Correlation between serum 25-OH-vitamin DLevel and diabetic foot ulcer in elderly diabetic patients

doi:10.21203/rs.3.rs-1613316/v1

Objective To investigate the relationship between the level of 25-OH-vitamin D [25 (OH) D] and diabetic foot ulcers (DFU) in aged Diabetes Mellitus (DM) patients.

Methods from January 2020 to March 2022, 339 elderly DM patients, aged 60 to 90 years old, hospitalized in the Department of Endocrinology, Air Force Special Medical Center, were selected and divided into DFU group (n=204) and DM group (n=135) according to the presence or absence of DFU. The clinical and biochemical characteristics of the two groups were compared. The change of 25 (OH) D and its relationship with DFU was analyzed.

Results SBP and BUN in DFU group were higher than those in DM group, and the course of disease was longer than that in DM group. The levels of TC, TG, HDL-C, ALT, AST, ALB, Hb, HCT and serum 25 (OH) D in DFU group were lower than those in DM group, the differences were statistically significant (p < 0.05). Logistic regression analysis showed that increased serum 25 (OH) D level was a protective factor for DFU in DM patients (p < 0.05). In this study, 80.5% of elderly DM patients suffered from vitamin D deficiency, and the proportion of vitamin D deficiency in DFU group was significantly higher than that in DM group. The difference was statistically significant (p < 0.05). With the increase of Wagner grade, the level of 25 (OH) D gradually decreased (p = 0.004). Multiple comparisons showed that the level of 25-OH-vitamin D in Wagner grade 2 patients was significantly higher than that in wager Grade 4 patients (P < 0.05). Spearman correlation analysis showed that the serum 25-(OH)-D level was negatively correlated with DFU (P =0.001, R =-0. 182).

Conclusion vitamin D deficiency or insufficiency is common in elderly DM patients, and is more serious in DFU patients.

diabetes mellitus

Diabetic foot ulcer

Vitamin D

25-OH-vitamin D

Diabetes Mellitus (DM) is an age-related disease with a prevalence of 33% in the United States aged 65 years or older, and nearly 50% of older adults meet the criteria for prediabetes^[1]. The prevalence of diabetes in the elderly over 60 years old in my country ranges from 22.5–23.5%^[2]. Diabetic foot ulcers (DFU) are one of the severe and costly chronic complications of diabetes, which can lead to amputation and death in severe cases. A recent survey found that the incidence of new foot ulcers within 1 year of diabetic patients over 50 years old in my country was 8.1%, and the incidence of new foot ulcers within 1 year of cured DFU patients was 31.6%^[3]. Vitamin D is a fat-soluble vitamin that comes in two different forms: vitamin D3 (cholecalciferol) from animal sources and vitamin D2 (ergocalciferol) from plant sources. Vitamin D is a prosteroid hormone that plays an important role in the regulation of calcium and phosphorus^[4–7]. More recently, studies have shown that vitamin D receptors (VDRs) are present in nearly all tissues of the body and that vitamin D has multiple pleiotropic effects that extend well beyond the regulation of bone metabolism^{[8, 9]}. Low vitamin D levels have been reported to impair the differentiation and proliferation of keratinocytes and dermal fibroblasts, and ultimately delay DFU healing^{[10, 11]}. In addition, vitamin D levels and low D concentrations have been shown to affect the chemotaxis and phagocytic activity of monocytes and macrophages and reduce the antibacterial activity of neutrophils, resulting in increased susceptibility to infection^{[12, 13]}. Serum vitamin D levels have been shown to improve glycemic control in DM patients^{[14, 15]}. Activated vitamin D is required for normal insulin receptor function and has been implicated in the development of diabetes^[16]. The relationship between DFU and vitamin D levels is still controversial, and Tiwari et al. demonstrated a beneficial effect of vitamin D on diabetic foot infections^[17]. However, Afarideh et al. reported no difference in vitamin D levels between diabetic foot patients and diabetic patients without foot complications ^[18]. The main purpose of this study was to investigate the prevalence of vitamin D deficiency in Chinese hospitalized elderly diabetic population and the correlation between 25(OH)D and elderly diabetic foot ulcers, in order to provide evidence for clinical treatment and prevention of DFU.

