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INTRODUCTION
The global prevalence of childhood obesity has increased considerably over the past 3 decades 1. Ten percent of school-aged children worldwide are estimated to have excess body fat, which is associated with an increased risk of chronic disease. Of these overweight children, a quarter are obese and thus have a significant likelihood of possessing multiple risk factors for the development of type 2 diabetes, heart disease, and various other co-morbidities before or during early adulthood. The increasing incidence of disorders in children, such as type 2 diabetes, is a consequence of the obesity epidemic 1,2.
Although the main physiologic role of vitamin D is the regulation of calcium and phosphorus homeostasis, it plays a variety of nonskeletal roles, such as the pathogenesis of several endocrine diseases, modification of immune competence, regulation of blood pressure, and modulation of cancer and infectious disease risks, and propensity for autoimmune diseases 3,4,5. However, cynicism surrounds the lack of randomized controlled trials to support association studies concerning the nonskeletal health benefits of vitamin D 5.
To date, many studies have observed low 25-hydroxyvitamin D (25[OH] D) levels in overweight and obese populations 6,7,8. In US children, the prevalence of vitamin D deficiency is nearly 21% among normal-weight population, 29-34% in overweight and obese populations, and 49% in a severely obese population 9.
Evidence from many studies indicates the existence of a strong association between vitamin D and cardiovascular risks, particularly blood pressure. Vitamin D deficiency might be linked to the pathophysiology of hypertension through its influence on the renin-angiotensin system 10. Vitamin D receptor (VDR) null mice exhibit significantly elevated renin activity and circulating plasma angiotensin II concentrations, as well as increased activity of the local cardiac tissue renin-angiotensin system 11.
Vitamin D has also been shown to modulate insulin synthesis and secretion 12. An analog of the active metabolite of vitamin D, 1,25(OH)2 D, has been found to directly enhance glucose-stimulated insulin release by increasing intracellular calcium levels in pancreatic β-cells 13.
In this study, we aimed to determine the associations between vitamin D deficiency and cardiovascular risks, such as hypertension, dyslipidemia, and insulin resistance (IR), in obese children and adolescents.
MATERIALS AND METHODS
PARTICIPANTS AND STUDY AREA
A total of 872 obese children who were followed up at the hospital of the Gaziosmanpasa University School of Medicine between January 2012 and February 2016 were retrospectively investigated, and we enrolled only children who were tested between February and May (i.e., in late winter and spring). Subjects were diagnosed with obesity according to a body mass index (BMI) value > 95th percentile in accordance with the sex-specific growth curves and cut-off levels proposed by Neyzi et al. 14. We excluded 562 obese children because of missing data, syndromic obesity, renal or hepatic disorders, metformin or vitamin D derivative usage, testing season, and age. Finally, 310 obese children aged 6-17 years were included in this study.
Subjects' demographic and clinical data, basic demographic information (age and sex), and physical data (body height, body weight, BMI, and systolic and diastolic blood pressure [BP]) were collected retrospectively from hospital records.
LABORATORY TESTS
Laboratory tests, including 25(OH) D, glucose, and insulin levels and lipid profiles, were conducted using fasting blood samples drawn from each participant. Laboratory and BP details were collected retrospectively from the electronic medical records used at the hospital.
Serum fasting glucose, triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and total cholesterol (TC) levels were detected using reagent kits adapted to the COBAS 6000 Autoanalyzer (Roche Diagnostics, Indianapolis, IN, USA). Vitamin D levels were analyzed using chemiluminescence immunoassay methods and a COBAS C-501&E-601 analyzer (Roche Diagnostics).
DEFINITIONS OF OBESITY, IR, AND ATHEROGENIC RISK
Children were weighed on a digital scale (Seca Corp., Chino, CA, USA) and subjected to height measurement with a portable stadiometer (Seca Corp.) while they were barefoot and wearing light clothing. If BMI was > 95th percentile, the children was recorded as obese. BP was measured using a digital sphygmomanometer (OMRON 705IT; Omron Healthcare Co., Kyoto, Japan); if the measured BP was high with respect to age and sex, the mean of two measurements was recorded. Hypertension was defined as a BP ≥ 95th percentile according to age, sex, and height.
