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Role of lowered level of serum vitamin D on diabetic foot ulcer and its possible
pathomechanism: A systematic review, meta-analysis, and meta-regression

Article in Diabetes Epidemiology and Management · August 2023

DOI: 10.1016/j.deman.2023.100175

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 Diabetes Epidemiology and Management 13 (2024) 100175

Contents lists available at ScienceDirect

Diabetes Epidemiology and Management

jo urn al h om ep ag e: ww w.elsevier.com

Review

Role of lowered level of serum vitamin D on diabetic foot ulcer and its
possible pathomechanism: A systematic review, meta-analysis, and
meta-regression
Muhammad Iqhrammullaha,*, Teuku Fais Dutab, Meulu Alinab, Intan Qanitab,
Muhammad Alif Naufalb, Najlaika Henirab, Ghina Tsurayyab, Raisha Fathimab,
Arita Yuda Katiara Rizkic, Shakira Amirahd
a
Faculty of Public Health, Universitas Muhammadiyah Aceh, Banda Aceh 23245, Indonesia
b
Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh 23111, Indonesia
c
Faculty of Nursing, Universitas Syiah Kuala, Banda Aceh 23111, Indonesia
d
Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia

A R T I C L E I N F O A B S T R A C T

Article History: Aim: To investigate the association between serum vitamin D (SVD) level and DFU development and to
Received 14 July 2023 emphasize the involved pathomechanism.
Revised 8 August 2023 Methods: The search was performed on 12 databases for literature published until 10 March 2023. The proto-
Accepted 21 August 2023
col has been registered on PROSPERO (CRD42023415744). The selection for the included records followed
Available online 23 August 2023
PRISMA framework. Meta-analyses using random effects model were performed and the data were pre-
sented as SMD and 95% CI. Meta-regression was performed to identify factors contributing to the heteroge-
Keywords:
neity in the pooled analysis.
Diabetic foot
Vitamin D
Results: Twenty-one studies were included in the systematic review with a total number of patients reaching
25-hydroxyvitamin D 9,570. Of which, as many as 18 studies were eligible for the meta-analysis. The SDV level is significantly lower
25-OH vitamin in DFU group (p-total=0.0037; SMD= -1.2758; [95% CI: -2.0786 to -0.4730]). Based on the meta-regression,
Inflammation age, study location (based on the continent), and total cholesterol level contribute to the high heterogeneity
(p<0.01). In the pooled analysis, inflammatory markers such as serum levels of CRP (n = 4), ESR (n = 3), IL-6
(n = 3), and IL-8 (n = 2) are found significantly higher in DFU group at p<0.01.
Conclusion: Lowered SVD level is associated with DFU, where the pathomechanism for this relationship
might involve inflammation and infection susceptibility.
© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/)

Introduction DFU include type 2 diabetes mellitus, older age, longer diabetes dura-
tion, being male, elevated body mass index, smoking, and the pres-
Diabetic foot ulcers (DFU) are a common and devastating compli- ence of complications such as diabetic nephropathy and peripheral
cation of longstanding diabetes, strongly associated with peripheral vascular disease [1,4].
arterial disease, peripheral neuropathy, and foot deformity [1]. The Among many efforts in understanding the complex pathomechan-
condition contributes to significant morbidity and mortality globally, ism of DFU, researchers have explored the possible involvement of
often leading to repeated hospital admissions and an increased risk vitamin D. The receptor of this fat-soluble vitamin has been found in
of lower extremity amputations, resulting in substantial healthcare pancreatic beta cells, implying its possible role in insulin secretion
costs [2,3]. The prevalence of DFU varies geographically, with Bel- [6,7]. Further, sensitivity and function of insulin have been associated
gium showing the highest prevalence at 16% and Australia − the low- with the level of serum vitamin D [6]. It is also suggested that vitamin
est at 1.2% [4]. In a recent meta-analysis, mortality among DFU D may regulate gene expression, modulate inflammation and oxida-
patients almost reached 50% with cardiac events and infection as the tive stress, and interact with insulin signaling pathways [6,8]. Vita-
two primary factors contributing to the death [5]. Risk factors for min D is, therefore, considered to play a substantial role in reducing
the complication of diabetes, such as DFU [9]. Nonetheless, results
from randomized clinical trials (RCTs) have a disagreement regarding
* Corresponding author. the effect of vitamin D supplementation on insulin resistance and
E-mail address: [email protected] (M. Iqhrammullah).