Patients and Methods

A retrospective analysis was conducted on 339 elderly DM inpatients(aged between 60 and 90 years old), including 204 patients with DFU (DFU group) and 135 patients without DFU (DM group), from January 2020 to March 2022 at the endocrinology department of the Air Force Medical Center, PLA. This study was conducted with the approval from the Ethics Committee of Air Force Medical Center, PLA (No.2021-100-PJ01). The patients all met the 1999 WHO diagnostic criteria for diabetes and diabetic foot. Exclusion criteria: 1) patients with acute complications of diabetes, parathyroid disease, severe liver and kidney disease, infection, bone metabolic disease, and acute cardiovascular and cerebrovascular diseases. 2) history of taking drugs that affect serum 25(OH)D levels, such as calcium, vitamin D, oral contraceptives, glucocorticoids, etc.

Data Collection

The following clinical data of the patients were retrospectively analyzed: including gender, age, body mass index (BMI), smoking history, drinking history, systolic blood pressure (SBP), diastolic blood pressure (DBP), DM duration, glycerogelatin hemoglobin (HbA1c), fasting plasma glucose (FPG), total cholesterol(TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), serum creatinine (Scr), serum uric acid (SUA), albumin (ALB), hemoglobin (Hb), hematocrit (hematocrit, HCT) and 25(OH)D. This study has been approved by the Ethics Committee of the Air Force Specialty Medical Center (No. 2021-100-PJ01). Judgment criteria for vitamin D level: <50 nmol/L (< 20 ng/mL) for vitamin D deficiency, 50–75 nmnol/L (20–30 ng/mL) for vitamin D insufficiency, > 75 nmol/L (> 30 nmol/L) for vitamin D deficiency ng/mL) is sufficient for vitamin D^[19].

Statistical Analysis

All analyses were conducted using Statistical Product and Service Solutions 23.0 (SPSS 23.0) or GraphPad Prism 8. Data for categorical variables were presented as numbers (%). Shapiro-Wilk test was used to determine normality of continuous data, and mean ± standard deviation (x ± s) was used to describe normally distributed data, while median and interquartile range (IQR, 25–75%) was used to describle non-normally distributed data. The biochemical and hematological parameters between the two groups were compared using the Student’s t-test (for normally distributed data), Mann–Whitney test (for non-normally distributed data) or X² test (for categorical variables). Comparison of 25-OH-vitamin D levels among five Wagner Grades was performed by nonparametric analysis using a Kruskal-Wallis test with post-hoc Dunn multiple comparison tests. Multivariate logistic regression was used to analyze the risk factors of DFU, and the OR value and 95%CI were calculated. The correlation between 25-OH-vitamin D and other clinical parameters was examined using spearman correlation analysis. A P-value of less than 0.05 was considered statistically significant.

Univariate analysis of the influencing factors of DFU in patients with diabetes mellitus

SBP and BUN in the DFU group were higher than those in the DM group, and the disease course was longer than that in the DM group. The levels of TC, TG, HDL-C, ALT, AST, ALB, Hb, HCT and serum 25(OH)D in the DFU group were lower than those in the DM group. , the difference was statistically significant (p < 0.05). There was no significant difference in other indicators between the two groups (p > 0.05). (Table 1)