The homeostasis model assessment of IR (HOMA-IR) index was calculated using the following equation: HOMA-IR = (fasting insulin [mIU/mL] × fasting glucose [mmol/L])/22.5. Positive IR was defined as a HOMA-IR > 2.67 in boys and > 2.22 in girls during the prepubertal period or > 5.22 in boys and > 3.82 in girls during the pubertal period 15.
Dyslipidemia was defined as the presence of any of the following criteria: TGs > 105 mg/dL in children < 10 years of age and > 136 mg/dL in children ≥ 10 years of age, HDL-C < 35 mg/dL, and TC > 95th percentile 16. We calculated the atherogenic dyslipidemia (AD) ratio (log [TGs/HDL-C]) 17,18 to determine the effect of 25(OH) D on the cardiovascular atherogenic risk.
Vitamin D groups were determined according to measured levels. Vitamin D deficiency, insufficiency, and sufficiency were defined as a 25(OH) D level < 15 ng/mL 19, 15-29 ng/mL, and ≥ 30 ng/mL, respectively 20.
Study children were divided into healthy obese and non-healthy obese groups. Non-healthy obesity was defined as the presence of metabolic disturbances, such as IR according to HOMA-IR, dyslipidemia, and hypertension. Children without any such disturbances were considered healthy obese.
STATISTICAL ANALYSIS
Descriptive analyses were performed to obtain information about the general characteristics of the study population. A one-way analysis of variance was used to compare continuous data among the groups. For multiple comparisons, Tukey's honest significant difference (HSD) test was used. Continuous data are presented as means ± standard deviations. Categorical variables are presented as numbers and percentages. The chi-square test was used to compare categorical variables between groups. A p-value < 0.05 was considered significant. Analyses were performed using SPSS 19 (IBM SPSS Statistics 19, SPSS Inc., an IBM Co., Somers, NY, USA).
RESULTS
There were 310 obese children aged 6-17 years (178 [57.4%] females and 132 [42.6 %] males) who met the aforementioned inclusion criteria. In this cohort, the prevalence rates of vitamin D deficiency, insufficiency, and sufficiency were 62.3%, 34.5%, and 3.2%, respectively.
IR was observed in 146 (47.1%) obese children. Dyslipidemia and hypertension were found in 96 (31%) and 60 (19.4%), respectively. Only 109 (35.2%) children were classified as healthy obese. Table I summarizes the distributions of qualitative variables in the entire cohort according to vitamin D status.
Table I Distribution of qualitative variables in entire participant cohort according to vitamin D status (n = 310)
Data are shown as n(%). Chi-square test was used. Deficient: 25(OH) D level < 15 ng/Ml; insufficient: 25(OH) D level = 15-29 ng/mL; sufficient: 25(OH) D level ≥ 30 ng/mL.
The means of subject age (p = 0.008), BMI (p = 0.010), and AD ratio (p = 0.049) were higher in the vitamin D deficient group.
Non-healthy obese children were more frequently recorded as vitamin D deficient than healthy obese children (p = 0.023). Otherwise, no statistically significant differences were observed between 25(OH) D groups with respect to hypertension frequency (p = 0.074).
The mean age of the cohort was 12.10 ± 2.82 years, and the mean BMI was 29.21 ± 4.71. The mean HOMA-IR value was 3.78 ± 2.23. Table II summarizes the mean values of laboratory and clinic quantitative variables in the cohort according to vitamin D status.
Table II The mean values of quantitative variables in the cohort according to vitamin D status
Data are shown as mean ± standard deviation. Different superscripts in the same row (one way ANOVA) indicate statistical significant difference. BMI: body mass index; BP: blood pressure; HOMA-IR: the homeostasis model assessment of insulin resistance index; HDL-C: high density lipoprotein cholesterol; LDL-C: low density lipoprotein cholesterol; 25 (OH) D: 25-hydroxyvitamin D. AD ratio: atherogenic dyslipidemia ratio, p = 0.045 for AD ratio between deficient and sufficient groups.