https://doi.org/10.1016/j.deman.2023.100175
2666-9706/© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
M. Iqhrammullah, T.F. Duta, M. Alina et al. Diabetes Epidemiology and Management 13 (2024) 100175

diabetes mellitus type 2 prevention among prediabetic patients; only screening would undergo a full-text review in which the criteria for
1 out of 8 reports that found the positive findings [10]. inclusion or exclusion were applied. Different results from these
Despite the debate on the role of vitamin D in glycemic control screening steps would be overcome by revisiting the article and
[10,11], there are several factors implying the vitamin is more corre- establishing a consensus. Consultation with another reviewer would
lated with DFU. In an vitro study, vitamin D has been reported to ini- be required if consensus could not be reached.
tiate the production of antimicrobial peptides leading to faster
wound healing in DFU [12]. A review article has highlighted that vita- Study quality assessment
min D is the inhibitor of bacterial biofilm and its deficiency contrib-
utes to susceptibility to infection [13]. In fact, vitamin D has been Newcastle Ottawa Scale and its modified version were used to
well-known for its immunomodulating activities and inhibiting the assess the quality of the included studies, as suggested previously
activation of inflammatory T-cells [14]. In observational studies, low [20]. This assessment was carried out by two independent reviewers
level of vitamin D is associated with higher levels of pro-inflamma- − M.I. and I.Q. Studies marked as “high risk” in the Newcastle Ottawa
tory cytokines and inflammatory markers during DFU [15,16]. Several Scale were not included in the meta-analysis.
systematic reviews have reported the association between serum
level of vitamin D with feet ulceration in diabetic patients [17,18]. Data extraction
Nonetheless, the evidence gathered in the foregoing studies is limited
to several databases. In this present systematic review and meta- Firstly, the first author’s name, year of publication, the study loca-
analysis, we aimed to establish more concrete evidence to confirm tion (country), study design, and sample size were collected. Patients’
the association between vitamin D and DFU. Further, the pathome- characteristics including age, sex, diabetes onset, body mass index,
chanism of vitamin D involvement in the development of DFU, based and glycated hemoglobin (HbA1c) level were extracted from each
on the current body of evidence, is elaborated. A meta-regression study. Levels of serum vitamin D of DFU and non-DFU patients were
was also performed to explore the source of the heterogeneity and extracted. Continuous data were presented as mean§standard devia-
possible related pathomechanism. tion (SD), while ordinal were presented as frequency (%). Data pre-
sented as median would be converted to mean§SD (https://www.
Search strategy math.hkbu.edu.hk/»tongt/papers/median2mean.html). In general,
no conversion was performed for data presented in different units;
The literature search was performed on 10 March 2023, using the instead, the standardized mean difference (SMD) would be used in
search engine from the following databases: PubMed, Scopus, the data analysis. Value of HbA1c presented in mmol/L was converted
Embase, Scillit, Sci-Finder, LILACS, EuropePMC, medRxiv, bioRvix, to% by using the following formula: HbA1c (%) = (HbA1c (mmol/L) /
Research Square, Google Scholar, and Garuda. The protocol has been 10.93) + 2.15. Corresponding authors of the included studies were
registered on PROSPERO (CRD42023415744). Keywords “Diabetes”, contacted in the case of incomplete data.
“Foot Ulcer”, and “Vitamin D” as well as their respective synonyms
were used in combinations as presented in Table S1. Data analysis

