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Inflammation in diabetes and cardiovascular disease: a new perspective on vitamin D

Su, Lei; Xiao, Haipeng

Cardiovascular Endocrinology & Metabolism: December 2015 - Volume 4 - Issue 4 - p 127–131
doi: 10.1097/XCE.0000000000000062
Review articles
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Epidemiological studies indicate an inverse association between vitamin D level and chronic, low-grade systemic inflammatory diseases, such as type 2 diabetes mellitus and cardiovascular disease. Vitamin D signaling may interfere with transcription factors, such as nuclear factor-kappa B, which regulate the expression of inflammatory markers at several levels. In this review, the latest advances in the anti-inflammatory effects of vitamin D from experimental, observational, and small interventional studies will be discussed.

Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China

Correspondence to Haipeng Xiao, MD, PhD, Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China Tel: +86 20 87755766 x8803; fax: +86 20 87330736; e-mail: xiaohp@mail.sysu.edu.cn

Received April 20, 2015

Accepted July 7, 2015

Atherosclerosis is the leading cause of death and disability in patients with type 2 diabetes mellitus (T2D). Metabolically driven, chronic, low-grade inflammation (or ‘metaflammation’) plays a crucial role in the pathogenesis of insulin resistance, T2D, and atherosclerosis 1.

According to a National Center for Health Statistics report, during the period 2001–2006, 32 and 8% of the US population had serum 25-hydroxyvitamin D [25(OH)D] levels <20 and <12 ng/ml, respectively. In five large cities in China, the prevalence of severe vitamin D deficiency (<10 ng/ml), vitamin D deficiency (10–20 ng/ml), and vitamin D insufficiency (20–30 ng/ml) was 5.9, 50.0, and 38.7%, respectively 2. Low vitamin D level was associated inversely with several cardiometabolic risk factors, such as waist circumference, systolic blood pressure, and homeostatic model assessment-insulin resistance (HOMA-IR) index, and risk of death from cardiovascular disease (CVD). 1α,25-Dihydroxyvitamin D3 [1,25(OH)2D; calcitriol] manifests diverse biological effects through binding to the vitamin D receptor (VDR) in most body cells, including T-lymphocytes, macrophages, monocytes, islet and endothelial cells, and vascular smooth muscle cells 3. There is growing interest in the nonskeletal action of vitamin D, including in inflammation, glucose metabolism, and atherosclerosis 4. Hence, vitamin D supplementation may be a new therapeutic approach in the already expanding range of options for the management of diabetes and CVD. The latest advances in the anti-inflammatory effects of vitamin D from experimental, observational, and interventional studies are discussed in the following sections.

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Inflammation in diabetes and cardiovascular disease

Current clinical studies

Inflammatory marker levels, such as C-reactive protein (CRP) and interleukin-6 (IL-6), may predict the risk of CVD in patients with stable coronary heart disease 5. CRP showed a positive association with the risk of CVD in a meta-analysis including 160 309 patients with no history of vascular disease 6. IL-6 was associated with visceral adiposity 7 and insulin resistance in patients with and without T2D 8.

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Emerging clinical studies

The transcription factor, nuclear factor-kappa B (NF-κB), is the inflammatory master switch that controls the synthesis of many proteins critical for the activation and maintenance of the inflamed state 9. The hypothesis is that obesity stimulates NF-κB activity and additional stress pathways in adipose tissue, liver, gut, hypothalamus, and leukocytes, thereby promoting insulin resistance. Salsalate belongs to the class of nonsteroidal anti-inflammatory drugs that exert their anti-inflammatory effects by directly targeting inhibitor of kappa β kinase (IKKβ) within the NF-κB pathway at high doses. Administration of salsalate to patients with T2D or obese prediabetic patients has been shown to reduce serum levels of glucose, triglycerides, and nonesterified fatty acids 10,1110,11, whereas high salsalate doses (4.5 g/day) also improved endothelial function, assessed by brachial artery flow-mediated dilation, in obese patients 12. In the multicenter, double-masked TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) study, patients randomly received placebo or salsalate 3.5 g/day in addition to their current therapy. After 48 weeks, glycohemoglobin concentrations were 0.37% lower in the salsalate than the placebo group. Compared with placebo, adiponectin levels increased more, and circulating leukocytes, neutrophils, and lymphocyte counts decreased with salsalate 13.

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Effects of vitamin D on inflammation

Metaflammation features the activation of inflammatory cytokines, lipids and their metabolites, reactive oxygen species produced by mitochondrial, hypoxia and endoplasmic reticulum (ER) stress, and changes in gut microbiota profiles.