Table 1 Baseline characteristics of the two groups of participants

Item	DM group（n=135）	DFU group（n=204）	t/x²/Z	P-value
Age	66（64,73）	68（64,73.8）	1.065	0.302
DM duration (year)	15（6,20）	20（14,25）	19.795	0.000
Male(%)	83（61.5）	130（63.7）	0.175	0.676
Smoking history (%)	43（31.9）	74（36.3）	0.703	0.402
Drinking history (%)	44（32.6）	63（30.9）	0.11	0.740
BMI (kg/m²)	24.71±2.60	24.30±3.08	4.621	0.200
SBP (mmHg)	131.87±17.26	135.94±17.98	0.034	0.039
DBP (mmHg)	77.27±10.57	75.89±9.90	0.010	0.220
HbA1c (%)	8.4（7,10）	8.2（7.4,10.08）	0.709	0.400
FPG (mmol /L)	7.8（6,10.1）	7.95（6.5,10.38）	0.304	0.581
BUN (mmol /L)	6（5.2,7.5）	6.8（5.03,8.68）	3.924	0.048
Scr (mol /L)	67（56,82）	72（57,92.8）	3.321	0.068
SUA (mol /L)	313.88±88.44	307.58±89.43	0.538	0.525
TC (mmol /L)	3.95（3.25,4.63）	3.55（2.91,4.34）	10.105	0.001
TG (mmol /L)	1.58（1.04,2.18）	1.27（0.99,1.79）	7.587	0.006
HDL-C (mmol /L)	1.07（0.94,1.3）	0.93（0.76,1.09）	31.682	0.000
LDL-C (mmol /L)	2.15（1.59,2.81）	1.98（1.48,2.51）	2.259	0.133
ALT (U/L)	15（11,25）	12（9.16）	18.176	0.000
AST (U/L)	16（14,22）	15（12,19）	11.766	0.001
ALB (g/L)	42.2（40,44.3）	39.2（35,41.98）	49.372	0.000
Hb (g /L)	131.02±15.15	113.71±17.61	3.350	0.000
HCT（L/L）	0.40（0.37,0.42）	0.35（0.31,0.38）	61.072	0.000
25(OH)D (nmol/L)	36.97（25.21,52.05）	29.02（21.28,40.95）	11.195	0.001

Abbreviations: The two groups, DFU group and DM group; DFU, diabetic foot ulcer; DM, Diabetes Mellitus; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; BUN, Blood urea nitrogen; Scr, Serum creatinine; SUA, serum uric acid; TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; Hb, hemoglobin; HCT, hematocrit.

Notes:Data presented as `x±s or Median (The Upper and Lower Quartiles) or Case (Composition Ratio).

Multivariate analysis of the influencing factors of DFU in patients with diabetes mellitus

The DM disease course, SBP, BUN, TC, TG, HDL-C, ALT, AST, ALB, Hb, HCT and serum 25(OH)D levels with single-factor statistical differences were used as independent variables, and the combination of LEAD was used as the factor. The variables were included in Logistic regression analysis, and the results showed that elevated serum 25(OH)D, TG and HDL-C levels were protective factors for DFU in patients with diabetes; prolonged disease duration and elevated SBP were independent risk factors for DFU in patients with diabetes ( P < 0.05). (Table 2)

Table 2 Multivariate logistic regression analysis of DFU risk

Variable	Β	SE	Waldχ2	P	OR	95% CI
DM duration	0.047	0.016	8.702	0.003	1.048	1.016-1.082
TG	-0.488	0.188	6.775	0.009	0.614	0.425-0.886
HDL-C	-3.050	0.627	23.641	0.000	0.047	0.014-0.162
25(OH)D	-0.018	0.008	4.621	0.032	0.982	0.966-0.998
SBP	0.017	0.007	4.183	0.041	1.017	1.001-1.033

Abbreviations: DM, Diabetes Mellitus; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; SBP, systolic blood pressure.

Comparison of the distribution composition of serum 25-(OH)-D between the two groups

DM group: 4 cases (3.0%) with sufficient vitamin D, 32 cases (23.7%) with insufficient vitamin D, and 99 cases (73.3%) with deficiency; DFU group: 4 cases (2.0%) with normal vitamin D, and 26 cases with insufficient vitamin D (12.7%), 174 cases (82.3%) were deficient. There was a statistically significant difference in the distribution of vitamin D between the two groups (P<0.05). (Table 3, Figure 1)

Table 3 Comparison of serum 25-(OH)-D distribution composition between two groups

Group

n

25(OH)D（nmol/L）

＜ 50 50-75 ＞ 75

x²

p

DM group

135

99（73.3）

32（23.7)

4(3.0)

7.491

0.024

DFUgroup

204

174(82.3)

26(12.7)

4(2.0)

Notes: Data presented as Median (The Upper and Lower Quartiles) or Case (Composition Ratio).

Abbreviations: DM, Diabetes Mellitus; DFU, diabetic foot ulcer; IQR, interquartile range.

