Genome-wide screening of m6A profiling of cutaneous wound healing in diabetic mice.

OBJECTIVE: Impaired wound healing in diabetes mellitus (DM) is a major health burden on patients, their families, and society. The present study aimed to systematically profile the m6A modification landscape in cutaneous wounds in a diabetic mouse model. APPROACH: Diabetes was induced in mice through a single intraperitoneal injection of streptozotocin (STZ); a single intraperitoneal injection of PBS was made in control mice for comparisons. Both groups then received an 8-mm diameter, full-thickness dorsal body wound with a biopsy punch. Five days after wound surgery, western blot analysis of harvested wound tissues from both groups was used to assess the expression of m6A-related enzymes. Genome-wide profiling of m6A-tagged transcripts was performed through MeRIP-seq and RNA-seq. RESULTS: ALKBH5, an m6A eraser, was significantly upregulated, while METTL3, METTL14, and WTAP, m6A writers, were markedly downregulated in the diabetic wounds. Additionally, a total of 1335 m6A peaks were differentially expressed in MeRIP-seq and RNA-seq analyses, with 558 upregulated and 777 downregulated peaks. Finally, there was hypomethylated and hypermethylated differentiation at the gene and transcript levels. INNOVATION: The present study was the first to reveal the m6A landscape in diabetic wounds in an animal model. CONCLUSION: This study, by deeply analyzing the role of m6A modifications in diabetic wound healing, provides new insights and understanding into the molecular mechanisms of diabetic wound healing. Future research could further explore how m6A modifications regulate the wound healing process, thereby offering new potential targets for the treatment of diabetic wounds.

Staphylococcus aureus enhances osteoclast differentiation and bone resorption by stimulating the NLRP3 inflammasome pathway.

BACKGROUND: Osteomyelitis is one of the most challenging infectious diseases and is mainly caused by Staphylococcus aureus (S. aureus). In this study, we analyzed the effect of S. aureus on osteoclast differentiation and its possible molecular mechanism. METHODS: We cultured RAW 264.7 cells with live S. aureus for 5 days. We assessed cell viability and the formation of resorption pits. We tested the NLRP3 inflammasome signaling pathways and measured the mRNA expression levels of osteoclastspecific genes, including TRAP, MMP9, cathepsin K, calcitonin receptor and ATP6V0d2. Furthermore, we analyzed the protein expression levels of the protein in the NF-κB and p38 MAPK signaling pathways to clarify the signaling pathways by which S. aureus promotes osteoclast differentiation. RESULTS: Staphylococcus aureus induced NLRP3 inflammasome activation. S. aureus promoted bone resorption and enhanced the expression of osteoclastspecific genes, such as TRAP, MMP9, cathepsin K, calcitonin receptor and ATP6V0d2. MCC950 was used to inhibit NLRP3 inflammasome activity. Osteoclast differentiation and the expression of osteoclastspecific genes induced by S. aureus were inhibited by MCC950 pretreatment. The degradation of IκBα and phosphorylation of P65 were increased under the induction of S. aureus, but proteins in the p38 MAPK signaling pathway did not change significantly. CONCLUSION: Staphylococcus aureus induces osteoclast differentiation and promotes bone resorption in vitro, and the NLRP3 inflammasome signaling pathway plays a significant role in this process. S. aureus-induced NLRP3 inflammasome activation was mainly dependent on the NF-κB signaling pathway during osteoclastogenesis.

Application of antibiotic bone cement in the treatment of infected diabetic foot ulcers in type 2 diabetes.

BACKGROUND: In this study, we try to investigate the effect of antibiotic bone cement in patients with infected diabetic foot ulcer (DFU). METHODS: This is a retrospective study, including fifty-two patients with infected DFU who had undergone treated between June 2019 and May 2021. Patients were divided into Polymethylmethacrylate (PMMA) group and control group. 22 patients in PMMA group received antibiotic bone cement and regular wound debridement, and 30 patients in control group received regular wound debridement. Clinical outcomes include the rate of wound healing, duration of healing, duration of wound preparation, rate of amputation, and frequency of debridement procedures. RESULTS: In PMMA group, twenty-two patients (100%) had complete wound healing. In control group, twenty-eight patients (93.3%) had wound healing. Compared with control group, PMMA group had fewer frequencies of debridement procedures and shorter duration of wound healing (35.32 ± 3.77 days vs 44.37 ± 7.44 days, P < 0.001). PMMA group had five minor amputation, while control group had eight minor amputation and two major amputation. Regarding the rate of limb salvage, there was no limb lose in PMMA group and two limb losses in control group. CONCLUSION: The application of antibiotic bone cement is an effective solution for infected DFU treatment. It can effectively decreased the frequency of debridement procedures and shorten the healing duration in patients with infected DFU.

