The effects of vitamin D supplementation on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial

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Abstract

Objective

This study was conducted to evaluate the effects of vitamin D supplementation on wound healing and metabolic status in patients with diabetic foot ulcer (DFU).

Methods

This randomized, double-blind, placebo-controlled trial was performed among 60 patients with grade 3 DFU according to "Wagner–Meggitt’s" criteria. Participants were randomly divided into two groups (each 30 participants) and received either 50,000 IU vitamin D supplements every 2 weeks for 12 weeks (group A) or placebo (group B). Fasting blood samples were taken at study baseline and after 12-week intervention to determine related markers.

Results

After 12 weeks of intervention, compared with the placebo, vitamin D supplementation resulted in a significant reduction in ulcer length (− 2.1 ± 1.1 vs. − 1.1 ± 1.1 cm, P = 0.001), width (− 2.0 ± 1.2 vs. − 1.1 ± 1.0 cm, P = 0.02) and depth (− 1.0 ± 0.5 vs. − 0.5 ± 0.5 cm, P < 0.001), and erythema rate (100% vs. 80%, P = 0.01). In addition, in supplemented patients changes in serum insulin concentration (− 3.4 ± 9.2 vs. + 2.8 ± 9.3 μIU/mL, P = 0.01), homeostasis model of assessment-estimated insulin resistance (− 1.5 ± 4.1 vs. + 1.7 ± 5.1, P = 0.01), the quantitative insulin sensitivity check index (+ 0.006 ± 0.02 vs. − 0.006 ± 0.02, P = 0.03) and HbA1c (− 0.6 ± 0.6 vs. − 0.1 ± 0.5%, P = 0.004) were significantly different from those of patients in the placebo group. Additionally, following supplementation with vitamin D, significant reductions in serum total- (− 15.8 ± 18.9 vs. + 5.3 ± 31.8 mg/dL, P = 0.003), LDL- (− 17.2 ± 19.8 vs. + 2.2 ± 28.6 mg/dL, P = 0.003), total-/HDL-cholesterol ratio (− 1.1 ± 0.8 vs. − 0.2 ± 1.1, P = 0.001), high sensitivity C-reactive protein (hs-CRP) (− 0.4 ± 2.5 vs. + 1.9 ± 4.2 μg/mL, P = 0.01), erythrocyte sedimentation rate (ESR) (− 34.7 ± 32.4 vs. − 18.0 ± 26.6 mm/h, P = 0.03) and plasma malondialdehyde (MDA) concentrations (− 0.7 ± 0.9 vs. − 0.2 ± 0.5 μmol/L, P = 0.008) were seen compared with the placebo.

Conclusions

Overall, vitamin D supplementation for 12 weeks among patients with DFU had beneficial effects on glucose homeostasis, total-, LDL-, total-/HDL-cholesterol, ESR, hs-CRP and MDA levels. In addition, vitamin D may have played an indirect role in wound healing due to its effect on improved glycemic control.

Introduction

The diabetic foot ulcer (DFU) is a common complication of diabetes mellitus affecting 10%–25% of people with diabetes (Armstrong et al., 2014). The annual incidence of ulceration and amputation among patients with DFU is as high as 2.5%–10.7% and 0.25%–1.8%, respectively (Tiaka, Papanas, Manolakis, & Maltezos, 2011). Patients with diabetic foot ulcer have a higher mortality compared with patients with diabetes who have not developed food ulcer. DFU is a major cause of morbidity in diabetic patients, and the mortality rate is about twice that of diabetic patients without foot ulcer (Daousi et al., 2004). Diabetic neuropathy and peripheral vascular disease are the main etiological factors in DFU (Sinwar, 2015). Furthermore, insulin resistance, dyslipidemia, inflammation and oxidative stress play a significant role in the pathogenesis of DFU (Karadurmus et al., 2010, Sytze Van Dam et al., 2013).

In recent years, there has been an effort to understand possible roles of vitamin D inadequacy including its role in pancreatic insulin secretion and insulin action, the immune system particularly on T cell medicated immunity and decreased inflammation and oxidative stress (Asemi et al., 2013, Zubair et al., 2013). Circulating levels of 25(OH)D were low in patients with DFU (Asemi et al., 2013, Tiwari et al., 2013) and the beneficial effects of vitamin D supplementation on markers of insulin resistance, biomarkers of inflammation and oxidative among patients without DFU were reported. We have previously indicated that supplementation with 50,000 IU vitamin D/week among patients with major depressive disorder for 8 weeks had the beneficial effects on parameters of glucose homeostasis, and oxidative stress, but did not affect lipid profiles (Sepehrmanesh et al., 2016). However, improvement in vitamin D status following administration with 280 μg/day for 2 weeks and 140 μg/day for 10 weeks did not improve insulin resistance among patients with diabetes (Kampmann et al., 2014).