Changes of different Wagner grades and 25-OH-vitamin D levels

DFU patients were divided into 5 subgroups according to the Wagner classification. As shown in Figure 2, with the increase of Wagner grade, the level of 25-OH-vitamin D gradually decreased (X²=15.579, p=0.004). Dunn's multiple comparison showed that the level of 25-OH-vitamin D in Wagner grade 2 patients Significantly higher than Wager grade 4 (p < 0.05). (figure 2)

Correlation analysis of serum 25-(OH)-D and other indicators

As shown in Table 4, the results of spearman correlation analysis showed that serum 25-(OH)-D levels were associated with the course of DM (p=0.012, r=-0.136), HbA1c (p=0.007, r=-0.147) and DFU ( p=0.001, r=-0.182) was negatively correlated, serum 25-(OH)-D level was significantly correlated with SCr (p=0.046, r=0.109), ALB (p=0.000, r=0.239), Hb (p=0.046, r=0.109) =0.014, r=0.134) and HCT (p=0.017, r=0.140) were positively correlated. (Table 4)

Table 4 Correlation analysis between 25(OH)D and other indicators

	r-value	p-value
Age	-0.091	0.096
DM duration (year)	-0.136	0.012
Male(%)	0.001	0.979
Smoking history (%)	0.025	0.641
Drinking history (%)	0.061	0.262
BMI (kg/m²)	0.025	0.645
SBP (mmHg)	-0.091	0.095
DBP (mmHg)	-0.002	0.972
HbA1c (%)	-0.147	0.007
FPG (mmol /L)	-0.024	0.666
BUN (mmol /L)	0.083	0.128
Scr (mol /L)	0.109	0.046
SUA (mol /L)	0.054	0.317
TC (mmol /L)	-0.082	0.130
TG (mmol /L)	0.037	0.295
HDL-C (mmol /L)	-0.016	0.772
LDL-C (mmol /L)	-0.039	0.274
ALT (U/L)	0.090	0.099
AST (U/L)	-0.045	0.414
ALB (g/L)	0.239	0.000
Hb (g /L)	0.134	0.014
HCT（L/L）	0.140	0.017
DFU	-0.182	0.001

Abbreviations: DM, diabetes mellitus; BMI, body mass index; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; BUN, Blood urea nitrogen; Scr, Serum creatinine; SUA, serum uric acid; TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; Hb, hemoglobin; HCT, hematocrit; DFU, diabetic foot ulcer.

In recent years, vitamin D and its pleiotropic effects have attracted widespread attention. Vitamin D deficiency is a common but treatable condition. There are two main sources of vitamin D, endogenous skin exposure to direct sunlight and exogenous dietary sources (eg, fish, dairy products, and supplements)^[16]. Vitamin D is hydroxylated in the liver to form 25-hydroxyvitamin D (25(OH)D) and further hydroxylated in the kidney to form 1,25-hydroxyvitamin D (1,25(OH)2D, calcitriol). Although 1,25(OH)2D is considered to be the active form of vitamin D, its levels in serum are independent of overall vitamin D status, whereas 25(OH)D levels reflect true systemic vitamin D levels^[20]. Many complications of diabetes are associated with low serum vitamin D levels, including cardiovascular disease and arterial wall stiffness. A higher ankle-brachial index (>1.3) was found in patients with lower vitamin D levels ^[21]. A meta-analysis by Iannuzzo et al. ^[22] found that patients with peripheral arterial disease (PAD) had lower vitamin D levels than controls, and vitamin D deficiency and vitamin D insufficiency were significantly associated with PAD. DFU is one of the most serious complications of diabetes and the most common cause of lower extremity amputation, with a 2.5-fold increased risk of death^[23]. Vitamin D not only improves blood sugar, but also promotes wound healing by acting on different stages of hemostasis, inflammation, proliferation, and remodeling^[24]. Results of a systematic review and meta-analysis showed that DFU patients had significantly lower vitamin D levels compared with diabetic patients, and severe vitamin D deficiency increased the risk of DFU^[25].

