: 1.2 - 3.5) only in the presence of TG ≥ 150 mg/dL and 3.51 times higher (95% CI: 0.7 -16.1) only in the presence of LDL-c ≥ 160 mg/dL. It was 11.1 (95% CI: 1.4 - 84.2) in the presence of the two RFs.

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Table 5. Bivariate Association of Risk for Hypovitaminosis D Between Serum Levels of Triglycerides (TG) > 150 md/dL, Visceral Fat Area (VFA) 11 - 20 cm3 and LDL-c > 160 mg/dL

Our results show that 23% of the participants had deficiency and 50% for vitamin D insufficiency. Given that hypovitaminosis D includes both groups, this percentage reaches 73%. The average of the 25(OH)D levels was low in this population, equal to 26.1 ng/mL (65.2 nmol/L). A significant dose-response pattern between hypovitaminosis D was observed (25(OH)D < 30 ng/mL or 75 nmol/L) along with disturbances in lipid profile (triglycerides and LDL-c) and the visceral adiposity in this population.

The shift work schedule is subject to studies that show its link to increased risk of developing metabolic disorders mainly related to components of Metabolic Syndrome (MS) [19, 32] and the etiology of atherosclerosis [33]. In an earlier study in this same shift worker population, Ambrosim (2014) [34] found a high prevalence of RFs for MS, such as dyslipidemia, obesity, and overweight.

Shift work is identified as a contributor to a pro-atherogenic profile of cardiovascular risk by means of an unfavorable lipid profile [35], which is characterized by hypertriglyceridemia, decreased HDL, and the formation of smaller particles from the LDL-c, the known small LDL and dense (LDLpd). These factors together characterize the artherogenic lipid phenotype of MS [36].

Even though considered a subclinical event, hypovitaminosis D is recognized as one of the most important factors that influence the health of the skeleton and some chronic diseases such as CVD [4]. Hypovitamnosis D is associated with the intensity of exposure to sunlight, which is significantly reduced due to the occupational environment, especially in individuals working in shifts or in an enclosed room [13]. Some authors [37] found levels of 25(OH)D in shift workers similar to those observed in this study, indicating the occupational environment as an important factor influencing sunlight exposure.

Among the biochemical parameters significantly associated with vitamin D insufficiency, LDL-c merits close attention. Hypovitaminosis D was 5.9 times more frequent in individuals with levels above 160 mg/dL compared to those with lower levels. Excessive amounts of LDL-c in circulation participate in the formation of the atheroma after being modified by oxidation. Increased concentrations of LDL-c increase cardiovascular risk, but it is known that its size can be an even more important predictor. Hypovitaminosis D has been considered an independent RF for atherosclerosis and is associated with endothelial dysfunction and increased lipid peroxidation occurring in plasma lipoproteins and other mechanisms [38, 39]. A study that evaluated the effect of vitamin D supplementation on endothelial function showed favorable effects [40]. Also, the concentration of substances reactive to thiobarbituric acid (TBARS), which are used as indicators of lipid peroxidation, significantly decreased after supplementation in individuals with inadequate levels of 25(OH)D. As the authors did not observe an association between flow-mediated dilation and 25(OH)D levels, it was concluded that the beneficial effects on endothelial function occurred due to a reduction in oxidative stress by 25(OH)D. Therefore, hypovitaminosis D associated with high levels of LDL-c may predispose the emergence of dysfunction in vascular endothelium and increase CVD rates in alternating shift workers.

Another biochemical parameter independently associated with vitamin D insufficiency was TG. Hypovitaminosis D was 2.3 times more frequent in patients with TG levels greater than 150 mg/dL than in those with lower levels. There are some mechanisms suggested to explain the reduction of TG levels mediated by 25(OH)D. The first mechanism is related to the function of classical vitamin D to increase the absorption of calcium via the intestines with consequent increase of its plasma levels. The elevation of serum calcium decreases hepatic TG synthesis and secretion through its suppressive effect on a TG microsomal transfer protein known as MTP (microsomal triglyceride transfer protein) [41]. The second mechanism relates to vitamin D suppressive effect on PTH concentration in serum. The post-heparin lipase activity is reduced by high concentrations of PTH and low serum PTH levels can reduce TG levels via enhanced peripheral removal [41]. In addition, two other mechanisms have also been implicated. Vitamin D increases the expression of VLDL-c receptors in some kinds of cells [42] promoting increased uptake of TG. Finally, insulin resistance may explain the association between 25(OH)D and TG: when vitamin D deficiency is present, it increases the risk of insulin resistance [43], which in turn is associated with an increase in VLDL-c and TG.

In the present study, hypovitaminosis D was 11 times more common in individuals with high concomitant levels of LDL-c and TG compared to no change in these factors and much more frequently than in the presence of these factors alone (OR_TG = 2.1; OR_LDL-c = 3.5). Vitamin D appears to have an effect on the regulation of lipid profile and is considered by some authors as one of the mechanisms that explain its relationship with the DCV [44]. Some observational studies claim that low levels of vitamin D are associated with an unfavorable lipid profile [14], but some clinical studies do not confirm these findings [14]. Gonzalez et al (2014) [16] found an inverse relationship between deficient levels of 25(OH)D (< 20 ng/mL or 50 nmol/L)) and hypertriglyceridemia. However, no association with dyslipidemia was observed in this study. Yet other authors [45] found similar results to our study, finding a significant inverse association between 25(OH)D and LDL-c and TG.

Additionally, the concomitant presence of excess visceral fat and hypertriglyceridemia indicated increased risk of hypovitaminosis D (OR: 8.2) compared with the absence of those factors and much higher when in the presence of these factors separately (OR_TG = 2.2; OR_VFA = 2.0). Visceral adiposity is another important factor involved in the etiology of atherogenic lipid phenotype present in the MS, which is considered the most pathogenic compartment and most often associated with the secretion of adipokines, among other factors [36]. Furthermore, in adults, the accumulation of visceral fat is strongly correlated with several other cardiovascular RFs such as hypertension, hypertriglyceridemia, impaired fasting glucose, MS, and insulin resistance [46-48]. Currently among the studies that aimed to assess the relationship of low levels of 25(OH)D with obesity, few have included direct measurements of adiposity. However, it is still difficult to establish the pattern of adiposity that affects more potential levels of vitamin D. More research is needed to explore these potential relationships.

Some limitations should be considered in this study, such as the adopted cross-sectional design, which cannot establish a causal relationship between the analyzed factors and hypovitaminosis D. The absence of information on the use of sunscreen, along with the intake of vitamin D in the diet, could have influenced the low levels of vitamin D in this population. Finally, a third limiting factor is that using a single measurement of serum levels of 25(OH)D can only reflect recent exposure, not taking into account intra-individual seasonal variations, which may be present.

Our results suggest that alternate shift mine workers are exposed to excess body weight and dyslipidemia, and that these factors constitute strong predictors of hypovitaminosis D. Therefore, it is necessary to assess whether an intervention in the vitamin D status, combined with behavioral changes such as diet and physical activity, could influence the reduction of atherogenic lipid phenotype of the metabolic syndrome, thus contributing to an improvement in the health of this population.

Acknowledgments

The authors are grateful for the technical assistance of Cristina de Oliveira Lisboa Pereira and Cassio Zumerle Masioli. This work was supported by the Federal University of Ouro Preto (UFOP); the National Council for Scientific and Technological Development (CNPq); the Foundation for Research Support in Minas Gerais (FAPEMIG); and Gorceix Foundation (Ouro Preto, MG).

Conflicts of Interest

The authors declare no conflict of interests.

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