Inclusion and exclusion criteria In this present study, Jamovi version 2.3.21 and Comprehensive
Meta-Analysis version 3 software were employed for the meta-analy-
This systematic review employed the PECOS framework to estab- sis. Random-effects model with restricted maximum-likelihood esti-
lish the inclusion and exclusion criteria for selecting relevant studies. mator was applied to the pooled data [21]. Heterogeneity of the
The participants included in the analysis were patients with diabetes, pooled data was judged based on I2 where the values of <25%, 26
and their eligibility was determined based on the criteria outlined in −50%, and >50% indicate low, moderate, and high heterogeneity,
the guideline provided by the American Diabetes Association (ADA) respectively. Standardized mean difference (SMD) and 95% confi-
[19]. The exposure of interest was serum vitamin D, and the study dence intervals (CIs) were computed from the pooled analysis. The
specifically focused on diabetic patients without foot ulcers as the threshold for statistical significance was p<0.05. Meta-regression
control group. The primary outcome of interest was the occurrence was carried out under random-effects model for age, continent, BMI,
of diabetic foot ulcers (DFUs), while peripheral artery disease (PAD) HbA1c level, total cholesterol (TC) high-density lipoprotein (HDL),
and diabetic foot infection (DFI) were considered secondary out- and low-density lipoprotein (LDL). Risks of publication bias were
comes. The study design included both retrospective and prospective assessed based on Egger’s test and Begg’s funnel plot. A sensitivity
observational studies. test based on leave-one-out approach was also carried out.
Studies that recruited pregnant and lactating women were not
included. Exclusions were applied to patients who routinely under- Results
took vitamin D, calcium supplement, or immune-suppressants before
the observation. Those with vascular insufficiency were also Characteristics of the included studies
excluded. Articles published as literature reviews, commentaries, edi-
torials, case reports, erratum, and conference abstracts were not As many as 4441 studies were identified in the initial stage, 1050
included. Articles reporting the results from in-vivo and in-vitro of those studies were then excluded automatically due to duplication
studies were also excluded. The included studies were limited to (Fig. 1). Full-text screening was carried out on 79 studies, where we
those reporting in English or Indonesian language only. made exclusion on 62 records due to irrelevance, document type,
non-eligible control, in-vivo/in-vitro, language barrier, and duplica-
Screening and selection of the records tion. Screening the list of the citing and cited literatures resulted in
the inclusion of 4 records, which contributed to the 21 studies
Preferred Reporting Items for Systematic Reviews and Meta-Anal- included in the systematic review. Some studies did not report com-
yses (PRISMA) was adopted for the screening as well as the selection plete data (such as standard deviation or other datasets required to
process, performed independently by M.I and Q.I (16). Duplication on generate mean§SD), and the corresponding authors of the foregoing
the retrieved records was removed automatically by Mendeley Desk- studies have been contacted via email but none responded [22−24].
top v1.19.8 (https://www.mendeley.com/). Thereafter, the title and Characteristics of the included studies and patients participated
abstract of each record were screened. Records passing the initial therein have been presented in Table 1. Countries of the study
2
M. Iqhrammullah, T.F. Duta, M. Alina et al. Diabetes Epidemiology and Management 13 (2024) 100175

Fig. 1. PRISMA flow-chart depicting the selection of the record for the systematic review and meta-analysis.