To our knowledge, this is the first study to assess vitamin D levels in elderly patients with DFU. This study found that the serum 25(OH)D level in the DFU group was significantly lower than that in the DM group, and the increased serum 25(OH)D level was a protective factor for elderly diabetic patients with DFU. In this study, 80.5% of the elderly DM patients suffered from vitamin D deficiency, and the vitamin D deficiency rate in the DFU group was significantly higher than that in the DM group, with a statistically significant difference (p < 0.05). And with the increase of Wagner grade, the level of 25(OH)D decreased gradually (p = 0.004). Dunn's multiple comparison showed that the level of 25-OH-vitamin D in Wagner grade 2 patients was significantly higher than that in wager grade 4 (p<0.05). The results of Spearman correlation analysis showed that serum 25-(OH)-D levels were negatively correlated with DFU (p=0.001, r=-0.182). A meta-analysis by Pei et al. ^[26] concluded that it was HDL-C levels, but not LDL-C, TC, or TG levels, that were associated with DFU. Ansell et al. ^[27] reported the anti-inflammatory effect of HDL-C, reducing inflammatory cytokines and vascular leukocyte adhesion molecules, participating in innate immunity and preventing LDL oxidation. Similar findings were also confirmed in our study, with lower levels of HDL-C in the DFU group compared with the DM group and HDL-C was an independent protective factor for DFU (P < 0.05).

In vitro studies have shown that vitamin D improves wound healing in streptozotocin (STZ)-induced diabetic mice by inhibiting endoplasmic reticulum stress ^[28] and NF-κB-mediated inflammatory gene expression ^[29]. Human dermal fibroblasts treated with vitamin D enhanced dermal fibroblast-mediated wound healing and suggested that vitamin D supplementation may be an important step in promoting wound healing and regeneration in patients with vitamin D deficiency^[11]. Vitamin D supplementation reduces higher concentrations of inflammatory cytokines in infected DFU^[17]. When a skin is injured, the findings of Oda et al. suggest that vitamin D receptors are required for self-renewal, migration and differentiation of epidermal stem cells and progeny during skin wound healing^[30]. In a DFU model, Trujillo et al. found that vitamin D promoted pro-angiogenic molecules in keratinocytes and induced the expression of antimicrobial peptides^[31]. Another study concluded that a combined loss of vitamin D receptors and calcium-sensing receptors delays wound re-epithelialization ^[32]. Playing an indirect role in the wound healing process, vitamin D can improve glycemic control^[33]. From the perspective of pathophysiological mechanism, elderly diabetic patients with vitamin D deficiency are more likely to develop diabetic foot ulcers. In other words, we can view vitamin D deficiency as a causative factor in the development of diabetic foot ulcers. On the other hand, patients who already have a diabetic foot ulcer are at increased risk of developing vitamin D deficiency due to prolonged bed rest, immobility of the affected limb, reduced physical activity, and decreased nutritional status. However, the causal relationship between vitamin D and diabetic foot is unclear.

The results of this study show that vitamin D deficiency is a common disease in elderly diabetic patients. Low serum vitamin D levels were significantly associated with higher prevalence of diabetic foot in elderly diabetic patients. The level of vitamin D gradually decreased with the increase of Wagner classification, and vitamin D screening or supplementation should be performed in elderly diabetic patients to prevent DFU or improve the prognosis of DFU. In the current study, we demonstrated an association of vitamin D with DFU in elderly. Some limitations were identified in our study, this study was a cross-sectional investigation, and further well-designed prospective studies are needed in the future to observe the causal relationship between vitamin D and DFU risk, and to explore whether vitamin D supplementation has any effect on DFU treatment. Benefits, providing a scientific basis for the prevention and treatment of elderly DFU.

In conclusion, this is the first study to assess vitamin D levels in elderly Chinese hospitalized patients with DFU. We confirmed the relationship between 25-oh vitamin D and DFU. 25-OH-vitamin D is an independent protective factor in elderly Chinese patients with DFU. We demonstrate that 25-OH-vitamin D levels tend to decrease in patients with DFU of Wagner grades 1-5. Therefore, regular detection of serum 25-OH-vitamin D levels in Chinese elderly DM population, and supplementation of 25-OH-vitamin D levels in elderly DM patients through diet or other methods may help prevent the occurrence of DFU or improve the prognosis of DFU.

DFU, diabetic foot ulcer; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; BUN, Blood urea nitrogen; Scr, Serum creatinine; SUA, serum uric acid; TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; Hb, hemoglobin; HCT, hematocrit.

Acknowledgments

Thanks for the support of the Beijing Capital Clinical Characteristic Application Research Project

Funding

This study was supported by Beijing Capital Clinical Characteristic Application

Research Project (Grant No. Z181100001718025).

Consent for publication

Not Applicable.

