Vitamin D Supplementation Modulates Platelet-Mediated Inflammation in Subjects With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

BackgroundRecently, our group identified increased platelet-mediated inflammation in type 2 diabetes (T2DM) patients, and it is a well-established risk factor for diabetes complications, particularly for the development of cardiovascular diseases (CVD). Furthermore, vitamin D is reported to play an important role in the modulation of platelet hyperactivity and immune function, although the effect of vitamin D on platelet-mediated inflammation is not well studied. Hence, we aimed to investigate the effect of vitamin D supplementation on platelet-mediated inflammation in T2DM patients.MethodsAfter screening a total of 201 subjects, our randomized, double-blind, placebo-controlled trial included 59 vitamin-D-deficient T2DM subjects, and the participants were randomly assigned to placebo (n = 29) or vitamin D3 (n = 30) for 6 months. Serum vitamin D metabolite levels, immunome profiling, platelet activation, and platelet–immune cell aggregate formation were measured at baseline and at the end of the study. Similarly, the serum levels of inflammatory cytokines/chemokines were assessed by a multiplex assay.ResultsSix months of vitamin D supplementation increases the serum vitamin D3 and total 25(OH)D levels from the baseline (p < 0.05). Vitamin D supplementation does not improve glycemic control, and no significant difference was observed in immune cells. However, platelet activation and platelet immune cell aggregates were altered after the vitamin D intervention (p < 0.05). Moreover, vitamin D reduces the serum levels of IL-18, TNF-α, IFN-γ, CXCL-10, CXCL-12, CCL-2, CCL-5, CCL-11, and PF-4 levels compared to the baseline levels (p < 0.05). Our ex vivo experiment confirms that a sufficient circulating level of vitamin D reduces platelet activation and platelet intracellular reactive oxygen species.ConclusionOur study results provide evidence that vitamin D supportive therapy may help to reduce or prevent the disease progression and cardiovascular risk in T2DM patients by suppressing oxidative stress and platelet-mediated inflammation.Clinical Trial RegistrationClinical Trial Registry of India: CTRI/2019/01/016921.

Vitamin D Determinants, Status, and Antioxidant/Anti-inflammatory-Related Effects in Cardiovascular Risk and Disease: Not the Last Word in the Controversy

“…In T2D hemodialysis patients, vitamin D supplementation induces a significant reduction in hsC-reactive protein and MDA, in parallel to a significant increase in TAC levels [ 190 ]. Some data suggested that vitamin D may reduce or prevent the disease progression and cardiovascular risk in T2D patients by decreasing oxidative stress and platelet-mediated inflammation (IL-18, TNF-α, IFN-γ, CXCL-10, CXCL-12, CCL-2, CCL-5, CCL-11, and PF-4), as well as blood vitamin D supplementation (2000 IU/day for six months) in T2D patients having vitamin D < 20 ng/mL resulted associated to a significant decrease in OxLDL, hsCRP, IL-6, PAI-1, and fibrinogen levels and a significant increase in FRAP, (although other studies failed to evidence any significant effect on different biomarkers of oxidative stress and inflammation in these type of patients) [ 191 , 192 , 193 , 194 ]. Furthermore, in patients with CAD, there are controversial data on the effects of vitamin D supplementation on oxidative or inflammatory biomarkers related to cardiovascular health [ 195 , 196 , 197 ].…”

Targeting the Platelet-Activating Factor Receptor (PAF-R): Antithrombotic and Anti-Atherosclerotic Nutrients

“…However, vitamin D has diverse physiological functions and is involved in inflammatory and procoagulatory pathways in the body due to its important role in immune function [ 164 ]. A randomized study found that vitamin D supplementation can reduce platelet-mediated inflammation and oxidative stress in diabetic patients [ 165 ]. Vitamin D can also regulate haemostasis, and its deficiency is associated with increased platelet aggregation in the presence of the agonist ADP [ 166 ].…”

“… Vitamin D Study the effect of vitamin D supplementation in volunteers with Type 2 diabetes in a placebo-controlled trial. Ex vivo Six months of vitamin D supplementation decreased platelet activation and inflammatory markers such as IL-18, TNF-α and IFN-γ [ 165 ]. Vitamin D Study the inhibitory effect of paricalcitol against PAF and thrombin-induced platelet aggregation In vitro Addition of paricalcitol effectively inhibited platelet aggregation as well as modulating the activity of metabolic enzymes PAF-CPT and PAF-AH in platelets and leukocytes [ 169 ].…”

Untargeted metabolomics reveals altered branch chain amino acids, glucose and fat metabolism contributing to coronary artery disease among Indian diabetic patients

“…People with diabetes exhibit 2-to 4-fold higher risk for developing cardiovascular diseases (CVDs) compared to non-diabetic subjects. [2][3][4] The multifactorial link between DM and CVDs has become one of the major causes of morbidity among patients globally. 5,6 Hence, a comprehensive goal should be to investigate the causative link between DM and CVDs, accompanied by the diagnosis of diabetes along with its complications and managing the onset of cardiovascular events.…”

“…People with diabetes exhibit 2- to 4-fold higher risk for developing cardiovascular diseases (CVDs) compared to non-diabetic subjects. 2–4…”