location are mostly China (n = 6, 28.6%) and India (n = 5, 23.8%), study was comprised of a relatively small size of sample with highly
where almost all of the reports used cross-sectional design with data possible selection bias on the selection of control (having vitamin D <
collected prospectively (n = 17, 81%). In total, 9570 patients were 12 ng/mL) [35]. The level of vitamin D was measured using standard-
recruited in the study (n = 21) comprised of DFU group (n = 2592) ized method namely chemiluminescence immunoassay (CLIA)
and non-DFU group (n = 6978). Todorova and colleagues (2020) com- [27,37,40], electrochemiluminescence immunoassay (ECLIA)
pared the serum vitamin D (SVD) from three groups, namely diabetic [25,26,28,29,34,41], radioimmunoassay (RIA) [16,23,30−33,39], liq-
patients with DFU, diabetic patients with no complications, and dia- uid chromatography-tandem mass spectrometry (LC-MS/MS) [36],
betic patients with diabetic peripheral neuropathy (DPN) [25]. The and enzyme-linked immunosorbent assay (ELISA) [22,35,38]. How-
patients’ age ranged from around 50 and above. A study specifically ever, a study did not report the analytical equipment used to measure
limited the participant’s age to only include elderly population [26]. SVD [24]. A study receiving ‘high risk’ remark because the sample
The gender proportion was mostly predominated by male, but a selection, demographic characteristics, and the statistical method
study from Indonesia had higher female proportion [27]. Five Studies were not clearly presented [22]. Details of NOS score evaluated for
had balance proportion of patients with HbA1c >8% (poor glycemic each study are presented in Table 2S.
control) between DFU and non-DFU control [16,28−31]. Others
(n = 7, 33.3%) had more number of patients with poor glycemic con- Difference in vitamin D
trol in DFU group than in non-DFU group [25−27,32−35]. Patients in
five studies (23.8%) were either overweight (25 kg/m2≤BMI<30 kg/ Level of SVD along with other measured parameters from the
m2) or obese (30 kg/m2≤BMI<35 kg/m2) [24,25,34−36], while others included studies are presented in Table 2. Almost all studies reported
had patients with normal weight (18.5 kg/m2≤BMI<25 kg/m2) significantly lower SVD in diabetic patients developing foot ulcera-
[16,26,29,30,32,33]. tion as compared to those without DFU, except in two studies
[35,36]. A study from Greece, reported that the level of SVD was not
Quality of the included studies significantly different between DFU and non-DFU patients [36].
Meanwhile, a study from Iran reported the elevated level of serum
Quality of the included studies was measured based on NOS, and vitamin D in patients with active DFU [35]. Five studies measured the
the summary of the analysis is presented in Table 1. Most of the study serum Ca2+ levels [23,25,26,36,37]. Lipid profiles of the patient,
were indicated as having low risk, except for three studies receiving including total cholesterol (TC), high-density lipoprotein (HDL), low-
‘medium risk’ remark [23,24,35,39] and one study − ‘high risk’ [22]. density lipoprotein (LDL), and/or triglycerides (TG), were also
Some studies did not have satisfying exclusion criteria such as preg- reported [23,26−29,31,32,34,35,37]. C-reactive protein (CRP) and/or
nancy and vitamin D or calcium supplement intake [24,39,41]. A erythrocyte sedimentation rate (ESR) were measured in seven studies
3
M. Iqhrammullah, T.F. Duta, M. Alina et al. Diabetes Epidemiology and Management 13 (2024) 100175

Table 1
Characteristics of the included studies and their subjects.

Author, Year [Ref.] Type of study (Country) Subject’s characteristics Level of risk

Variable DFU Non-DFU

Todorova et al., 2020 [25] Cross-sectional (Bulgaria) n 73 106 Low

Age, years 60.6 § 8.7 55.1 § 11.5
M/F 56/17 54/52
HbA1c,% 8.9 § 2.2 7.73 § 1.6
Onset, years 13.35§9.83 5.35§5.26
BMI, kg/m2 30.6 § 6.1 31.2 § 5.9
Todorova et al., 2020 [25] Cross-sectional (Bulgaria) n 73 63 Low
Age, years 60.6 § 8.7 60.3 § 9.5
M/F 56/17 30/33
HbA1c,% 8.9 § 2.2 8.43§1.5
Onset, years 13.35§9.83 14.92§7.74
BMI, kg/m2 30.6 § 6.1 32.1 § 6.6
Zubair et al., 2013 [32] Cohort (India) n 162 162 Low
Age, years 46.29§13.19 47.10§12.13
M/F 103/28 146/16
HbA1c,% 9.6 § 2.03 7.9 § 0.86
Onset, n (< 10 years) 111 123
BMI, kg/m2 24.84§4.54 24.03§4.23
Tang et al., 2023 [37] Cross-sectional (China) n 156 100 Low
Age, years 55.6 § 11.2 54.9 § 12.3
M/F 88/68 54/46
HbA1c,% 9.3 § 1.6 8.5 § 1.7
Onset, year 12.1 § 6.4 0.4 § 0.2
Tsitsouet al., 2021 [36] Cross-sectional (Greece) n 33 35 Low
Age, years 61.9 § 9.9 66.1 § 9.4
M/F 24/9 27/8
HbA1c,% 7.34§1.78 6.54§0.77
Onset, year 17.2 § 13.7 14.2 § 9.3
BMI, kg/m2 28.2 § 4.7 31.1 § 6.0
Wang et al., 2022a [28] Cross-sectional (China) n 204 135 Low
Age, years 68.63§7.31 67.76§6.74
M/F 130/74 83/52
HbA1c,% 8.57§2 8.47§2.25
Onset, year 19.65§8.21 13.59§10.49
BMI, kg/m2 24.30§3.08 24.71§2.60
Wang et al., 2022b [29] Cross-sectional (China) n 242 187 Low
Age, years 63.05§9.92 60§2.58
M/F 168/178 108/79
HbA1c,% 8.69§2.16 8.61§2.17
Onset, year 16.95§9.7 12§9
BMI, kg/m2 24.68§3.36 25.11§2.84
Priyanto et al., 2023 [27] Cross-sectional (Indonesia) n 41 40 Low
Age, years 56.93 § 8.09 54.98 § 8.96
M/F 16/25 16/24
HbA1c,% 8.86§1.14 7.42 § 0.64
Onset (< 10 years), n 6.54 § 2.42 6.92 § 1.57
BMI, kg/m2 25.42 § 4.09 27.74 § 4.57
Tang et al., 2022 [26] Cross-sectional (China) n 547 1174 Low
Age, years 67§2.62 65.98§2.75
M/F 346/201 501/673
HbA1c,% 7.81§0.44 7.81§0.46
Onset (< 10 years), n 245 641
Onset (> 10 years), n 302 533
BMI, kg/m2 23.31§0.64 24.52§0.74
Tiwari et al., 2022 [30] Cross-sectional (India) n 112 107 Low
Age, years 53.6 § 1 51.9 § 1
M/F 76/36 72/35
HbA1c,% 9.7 § 0.25 9 § 0.28
Onset, years 6.7 § 0.5 6.5 § 0.7
BMI, kg/m2 23.6 § 0.5 24.4 § 0.4
Tiwari et al., 2014 [16] Cross-sectional (India) n 112 107 Low
Age, years 53.6 § 1 51.9 § 1
M/F 76/36 72/35
HbA1c,% 9.7 § 0.25 9 § 0.28
Onset, years 6.7 § 0.5 6.5 § 0.7
BMI, kg/m2 23.6 § 0.5 24.4 § 0.4
Tiwari et al., 2013 [33] Cross-sectional (India) n 125 164 Low
Age, years 53.6 § 10.7 51§10.8
M/F 85/40 103/61
HbA1c,% 8.6 § 6 7.7 § 8
Onset, years 6.9 § 0.53 5.4 § 0.52
BMI, kg/m2 24§3.7 24.7 § 4.2