No correlations of 25(OH) D levels were observed with lipid levels (TC, r = -0.032 and p = 0.571; TGs, r = -0.041 and p = 0.472; HDL, r = -0.01 and p = 0.858) or systemic BP (systolic, r = -0.099 and p = 0.082; diastolic, r = -0.065 and p = 0.256) (p > 0.01). Otherwise, weak but significant inverse correlations of 25(OH) D levels were observed with BMI (r = -0.167, p = 0.003) and HOMA-IR values (r = -0.146, p = 0.010). Fig. 1 and Fig. 2 present scatter plots of 25(OH) D with BMI and HOMA-IR values, respectively.
The mean 25(OH) D values (ng/mL) were lower in girls (12.15 ± 6.60) vs. boys (16.48 ± 8.69) (p < 0.05), in children with hypertension (11.92 ± 5.48) vs. non-hypertensive children (14.50 ± 8.24) (p < 0.05), and in the nonhealthy obese group (13.29 ± 6.90) vs. the healthy obese group (15.30 ± 9.24) (p < 0.05). Table III summarizes the mean 25(OH) D levels according to sex and cardiovascular risk status.
DISCUSSION
Hypovitaminosis D (both insufficiency and deficiency) was observed more frequently than expected in obese children and adolescents. In a previous meta-analysis, the prevalence of vitamin D deficiency was 24% in obese adults and 14% in obese children and adolescents 21. In another study, hypovitaminosis D was identified in 74% of obese subjects, whereas vitamin D deficiency was observed in 32.3% of the cohort 22.
The higher prevalence of vitamin D deficiency observed in our study might be attributable to decreased exposure of these obese children to sunlight, as testing was conducted in late winter and spring, and might also be a consequence of a low intake of vitamin D-rich foods. However, we did not have access to dietary data for these children. This should be considered a limitation of this study. Nevertheless, our findings with consistent with those of Buyukinan et al. who reported vitamin D deficiency and insufficiency values of 62.2% and 34.0%, respectively, in obese children 23.
Previously, obese children were reported to have a greater risk of developing vitamin D deficiencies. The association between obesity and 25(OH) D deficiency is complex because in addition to the sequestration of vitamin D in adipose tissue 24, obese children might also have more sedentary, indoor lifestyles. In addition, obese children might obtain lower levels of vitamin D than non-obese children from food sources 22; however, a combination of the above factors, as well as other potential factors, is most likely.
In our study, vitamin D levels were lower in girls, consistent with the findings of previous studies 20,25; girls also more frequently exhibited vitamin D deficiency. These findings were consistent with an earlier study that reported a higher prevalence of vitamin D insufficiency among girls relative to boys 26.
As in previous studies 3,27, we observed a weak but significant inverse relationship between BMI and 25(OH) D levels. This finding has been attributed to the sequestration of vitamin D within adipose tissue 24 and the reduced hepatic synthesis of 25(OH) D in obese individuals with nonalcoholic fatty liver disease 28. In contrast, another study found no significant association between BMI and 25(OH) D 25.
In an analysis of multiple cohorts, Vimaleswaran et al. calculated that each 10% increase in BMI would lead to a 4.2% decrease in the 25(OH) D concentrations. The authors concluded that the efforts of vitamin D deficiency monitoring and treatment in obese individuals would alleviate the adverse influences of excess adiposity on health; in addition, attempts to reduce BMI are expected to reduce the prevalence of vitamin D deficiency 29.
Inconsistent with a recent report 25, our study did not observe any correlation of 25(OH) D levels with TG, LDL-C, or HDL-C levels. However, Dolinsky et al. suggested that there was insufficient evidence to support an association between vitamin D and lipid levels, which is consistent with our findings 30.