Ethics approval and consent to participate

This study was conducted with the approval from the Ethics Committee of Air Force Medical Center, PLA (No.2021-100-PJ01).

This study was conducted in accordance with the declaration of Helsinki.

Written informed consent was obtained from all participants.

Availability of data and materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Competing interests

The authors report no conflicts of interest in this work

Authors' contributions

Fenglin Wang:Methodolog, Software, Writing-Original draft preparation; Jia Xu: Data collection, Validation; Caizhe Yang: Supervision; Di Zhu: Writing-Reviewing and Editing,

Menke A, Casagrande S, Geiss L, et al. Prevalence of and Trends in Diabetes Among Adults in the United States, 1988–2012. Jama 2015; 314 (10): 1021–1029. doi: 10.1001/jama.2015.10029.
Xu Y, Wang L, He J, et al. Prevalence and control of diabetes in Chinese adults. Jama 2013; 310 (9): 948–959. doi: 10.1001/jama.2013.168118.
Jiang Y, Wang X, Xia L, et al. A cohort study of diabetic patients and diabetic foot ulceration patients in China. Wound Repair Regen 2015; 23 (2): 222–230. doi: 10.1111/wrr.12263.
Charoenngam N, Shirvani A, Holick MF. Vitamin D for skeletal and non-skeletal health: What we should know. J Clin Orthop Trauma 2019; 10 (6): 1082–1093. doi: 10.1016/j.jcot.2019.07.004.
Lips P. Vitamin D physiology. Prog Biophys Mol Biol 2006; 92 (1): 4–8. doi: 10.1016/j.pbiomolbio.2006.02.016.
Christakos S, Ajibade DV, Dhawan P, et al. Vitamin D: metabolism. Endocrinol Metab Clin North Am 2010; 39 (2): 243–253, table of contents. doi: 10.1016/j.ecl.2010.02.002.
Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 2014; 21 (3): 319–329. doi: 10.1016/j.chembiol.2013.12.016.
Hossein-nezhad A, Holick MF. Vitamin D for health: a global perspective. Mayo Clin Proc 2013; 88 (7): 720–755. doi: 10.1016/j.mayocp.2013.05.011.
Christakos S, Dhawan P, Verstuyf A, et al. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiol Rev 2016; 96 (1): 365–408. doi: 10.1152/physrev.00014.2015.
Costa PLF, França MM, Katayama ML, et al. Transcriptomic Response to 1,25-Dihydroxyvitamin D in Human Fibroblasts with or without a Functional Vitamin D Receptor (VDR): Novel Target Genes and Insights into VDR Basal Transcriptional Activity. Cells 2019; 8 (4): doi: 10.3390/cells8040318.
Ding J, Kwan P, Ma Z, et al. Synergistic effect of vitamin D and low concentration of transforming growth factor beta 1, a potential role in dermal wound healing. Burns 2016; 42 (6): 1277–1286. doi: 10.1016/j.burns.2016.03.009.
Al-Rawaf HA, Gabr SA, Alghadir AH. Molecular Changes in Diabetic Wound Healing following Administration of Vitamin D and Ginger Supplements: Biochemical and Molecular Experimental Study. Evid Based Complement Alternat Med 2019; 2019 4352470. doi: 10.1155/2019/4352470.
Mostafa WZ, Hegazy RA. Vitamin D and the skin: Focus on a complex relationship: A review. J Adv Res 2015; 6 (6): 793–804. doi: 10.1016/j.jare.2014.01.011.
Aljabri KS, Bokhari SA, Khan MJ. Glycemic changes after vitamin D supplementation in patients with type 1 diabetes mellitus and vitamin D deficiency. Ann Saudi Med 2010; 30 (6): 454–458. doi: 10.4103/0256-4947.72265.
Mirhosseini N, Vatanparast H, Mazidi M, et al. Vitamin D Supplementation, Glycemic Control, and Insulin Resistance in Prediabetics: A Meta-Analysis. J Endocr Soc 2018; 2 (7): 687–709. doi: 10.1210/js.2017-00472.
Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357 (3): 266–281. doi: 10.1056/NEJMra070553.