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Cellular and animal studies

Increasingly, laboratory data show that vitamin D plays a regulatory role in proinflammatory cytokine production 14. In-vitro studies show that 1,25(OH)2D decreases the production of proinflammatory cytokines, such as IL-6 and tumor necrosis factor-α (TNF-α), by macrophages and lymphocytes 15,1615,16, and upregulates the production of the anti-inflammatory cytokine, IL-10, from human peripheral blood monocytes 17. Work on platelets and megakaryocytes presented evidence of an abundant mitochondrial expression of VDR, which may be important for their role in mitochondrial metabolism 18.

ER stress-mediated proinflammatory effects in macrophages may affect early atherogenesis 19. In mouse models of diet-induced insulin resistance and atherosclerosis, ER stress markers were detected in intimal macrophages at early stages of vascular inflammation. Studies show that 1,25(OH)2D suppresses ER stress in monocytes and macrophages from diabetic patients, in addition to preventing monocyte adhesion and migration, and macrophage cholesterol deposition 20,2120,21.

An altered or less diverse gut microbiota composition has been linked to low-grade inflammation through activation of the lipopolysaccharide (LPS)-toll-like receptor (TLR)-4 axis 22,2322,23. A small clinical study in African–Americans suggested that decreased vitamin D intake correlated with differences in fecal microbiota composition 24. Low dietary vitamin D intake resulted in increased expression of proinflammatory genes and higher serum LPS levels in healthy 3-month-old CD-1 male mice 25. Whether vitamin D supplementation may control inflammation by altering gut microbiota composition needs further investigation.

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Vitamin D and the NF-κB pathway

Proinflammatory stimuli such as inflammatory cytokines, fatty acids, reactive oxygen species, and ER stress are increased in adiposity, and have also been shown to activate NF-κB 26–2826–2826–28. Canonical NF-κB activation involves IKKβ-mediated phosphorylation of the IκB inhibitory subunits that sequester gene-regulatory subunits in the cytoplasm, where they are inactive. Once phosphorylated, the IκB subunits are degraded through ubiquitination, and the free active form of NF-κB, usually the p65-p50 heterodimer, is then transported to the nucleus.

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Cellular studies

Pretreatment with 1,25(OH)2D resulted in significant inhibition of both TNF-α-induced activation of NF-κB and expression of E-selectin in coronary artery endothelial cells 29. Preincubation with 1,25(OH)2D also reduced LPS-stimulated IL-6 secretion and mRNA levels in human mesenchymal stromal cells and isolated adipocytes 30 and in a murine macrophage cell line 31. Moreover, 1,25(OH)2D reduced NF-κB activation (measured by p65 translocation, p65 DNA-binding activity 32,3332,33, and the luciferase reporter system 34) in cultured proinflammatory stimulus-activated endothelial cells. This effect of 1,25(OH)2D could be because of an increase in total IκBa expression and/or reduced IκBα phosphorylation 32,3332,33. Genome-wide microarray analysis of 1,25(OH)2D-treated white blood cells collected from healthy adults also suggests that vitamin D3 supplementation regulates the expression of IκBα in the NF-κB pathway 35.

It was found that the VDR physically interacts with NF-κB p65 in osteoblasts 36, fibroblasts 37, and colonic epithelial cells 38. Recently, it was reported that in mouse embryonic fibroblasts, C-terminal portions of the VDR interacted with IKKβ protein and this interaction was enhanced by 1,25(OH)2D. VDR–IKKβ interaction disrupts the formation of the IKK complex and, thus, abrogates IKKβ phosphorylation and abolishes IKK’s ability to phosphorylate IκBα, resulting in reduced p65 nuclear translocation 39.

Mammalian microRNAs (miRNAs) have recently been identified as important regulators of the innate and adaptive immune response 40. miRNA-155 (miR-155) is a key regulator of TLR signaling that targets suppressor of cytokine signaling-1 (SOCS-1) in activated macrophages, whereas SOCS-1 protein is a key component of the negative feedback loop that regulates cytokine signaling. Studies show that VDR inactivation leads to a hyperinflammatory response in mice and macrophage cultures when challenged with LPS, which can be attributed to the overproduction of miR-155 that excessively suppresses SOCS-1. Deletion of miR-155 attenuates vitamin D suppression of LPS-induced inflammation 31. These studies suggest a new anti-inflammatory mechanism whereby vitamin D signaling limits TLR4/NF-κB-mediated inflammation by enhancing negative feedback inhibition.

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Clinical trial of vitamin D and inflammation

Current observational studies

In observational human studies, the VDR gene polymorphism [VDR 2228570 C>T (FokI)] was associated with HOMA-IR, and insulin, and IL-6 levels in type 2 diabetic patients were associated with metabolic syndrome 41. Low vitamin D level has been associated with elevated levels of markers of systemic inflammation in patients scheduled for coronary angiography 42 and with abnormal glucose tolerance 43, but not in relatively healthy adolescents 44 and older individuals 45,4645,46 and established T2D 47.