IL-1ß Impaired Diabetic Wound Healing by Regulating MMP-2 and MMP-9 through the p38 Pathway.

Diabetes mellitus is one of the most prominent metabolic disorders in the world, and insulin resistance in diabetic patients leads to several complications including increased inflammation and delayed wound healing. Fibroblast migration and reepithelialization play a significant role in wound healing. In this study, we explored the effects of IL-1ß signaling on proliferation and migration of human fibroblasts from diabetic wound tissues. We observed elevated levels of IL-1ß in samples from diabetic patients when compared to normal wound tissues. At high concentrations, IL-1ß inhibited cell proliferation and migration in ex vivo fibroblast cultures. Moreover, expression of matrix metalloproteinases (MMPs) was upregulated, and tissue inhibitor of metalloproteinases (TIMPs) was downregulated in diabetic wound tissues and cells. These effects were regulated by levels of IL-1ß. Furthermore, IL-1ß induced p38 phosphorylation thereby activating the p38 MAPK pathway that in turn regulated the expression of MMPs and TIMPs. Together, our study identifies a novel mechanism behind delayed wound closure in diabetes mellitus that involves IL-1ß-dependent regulation of cell proliferation and migration.

Advanced Glycation End Products (AGEs) Induce Apoptosis of Fibroblasts by Activation of NLRP3 Inflammasome via Reactive Oxygen Species (ROS) Signaling Pathway.

BACKGROUND Type 2 diabetes impairs the healing process and induces apoptosis of fibroblasts, which are thought to be involved in this process. We investigated the possible mechanisms involved in AGEs-induced apoptosis of human dermal fibroblasts. MATERIAL AND METHODS We examined the expression of apoptosis-related proteins in fibroblasts isolated from human diabetic wounds. Human dermal fibroblasts exposed to AGEs were used to study the links among apoptosis, ROS, and NLRP3 inflammasome activation. Signaling mechanisms were evaluated by preincubating the cells with appropriate inhibitors. Cleaved caspase-8, cleaved caspase-3, BAX, Bcl-2, and NLRP3 inflammasome expression were measured by Western blot analysis. ROS generation, cell viability, and cell apoptosis were assessed. RESULTS We observed a higher level of cleaved caspase-8 and cleaved caspase-3 expression in fibroblasts isolated from human diabetic wounds compared with controls. AGEs decreased the proliferation of cells in a concentration-dependent and time-dependent manner. The exposure of fibroblasts to AGEs significantly increased the number of cells in early and late apoptosis stages. AGES-induced human dermal fibroblasts showed high expressions of cleaved caspase3, cleaved caspase8, and Bax. Treatment with AGEs induced the expression of NLRP3, caspase-1, and ASC. AGES-induced apoptosis was blocked by BAY 11-7082, an inhibitor of the NLRP3 inflammasome. AGEs increased the production of ROS in fibroblasts, and its apoptogenic effect was blocked by NAC. CONCLUSIONS AGEs cause apoptosis of fibroblasts by inducing the generation of ROS and activating the NLRP3 inflammasome. In vivo experiments are needed to confirm these results.

Autophagy Inhibition Contributes to ROS-Producing NLRP3-Dependent Inflammasome Activation and Cytokine Secretion in High Glucose-Induced Macrophages.

BACKGROUND: Type 2 diabetes is a persistent inflammatory response that impairs the healing process. We hypothesized that stimulation with high glucose following a pro-inflammatory signal would lead to autophagy inhibition, reactive oxygen species (ROS) production and eventually to the activation of the Nod-like receptor protein (NLRP) -3. METHODS: Macrophages were isolated from human diabetic wound. We measured the expression of NLRP3, caspase1 and interleukin-1 beta (IL-1ß) by western blot and real-time PCR, and the surface markers on cells by flow cytometry. THP-1-derived macrophages exposed to high glucose were applied to study the link between autophagy, ROS and NLRP3 activation. LC3-II, P62, NLRP3 inflammation and IL-1ß expression were measured by western blot and real-time PCR. ROS production was measured with a Cellular Reactive Oxygen Species Detection Assay Kit. RESULTS: Macrophages isolated from diabetic wounds exhibited a pro-inflammatory phenotype, including sustained NLRP3 inflammasome activity associated with IL-1ß secretion. Our data showed that high glucose inhibited autophagy, induced ROS production, and activated NLRP3 inflammasome and cytokine secretion in THP-1-derived macrophages. To study high glucose-induced NLRP3 inflammasome signalling, we performed studies using an autophagy inducer, a ROS inhibitor and a NLRP3 inhibitor and found that all reduced the NLRP3 inflammasome activation and cytokine secretion. CONCLUSION: Sustained NLRP3 inflammasome activity in wound-derived macrophages contributes to the hyper-inflammation in human diabetic wounds. Autophagy inhibition and ROS generation play an essential role in high glucose-induced NLRP3 inflammasome activation and cytokine secretion in macrophages.

