Effects of a 1-year supplementation with cholecalciferol on interleukin-6, tumor necrosis factor-alpha and insulin resistance in overweight and obese subjects
Highlights
► We proposed that high dose vitamin D supplementation influences cytokine levels. ► The corresponding effect of vitamin D on insulin resistance was also proposed. ► 332 obese subjects underwent a 12 months randomised intervention with vitamin D. ► Positive significant association between TNF-α and insulin resistance was found. ► Vitamin D supplementation had a lowering effect on IL-6 levels.
Introduction
Vitamin D is a fat soluble vitamin and its main role is maintenance of mineral homeostasis and bone health [1]. Epidemiological studies have linked vitamin D insufficiency to increased risk for cardiovascular disease, infections and even cancer [2], [3], [4]. Among other non-classical vitamin D effects, regulation of cell proliferation, innate and anti-bacterial immune responses and hormone control can be mentioned [5], [6]. Patients with systemic connective tissue diseases like rheumatoid arthritis and systemic lupus erythematosus [7] are reported to have lower serum 25-hydroxyvitamin D (25(OH)D) levels, which is the metabolite used to evaluate a subject’s vitamin D status [8] when compared to healthy individuals. In addition, both adult and pediatric patients with inflammatory bowel diseases (IBD) like Crohns’ disease [9] and ulcerative colitis [10], which also have altered innate immunity, demonstrate the same pattern. It has been also suggested that decreased cutaneous synthesis of vitamin D due to low sun exposure might be an important contributing factor in the development of immunological alterations in these diseases [11], [12].
The vitamin D receptor (VDR) has been found in human immune cells [13], [14]. VDR binding activity was found elevated around the genes that were associated with a chain of immunological disturbances, inflammation and diseases like Crohns’ disease, type I diabetes, multiple sclerosis, and chronic lymphocytic leukaemia [15]. In vitro, 1,25-dihydroxyvitamin D (1,25(OH)2D) inhibits differentiation of dendritic cells and decreases T cell activation by augmenting the synthesis of interleukin 10 (IL-10) and inhibiting the IL-12 [16]. Moreover, in animal studies calcitriol inhibits the production of such cytokines as IL-17A and IL-17B, which are the markers of T helper cell 17 (TH17) function, linked to infections and some severe autoimmune diseases [17].
Tumor necrosis factor-alpha (TNF-α) is a pleiotropic inflammatory cytokine [18] and is largely involved in regulation of immune system with several beneficial as well as pathological functions of both inflammatory and non-inflammatory origin [19], [20]. As other acute-phase cytokines it initiates a cascade of immune cellular responses usually in interaction with IL-6 [21]. Interleukin 6 is also an important acute phase mediator with both pro-inflammatory and anti-inflammatory properties [22]. In addition, these cytokines have been linked to insulin resistance and obesity; and weight loss interventions in obese subjects have resulted in amelioration of IL-6 and TNF-α levels as well as the corresponding improvement of the metabolic profile was observed [23].
Vitamin D has also been linked to some pro-inflammatory conditions like metabolic syndrome [24] and atherosclerosis [25]. Low serum 25(OH)D levels are associated with insulin resistance and overweight [26], [27]. Considering the strong association between vitamin D and the immune system, the relationship between vitamin D and metabolic syndrome could possibly be mediated through an effect of vitamin D on cytokines like IL-6 and TNF-α. To test this hypothesis we have measured these cytokines in sera from overweight and obese subjects who have participated in a 1-year intervention study with high dose vitamin D supplementation versus placebo, and also related cytokines to hallmarks of insulin resistance.
Section snippets
Study design and subjects
The present work is the ancillary study to the 1-year intervention trial with high dose vitamin D supplementation versus placebo and was performed as previously described in detail [28]. In short, males and females 21–70 years old, with body mass index (BMI) between 28.0 and 47.0 kg/m2, and without concomitant diseases, were recruited by advertisements in the local newspapers and from the Out-patient Department, University Hospital of North Norway, Tromsø. Subjects with serum calcium >2.55 mmol/L,
Results
A total of 445 subjects met the inclusion criteria, and of these 332 fulfilled the intervention and had complete datasets, including IL-6 and TNF-α. The variables IL-6, TNF-α and hs-CRP were severely skewed, and before their inclusion in the statistic analysis the logarithmic, negative reciprocal and square root transformations were applied, respectively.
The baseline characteristics of the study population are shown in Table 1. Of the 62 smokers, 15 quit smoking during the study. The compliance
Discussion
In the present study we have found a strong positive association between levels of the TNF-α and insulin resistance, and a negative association between serum 25(OH)D and insulin resistance. At baseline there were no significant associations between serum 25(OH)D and the cytokines, whereas supplementation with vitamin D appeared to lower the serum IL-6 levels and increase the hs-CRP levels. However, no corresponding effect on insulin resistance after vitamin D supplementation was seen.
There are
Acknowledgments
The study was supported by a grant from The Regional Health Authority of North Norway. The superb assistance by the staff at the Clinical Research Unit and by Inger Myrnes and Astrid Lindvall at the Department of Medical Biochemistry, University Hospital of Northern Norway, is gratefully acknowledged. We are grateful for the generous supply of calcium tablets from Nycomed Norway.
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