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Emerging interventional studies in nondiabetic patients

Within an unselected population of African–Americans, three winter months’ exposure to vitamin D3 supplementation produced no change in circulating inflammatory markers such as CRP, IL-6, IL-10, and soluble TNF-α receptor type 2 48. In postmenopausal women who received vitamin D3 2500 IU daily or placebo for 4 months, there were no significant between-group differences in CRP, brachial artery flow-mediated vasodilation, or carotid-femoral pulse wave velocity 49. In patients with coronary heart disease or peripheral artery disease, vitamin D intervention did not improve endothelial function or reduce CRP, IL-6, and PAI-1 50. Oral or intravenous supplementation with 1,25(OH)2D decreased serum levels of IL-1 and IL-6 51, and left ventricular mass index 52, in hemodialysis patients with vitamin D deficiency. A randomized-controlled trial (RCT) in patients with congestive heart failure found that vitamin D3 (2000 IU/day for 9 months) decreased TNF-α and increased IL-10, with no effect on CRP 53. Higher doses of vitamin D3 supplementation (4000 IU/day for 6 months) significantly improved ejection fraction in elderly patients with heart failure and vitamin D deficiency 54. The above clinical trials suggest that vitamin D supplementation may improve hemodynamic properties in patients with heart failure by an anti-inflammatory mechanism.

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Emerging interventional studies in diabetic patients

In patients with type 2 diabetes, a few RCTs reported some moderate effects of vitamin D on glycemic control and insulin resistance 55,5655,56. We therefore aimed to present an up-to-date overview on the role of vitamin D supplementation in inflammatory markers in diabetic patients. PubMed-Medline and Web of Science were searched through 2012–2015 (Table 1). Selected articles were restricted to the English language and to RCTs of vitamin D supplementation with direct measures of inflammatory marker.

Table 1

Table 1

In 59 postmenopausal women with type 2 diabetes, daily consumption of 2000 IU vitamin D-fortified yogurt for 12 weeks improved serum fasting insulin, HOMA-IR, and HOMA-B, but not fasting glucose, HbA1c and high-sensitive CRP (hsCRP) 57. In two small trials that included less than 20 patients, vitamin D supplementation did not improve inflammatory makers such as TNF-α, adiponectin, IL-6, and leptin levels 58,6058,60. In a study carried out in the Chinese population, 12 weeks of oral supplementation of vitamin D did not affect vascular function or serum biomarkers of inflammation (hsCRP) and oxidative stress 61. In 118 diabetic patients who were assigned to receive vitamin D (50 000 IU/week) with or without calcium, calcium and vitamin D alone and joint calcium-vitamin D supplementation resulted in a significant reduction in serum leptin, IL-6, and TNF-α 59. In 90 diabetic patients, 500 IU vitamin D daily plus calcium decreased hsCRP, IL-1β, IL-6, fibrinogen, and retinol-binding protein-4 concentrations 62. A double-blind RCT compared vitamin D3-fortified yogurt (1000 U/day, 12 weeks) plus calcium supplements versus placebo plus calcium supplements. Diabetic patients who received a vitamin D-fortified drink had significantly decreased levels of hsCRP, serum amyloid A, and IL-6, and higher levels of IL-10 63.

The above clinical trials suggest that vitamin D treatment plus additional calcium supplementation may decrease inflammation in patients with established T2D and vitamin D deficiency. This may suggest an interaction of vitamin D and calcium, hypothetically related to the fact that calcium intake is known to increase the half-life of 25(OH)D and that both calcium and vitamin D metabolites decrease parathyroid hormone secretion. Definitive conclusions may be limited in the context of the moderate degree of heterogeneity, inclusion criteria, variable risk of bias, mode of vitamin D supplementation, and duration of follow-up.

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Concluding remarks

Experimental studies show that vitamin D signaling modulates many inflammatory responses on several levels. Further data are required to increase our understanding of the genetic, molecular, biochemical, and physiological properties of the vitamin D pathway that link inflammation and insulin resistance. Epidemiological studies show that vitamin D deficiency is associated with chronic, low-grade, systemic inflammatory disease, such as T2D and CVD. However, the evidence from interventional studies is not consistent. Future investigations should include larger cohorts of patients with chronic inflammatory disease and documented vitamin D deficiency, and use careful selection of the dose, dosing regimen, and achievement of target 25(OH)D serum concentrations.

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Acknowledgements

The author was supported by funds from the Guangdong Province Natural Science Foundation of China (S2012040007756).

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

cardiovascular disease; diabetes; inflammation; NF-κB; vitamin D

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