Notoginsenoside R1 stimulates osteogenic function in primary osteoblasts via estrogen receptor signaling.

Notoginsenoside R1 (NGR1), a novel phytoestrogen isolated from Panax notoginseng, has been widely used in the treatment of microcirculatory diseases in Asian countries. Here we investigated the effect of NGR1 on osteoblast differentiation and mineralization process. Furthermore, we also evaluated NGR1's estrogenic properties, especially its effects on estrogen receptors (ERs). NGR1 activated the transcriptional activity of phosphorylated estrogen response element (pERE)-luciferase (Luc) and induced ERα phosphorylation in hBMSC. In addition, ER activation correlated with induction and was associated with osteoblast differentiation biomarkers including alkaline phosphatase activity and transcription of osteoblastic genes, e.g., type I collagen (COL1), osteonectin, osteocalcin (OC), runt related protein 2 (Runx2), and osterix. NGR1 also promoted the mineralization process of osteoblasts. The NGR1-induced effects were confirmed to be mediated by the ER by the observation that pretreatment of the osteoblasts with the ER antagonist, ICI 182,780 fully blocked the effects. Our results showed that NGR1 stimulates osteogenic differentiation of cultured osteoblasts by activating ER signaling and in turn might be a potential therapeutic alternative for the prevention and treatment of osteoporosis.

Dynamic compression plating versus locked intramedullary nailing for humeral shaft fractures: a meta-analysis of RCTs and nonrandomized studies.

PURPOSE: There is no consensus regarding treatment of humeral shaft fracture. In this meta-analysis, we pooled studies to compare dynamic compression plate with locked intramedullary nail for this injury. METHODS: PubMed, MEDLINE, and Embase databases were searched for relevant studies published between January 1995 and July 2012. Evaluated endpoints were method-related complications and revision. Study quality was assessed, and meta-analyses were analyzed using the Cochrane Collaboration's REVMAN 5.0 software. RESULTS: Fourteen randomized controlled (RCTs) and nonrandomized studies with 727 patients were analyzed. There was a significantly higher risk of total method-related complications and shoulder impairment resulting from locked intramedullary nailing compared with dynamic compression plating. Plating was significantly associated with a higher risk of infection and postoperative nerve palsy. There was no significant difference with respect to nonunion and revision rate. CONCLUSIONS: Nailing may cause more method-related complications and shoulder impartment than plating, although it may lead to a lower risk of infection and postoperative nerve palsy. In the future, more high-quality RCTs are required to enhance these conclusions.

Meta-analysis comparing locking plate fixation with hemiarthroplasty for complex proximal humeral fractures.

BACKGROUND: There remains no consensus on the surgical treatment of complex proximal humeral fractures. In this meta-analysis, we pool available trials to compare the clinical outcomes of locking plate fixation and hemiarthroplasty for this injury. METHODS: A literature search between January 1990 and May 2012 in the main medical search engines (Pubmed, Medline, Embase search, and the Cochrane library) was included. We selected available trials that compared locking plate fixation and hemiarthroplasty in patients with complex proximal humeral fractures and that reported on functional outcomes, revisions, and method-related complications. The quality of the studies was assessed, and meta-analyses were performed with the Cochrane Collaboration's REVMAN 5.0 software. RESULTS: A total of 567 patients from 9 trials were included in this meta-analysis (302 fractures treated with locking plate and 265 with hemiarthroplasty). In this comparison, we found that patients with locking plate fixation had better Constant-Murley score than with hemiarthroplasty, and hemiarthroplasty could reduce the rate of revisions and the method-related complications significantly. CONCLUSIONS: Compared with hemiarthroplasty, patients with locking plate fixation could obtain more favorable functional outcomes, but technical detail was critical to minimize the risk of implant failure, avascular necrosis, and re-operation. As the possible significant bias and inconclusive evidence arising from the included trials, further randomized trials and observational studies should be recommended to support these finding.