In recent years, the AD ratio, derived from a log transformation of the ratio of fasting TG to HDL-C levels, has gained importance as an indicator of atherosclerosis, an established cardiovascular risk factor 17,18. In the present study, the AD ratio was higher in the vitamin D-deficient group, consistent with many other reported findings 20. Vitamin D deficiency causes an increase in AD, a component of cardiovascular risk factors, and thus leads to worse long-term consequences 20.
In our study, hypertensive children exhibited lower 25(OH) D levels. Accordingly, and consistent with many recent studies, hypertension in obese patients was associated with reduced vitamin D levels; in an earlier study, a lower HDL-C level and higher systolic BP were associated with lower levels of 25(OH) D 31. In addition, 25(OH) D deficiency in children and adolescents has been associated with hypertension as a cardiovascular risk factor 20.
As we specified earlier, vitamin D deficiency has been linked to the pathophysiology of hypertension through its augmenting influence on renin-angiotensin system activity 10 both in obese individuals 32 or independently of obesity 33. On the other hand, VDRs are present in vascular smooth muscle, which suggests that vascular smooth muscle is a target organ of vitamin D 34. Furthermore, studies have linked vitamin D deficiency with low levels of adiponectin 35, a protein associated with hypertension.
An inverse correlation was observed between 25(OH) D levels and HOMA-IR values. In other words, 25(OH) D levels affect insulin sensitivity, consistent with previous research 22. Hypovitaminosis D has been implicated in the pathogenesis of IR, -cell dysfunction, and both type 1 and type 2 diabetes mellitus 36,37. Furthermore, obese children and adolescents with low levels of vitamin D might have an increased risk of glucose metabolism impairment, independent of body adiposity 22.
A previous study found a significant positive association between vitamin D and -cell function, as well as significant relationships of vitamin D with IR and -cell function in a multi-ethnic sample at risk for type 2 diabetes 12. In addition, vitamin D has been implicated in the development of type 1 diabetes mellitus through its modulatory effects on the immune system 38.
Multiple factors, such as the levels of vitamin D and reactive oxidative species, might have a synergistic effect on the pathogenesis of obesity-related morbidities. In recent decades, some studies have demonstrated that similar to vitamin D, oxidative stress, which increases in the context of obesity, is directly and indirectly associated with IR pathogenesis via the respective inhibition of insulin signals and dysregulation of adipocytokines/adipokines 39. We believe that other factors, in addition to vitamin D, affect and contribute to IR in obese children.
Over time, oxidative stress in several other cells or tissues (e.g., pancreatic -cells, myocytes, vascular endothelial cells, and some types of tumors) has been implicated in the pathogenesis of diabetes, hypertension, atherosclerosis, and cancer 40.
Metabolic disturbances and/or hypertension would be expected to occur more frequently in the context of vitamin D hypovitaminosis. We observed lower 25(OH) D levels in non-healthy obese children than in healthy obese children. Accordingly, we can suggest that some of the long-term morbidities associated with obesity might be prevented by improving vitamin D levels.
The main limitations of our study involved the lack of data regarding dietary habits and physical activity. Therefore, we could not exclude lifestyle factors, such as dietary habits and social status, that might have affected vitamin D metabolism and the other laboratory variables measured in our study participants. In addition, because the children were evaluated retrospectively, we could not incorporate methods to measure adiposity. Furthermore, we did not observe statistical significance in the comparisons of some variables with respect to vitamin D status, possibly because of the very small number of vitamin D sufficient children.
CONCLUSION
Vitamin D deficiency is observed more frequently than expected in obese children and adolescents. Lower 25(OH) D levels are associated with a high BMI, and this relationship might be attributable to the increased adiposity of obese individuals. In addition, low 25(OH) D levels might be associated with IR. Vitamin D deficiency might therefore be prevented by reducing the BMI and incorporating some simple lifestyle precautions. Vitamin D deficiency might contribute to obesity-related morbidities, such as IR or diabetes mellitus, increased cardiovascular/cardiometabolic risk, atherogenic dyslipidemia, and hypertension. The long-term morbidities associated with obesity could be reduced by improving vitamin D levels.