Tiwari S, Pratyush DD, Gupta SK, et al. Vitamin D deficiency is associated with inflammatory cytokine concentrations in patients with diabetic foot infection. Br J Nutr 2014; 112 (12): 1938–1943. doi: 10.1017/s0007114514003018.
Afarideh M, Ghanbari P, Noshad S, et al. Raised serum 25-hydroxyvitamin D levels in patients with active diabetic foot ulcers. Br J Nutr 2016; 115 (11): 1938–1946. doi: 10.1017/s0007114516001094.
Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab 2010; 95 (2): 471–478. doi: 10.1210/jc.2009-1773.
Mosekilde L. Vitamin D requirement and setting recommendation levels: long-term perspectives. Nutr Rev 2008; 66 (10 Suppl 2): S170-177. doi: 10.1111/j.1753-4887.2008.00103.x.
Depczynski B, Young T, White C. A high ankle-brachial index is associated with obesity and low serum 25-hydroxyvitamin D in patients with diabetes. J Clin Transl Endocrinol 2018; 11 7–10. doi: 10.1016/j.jcte.2018.02.001.
Iannuzzo G, Forte F, Lupoli R, et al. Association of Vitamin D deficiency with peripheral arterial disease: a meta-analysis of literature studies. J Clin Endocrinol Metab 2018; doi: 10.1210/jc.2018-00136.
Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. N Engl J Med 2017; 376 (24): 2367–2375. doi: 10.1056/NEJMra1615439.
Sinno S, Lee DS, Khachemoune A. Vitamins and cutaneous wound healing. J Wound Care 2011; 20 (6): 287–293. doi: 10.12968/jowc.2011.20.6.287.
Dai J, Jiang C, Chen H, et al. Vitamin D and diabetic foot ulcer: a systematic review and meta-analysis. Nutr Diabetes 2019; 9 (1): 8. doi: 10.1038/s41387-019-0078-9.
Pei E, Li J, Lu C, et al. Effects of lipids and lipoproteins on diabetic foot in people with type 2 diabetes mellitus: a meta-analysis. J Diabetes Complications 2014; 28 (4): 559–564. doi: 10.1016/j.jdiacomp.2014.04.002.
Ansell BJ, Fonarow GC, Navab M, et al. Modifying the anti-inflammatory effects of high-density lipoprotein. Curr Atheroscler Rep 2007; 9 (1): 57–63. doi: 10.1007/bf02693941.
Yuan YF, Das SK, Li MQ. Vitamin D Ameliorates Impaired Wound Healing in Streptozotocin-Induced Diabetic Mice by Suppressing Endoplasmic Reticulum Stress. J Diabetes Res 2018; 2018 1757925. doi: 10.1155/2018/1757925.
Yuan Y, Das SK, Li M. Vitamin D ameliorates impaired wound healing in streptozotocin-induced diabetic mice by suppressing NF-κB-mediated inflammatory genes. Biosci Rep 2018; 38 (2): doi: 10.1042/bsr20171294.
Oda Y, Hu L, Nguyen T, et al. Vitamin D Receptor Is Required for Proliferation, Migration, and Differentiation of Epidermal Stem Cells and Progeny during Cutaneous Wound Repair. J Invest Dermatol 2018; 138 (11): 2423–2431. doi: 10.1016/j.jid.2018.04.033.
Trujillo V, Marín-Luevano P, González-Curiel I, et al. Calcitriol promotes proangiogenic molecules in keratinocytes in a diabetic foot ulcer model. J Steroid Biochem Mol Biol 2017; 174 303–311. doi: 10.1016/j.jsbmb.2017.10.013.
Oda Y, Hu L, Nguyen T, et al. Combined Deletion of the Vitamin D Receptor and Calcium-Sensing Receptor Delays Wound Re-epithelialization. Endocrinology 2017; 158 (6): 1929–1938. doi: 10.1210/en.2017-00061.
Wu C, Qiu S, Zhu X, et al. Vitamin D supplementation and glycemic control in type 2 diabetes patients: A systematic review and meta-analysis. Metabolism 2017; 73 67–76. doi: 10.1016/j.metabol.2017.05.006.

No competing interests reported.

Correlation between serum 25-OH-vitamin DLevel and diabetic foot ulcer in elderly diabetic patients

Status:

Version 1

Abstract

Figures

Introduction

Methods

Patients and Methods

Data Collection

Statistical Analysis

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1