Distally based saphenous neurocutaneous perforator flap for reconstructive surgery in the lower leg and the foot: a long-term follow-up study of 70 patients.

BACKGROUND: The management of soft-tissue defects in the distal third of the lower leg and foot remains disputed. In this article, we describe a long-term follow-up research study on the clinical results and complications of using this flap for the reconstruction of soft-tissue defects around the lower leg and foot. METHODS: Between 2006 and 2008, 70 patients with soft-tissue defects around the lower leg and foot were treated with distally based saphenous neurocutaneous perforator flaps. The mean age of patients was 46.0 years (range, 22 to 70 years). An end point survey was performed after flap coverage; the mean follow-up was 54.2 months (range, 40 to 68 months), and response rate was 92.9% (65/70). A sensory morbidity was measured with a static two-point discrimination test and Semmes-Weinstein monofilament test. RESULTS: A total of 58 flaps survived completely, 6 flaps developed partial necrosis, and 1 experienced total failure. No severe venous congestion was observed and the skin grafts in the donor sites survived entirely. Sensitivity tests have shown an acceptable sensory recovery at the skin-grafted donor site and on the flap. CONCLUSION: Distally based saphenous neurocutaneous flap is a reliable and safe method for reconstruction of the defects around the lower leg and foot, with a lower sensorial morbidity.

Proximal-based saphenous neurocutaneous flaps: a novel tool for reconstructive surgery in the proximal lower leg and knee.

BACKGROUND: Soft tissue defects around the knee region are usually complex and require adequate reconstruction with flaps. In this article, we present our experience using the proximal-based saphenous neurocutaneous flap for the reconstruction of soft tissue defects around the knee and the proximal lower leg. METHODS: Between 2008 and 2010, 17 patients with soft tissue defects around the knee and the proximal lower leg were treated with proximal-based saphenous neurocutaneous flaps. The age of patients ranged from 19 to 61 years (mean 35.6 years). Defect sizes ranged from 3 cm × 4 cm to 9 cm × 18 cm and the flaps were designed with sizes ranging from 3 cm × 5 cm to 11 cm × 20 cm. The mean follow-up was 16 months (range 8 to 26 months). RESULTS: Sixteen flaps survived completely, and one flap developed partial necrosis. Mild swelling was observed within a few days postoperatively, and no severe venous congestion occurred. The skin grafts in the donor sites survived completely. All of the 17 flaps gained a good sensory recovery, and only 2 patients complained of numbness on the grafted donor-site during extended follow-up. CONCLUSION: Our experience has demonstrated that the proximal-based saphenous neurocutaneous flap is a safe and reliable tool for reconstruction of the defects around the proximal lower leg and knee.

Comparative study of two types of distally based sural neurocutaneous flap for reconstruction of lower leg, ankle, and heel.

BACKGROUND: Soft-tissue defects in the lower leg, ankle, and heel often require reconstruction with local or free flaps. We try to compare the clinical outcome and complications following transfer of a perforator pedicle-based sural neurocutaneous flap (P-NCF) or a fascia pedicle-based sural neurocutaneous flap (F-NCF). METHODS: Between March 2007 and December 2010, 92 patients (mean, 36.52 years) with a distal leg soft-tissue defect were included. Forty-eight patients treated with P-NCF were compared with 44 patients treated by F-NCF. The etiology, size, and operation time were noted. The clinical outcomes and the complications have been analyzed. RESULTS: Age, sex, and defect etiology, duration of surgery and, area of flaps did not reveal significant differences in term of clinical outcome. Minor flap necrosis (<10%) was observed in 20.5% of the F-NCF group and 6.25% of the P-NCF group. Patient satisfaction, aesthetic appearance, and functional outcome were comparable in both groups. CONCLUSION: A high rate of complications was observed in the F-NCF group. Based on our finding, a perforator-based flap is more reliable than a fascia-based flap and the two types of flaps are both valuable choices for reconstructive surgery.

Application of the distally based sural neurocutaneous flaps in the management of foot and ankle defects in patients with diabetic foot.