The favorable effects of vitamin D supplementations on wound healing, insulin resistance, biomarkers of inflammation and oxidative stress may be mediated by its impact on stimulating the phagocytosis and killing the bacteria by macrophages (van Etten, Decallonne, Bouillon, & Mathieu, 2004), suppressing interferon-g-mediated macrophage activation (Helming et al., 2005), activating insulin receptor expression, and the downregulation of cytokine generation (Pittas, Lau, Hu, & Dawson-Hughes, 2007). As there is evidence that vitamin D intake may accelerate wound healing and has anti-inflammatory and antioxidant effects, we hypothesized that vitamin D supplementation might help patients with DFU to heal their wound faster, and have better metabolic profiles, and biomarkers of inflammation and oxidative stress. The objective of this study was to evaluate the effects of vitamin D supplementation on wound healing and metabolic status in patients with DFU.

Section snippets

Trial design

The current study was a prospective randomized double-blind placebo-controlled clinical trial.

Participants

In the current study, 60 patients with grade 3 DFU aged 40–85 years who referred to the Shahid Beheshti Clinic in Kashan, Iran, between November 2015 and January 2016 were recruited. The Wagner–Meggitt’s original system has six grades of lesions. This system assesses ulcer depth and the presence of osteomyelitis or gangrene by using the following grades: grade 0 (pre-or postulcerative lesion), grade 1

Results

Among participants in the placebo group, 2 patients [withdrawn for personal reasons (n = 2)] were excluded (Fig. 1). At the end, 58 patients with DUF [vitamin D (n = 30) and placebo (n = 28)] completed the trial. However, as the analysis was based on the ITT principle, all 60 patients (30 in each group) were included in the final analyses.

Gender distribution, mean age, weight and BMI at the baseline and end-of-trial, METs at the baseline and end-of-trial, and insulin and metformin therapy were not

Discussion

In this trial, which to the best of our knowledge is the first of its kind, we evaluated effects of vitamin D supplementation on wound healing, glycemia status, lipid concentrations, and biomarkers of inflammation and oxidative stress among patients with DFU. We demonstrated that vitamin D supplementation for 12 weeks among patients with DFU had beneficial effects on glucose homeostasis, total-, LDL-, total-/HDL-cholesterol, ESR, hs-CRP and MDA levels, but it did not had any effect on FPG, other

Acknowledgments

The current study was funded by a grant from the Vice-chancellor for Research, KUMS, and Iran. The authors would like to thank the staff of Shahid Beheshti Clinic (Kashan, Iran) for their assistance on this project. The authors gratefully acknowledge Dr. Fariba Kolahdooz, who reviewed the manuscript and offered critical comments.

References (42)

  • Z. Sepehrmanesh et al.

    Vitamin D supplementation affects the Beck Depression Inventory, insulin resistance, and biomarkers of oxidative stress in patients with major depressive disorder: A randomized, controlled clinical trial

    The Journal of Nutrition

    (2016)
  • P.D. Sinwar

    The diabetic foot management — recent advance

    International Journal of Surgery

    (2015)
  • E. Tatsch et al.

    A simple and inexpensive automated technique for measurement of serum nitrite/nitrate

    Clinical Biochemistry

    (2011)
  • E. van Etten et al.

    NOD bone marrow-derived dendritic cells are modulated by analogs of 1,25-dihydroxyvitamin D3

    The Journal of Steroid Biochemistry and Molecular Biology

    (2004)
  • M. Zubair et al.

    25-Hydroxyvitamin D [25(OH)D] levels and diabetic foot ulcer: Is there any relationship?

    Diabetes & Metabolic Syndrome

    (2013)
  • M.S. Agren et al.

    Causes and effects of the chronic inflammation in venous leg ulcers

    Acta Dermato-Venereologica. Supplementum

    (2000)
  • B.E. Ainsworth et al.

    Compendium of physical activities: An update of activity codes and MET intensities

    Medicine and Science in Sports and Exercise

    (2000)
  • D.G. Armstrong et al.

    Effect of oral nutritional supplementation on wound healing in diabetic foot ulcers: A prospective randomized controlled trial

    Diabetic Medicine

    (2014)
  • E.F. Berbari et al.

    2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults

    Clinical Infectious Diseases

    (2015)
  • E. Beutler et al.

    Plasma glutathione in health and in patients with malignant disease

    The Journal of Laboratory and Clinical Medicine

    (1985)
  • S. Chandrashekara et al.

    Role of vitamin D supplementation in improving disease activity in rheumatoid arthritis: An exploratory study

    International Journal of Rheumatic Diseases

    (2015)
  • Cited by (0)

    Clinical trial registration number: http://www.irct.ir: IRCT201510315623N54.

    Conflicts of interest: None declared.

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