Background: We report our experience on the use of a distally based sural flap for soft tissue reconstruction of foot and ankle defects in patients with diabetic foot. Methods: The actual study is a retrospective, open, non-controlled, and clinical study of 25 patients treated with diabetic foot on whom reconstruction with distally based sural neurocutaneous flaps was performed from May 2019 to December 2021. Results: The mean age was 64.9 years, and there were 15 male and 10 female patients. The mean follow-up was 9.8 months, which ranged from 6 to 12 months. The size of the flaps ranged from 6 × 5 to 15 × 9 cm2. Twenty-two of the 25 flaps survived intact with sufficient blood supply. Two cases had a small superficial necrosis, which was resolved after a change of daily dressing and was heeled eventually. In one case, partial necrosis was observed that was managed with minor revision and the use of split-thickness skin graft. Conclusions: The distally based sural flap is considered to be useful for reconstruction of foot and ankle defects in patients with diabetic foot.

Corrigendum: Application of the distally based sural neurocutaneous flaps in the management of foot and ankle defects in patients with diabetic foot.

[This corrects the article DOI: 10.3389/fendo.2022.1009714.].

Association Between Serum 25-OH-Vitamin D and Diabetic Foot Ulcer in Patients With Type 2 Diabetes.

Background: Vitamin D deficiency has been associated with an increased risk in several diabetic complications. We aimed to evaluate the association between vitamin D and diabetic foot ulcer (DFU) in patients with type 2 diabetes. Methods: Fifty one patients were included in the study and divided into two groups for study of vitamin D, cholesterol, and triglycerides in blood serum on DFU. The association between vitamin D and DFU was measured by binary logistic regression analysis. The cut point of vitamin D for DFU was assessed by the receiver operating characteristic curve. Results: Levels of 25-OH-vitamin D were lower in patients with DFU than in DM group (P < 0.0001). The AUC of 25-OH-vitamin D was 0.8254 and had an optimal cut point value (13.68 ng/ml) for the identification of DFU, with a sensitivity of 90% and a specificity of 66.67% in all patients. Multivariate logistic regression analysis indicated that the significant risk factors included 25-OH-vitamin D level (P = 0.001, OR = 0.618) and HDL-C level (P = 0.038, OR = 0.012). Conclusion: Low serum 25-OH-vitamin D level was associated with DFU. This indication was more specific than cholesterol and triglycerides levels.

Treatment of Diabetic Foot with Autologous Stem Cells: A Meta-Analysis of Randomized Studies.

BACKGROUND: This meta-analysis was to evaluate the efficacy of autologous stem cell administration for the treatment of diabetic foot. METHODS: The electronic databases included PubMed, EMBASE, BIOSIS, Cochrane central, and Google Scholar internet, last updated on May 30, 2019. Evaluated outcomes included the rate of wound healing and amputation. Dichotomous outcomes were described as risk ratios (RR) with 95% confidence intervals (CIs). Statistical analysis was performed with RevMan 5.0 software and STATA 10.0 software. RESULTS: Eight randomized controlled trial (RCT) studies were included in this study. The meta-analysis showed a lower amputation (RR 0.25, 95% CI 0.11 to 0.54, I 2 = 0) and a higher wound healing rate (RR 2.05, 95% CI 1.67 to 2.51, I 2 = 4) in the cell therapy group compared with control. CONCLUSION: This meta-analysis supports the effective role of stem cell therapy in promoting wound healing and decreasing rate of amputation in diabetic foot. In the future, more high quality and well-designed studies are need.

Autologous platelet-rich plasma treatment for patients with diabetic foot ulcers: a meta-analysis of randomized studies.

BACKGROUND: This study will explore the effectiveness and safety of autologous PRP in the treatment of patients with DFU. METHODS: The electronic databases of PubMed, EMBASE, BIOSIS, Cochrane central, and Google Scholar internet were searched updated on Jan 30, 2020. Evaluated outcomes included rate of complete ulcer healing, time to healing and adverse events. Statistical analysis was performed with RevMan 5.0 software and STATA 10.0 software. RESULTS: Ten RCTs with 456 patients were included in this study. The meta-analysis showed a higher complete ulcer healing rate (RR = 1.32, 95% CI 1.06 to 1.65, P = 0.01, I2 = 57%), a shorter healing time (MD = -23.42, 95% CI -37.33 to -9.51, P = 0.01, I2 = 78%), with no increasing the incidence of adverse events (RR = 0.48, 95% CI 0.22 to 1.05, P = 0.75, I2 = 0%) in PRP group compared with control. Mixed evidence was seen for publication bias, but analyses by using the trim-and-fill method did not appreciably alter results. CONCLUSION: Our findings suggest that autologous PRP may improve the complete ulcer healing rate, shorten the healing time, with no increasing the incidence of adverse events.

Assessment of the Risk Factors of Multidrug-Resistant Organism Infection in Adults With Type 1 or Type 2 Diabetes and Diabetic Foot Ulcer.

OBJECTIVES: To our knowledge, this is the first review to analyze the literature identifying risk factors for multidrug-resistant organism (MDRO) infection in patients with diabetic foot ulcer. The purpose of this study was to collect the currently published data to determine the most commonly and consistently identified risk factors for MDRO infection. METHODS: PubMed, MEDLINE, BIOSIS, Web of Science and the Cochrane Library electronic databases were searched. The last search updated was in September 2019. The evaluated outcomes included age, male sex, type of diabetes, diabetes duration, level of glycated hemoglobin, ulcer type, wound duration, ulcer size, ulcer grade, osteomyelitis, previous antibiotic therapy and previous hospitalization. The standard mean difference or the odds ratio (OR) was calculated for continuous or dichotomous data, respectively. The quality of the studies was assessed, and meta-analyses were performed with Cochrane Collaboration's RevMan 5.0 software. RESULTS: A total of 11 studies, including 1,229 patients provided evidence for 6 possible risk factors for MDRO infection. Ischemic ulcer (OR, 0.50; 95% confidence interval [CI], 0.35 to 0.71), ulcer size (standard mean difference, -0.27; 95% CI, -0.46 to -0.08), ulcer grade (OR, 0.36; 95% CI, 0.15 to 0.83), osteomyelitis (OR, 0.33; 95% CI, 0.25 to 0.45), previous antibiotic therapy (OR, 0.08; 95% CI, 0.04 to 0.14) and previous hospitalization (OR, 0.15; 95% CI, 0.08 to 0.28) were identified as risk factors for MDRO infection in patients with diabetic foot ulcer. CONCLUSIONS: Our meta-analysis indicated that ischemic ulcer, ulcer size, ulcer grade, osteomyelitis, previous antibiotic therapy and previous hospitalization were associated with MDRO infection in patients with diabetic foot ulcer.

Rapamycin Attenuates High Glucose-Induced Inflammation Through Modulation of mTOR/NF-κB Pathways in Macrophages.

Background: The NLRP3 inflammasome is one of the key contributors to impaired wound healing in diabetes. In this study, we assessed the role of rapamycin on high glucose-induced inflammation in THP-1-derived macrophages and investigated the underlying signaling mechanisms. Methods: THP-1-derived macrophages were treated with high glucose to induce NLRP3 inflammasome activation. The cells were pretreated with rapamycin, BAY 11-7082, or PDTC before exposure to HG. mTOR, NF-κB, and NLRP3 inflammasome expression were measured by western blotting. Results: We found that rapamycin reduced NLRP3 inflammasome activation in macrophages. Rapamycin reduced NLRP3 inflammasome activation by inhibiting mTOR phosphorylation and NF-κB activation. Moreover, mTOR siRNA inhibited NF-κB activation, leading to the suppression of NLRP3 inflammasome activation. Conclusion: Rapamycin can ameliorate high glucose-induced NLRP3 inflammasome activation by attenuating the mTOR/NF-κB signaling pathway in macrophages. Rapamycin may act as a possible therapeutic option for high glucose-induced inflammatory response in impaired wound healing in the future.

Vitamin D and diabetic foot ulcer: a systematic review and meta-analysis.

We aimed to evaluate the association between vitamin D deficiency and diabetic foot ulcer (DFU) in patients with diabetes. Pubmed, EMBASE, BIOSIS, the Cochrane Library, and Web of Knowledge, last updated in July 2018, were searched. We assessed eligible studies for the association between vitamin D deficiency and DFU in diabetic patients. The mean difference (MD) or the odds ratio (OR) was calculated for continuous or dichotomous data respectively. Data were analyzed by using the Cochrane Collaboration's RevMan 5.0 software. Seven studies that involved 1115 patients were included in this study. There were significantly reduced vitamin D levels in DFU (MD -13.47 nmol/L, 95%CI -16.84 to -10.10; P = 0.34, I2 = 12%). Severe vitamin D deficiency was significantly associated with an increased risk of DFU (OR 3.22, 95%CI 2.42-4.28; P = 0.64, I2 = 0%). This is the first meta-analysis demonstrating the association between serum vitamin D levels and DFU. Severe vitamin D deficiency is significantly associated with an increased risk of DFU.