(continued)

4
M. Iqhrammullah, T.F. Duta, M. Alina et al. Diabetes Epidemiology and Management 13 (2024) 100175

Table 1 (Continued)

Author, Year [Ref.] Type of study (Country) Subject’s characteristics Level of risk

Variable DFU Non-DFU

Qasim et al., 2013 [22] Cross-sectional (Iraq) n 70 128 High

Darlington et al., 2019 [38] Cross-sectional (India) n 101 75 Low
Age, years 56.58§8.99 58.08§10.37
HbA1c,% 25.51§4.03 8.49§1.84
Type T2DM T2DM
Onset (≤10 years), n 63 66
BMI, kg/m2 23.21§4.07 25.51§4.03
Dai et al., 2020 [31] Cross-sectional (China) n 21 30 Low
Age, year 62.00 § 5.93 59.23 § 5.70
M/F 13/8 16/14
HbA1c,% 8.60 § 2.41 8.39 § 1.36
Onset, year 11.00 § 3.70 10.03 § 4.38
BMI, kg/m2 23.74 § 3.05 25.55 § 3.70
Feldkamp et al., 2018 [39] Cross-sectional (Germany) n 104 103 Medium
Age, years 70.2 § 12.2 69.4 § 10.3
M/F 64/40
a
HbA1c,% 7.60§1.33 7.70§1.49
Onset, years 17.5 § 10.9 16.8 § 12.3
Najafipour et al., 2019 [34] Cross-sectional (Iran) n 35 35 Low
Age, years 62.09§11.23 56.34§14.22
Male,% 77.1 48.6
HbA1c,% 9.33§2.54 7.4 § 0.98
Onset, years 17.24§9.26 6.69§5.09
BMI, kg/m2 26.55§3.21 30.26§5.84
Greenhagen et al., 2019 [24] Cohort (USA) n 54 46 Medium
Age, years 56.1 55.5
M/F 39/15 17/29
a
HbA1c,% 7.9 7.5
BMI, kg/m2 26.55§3.21 30.26§5.84
Xiao et al., 2020 [40] Cross-sectional (China) n 245 4039 Low
M/F 139/106 2113/1926
Kanwal et al., 2022 [23] Cross-sectional (Pakistan) n 67 65 Medium
M/F 43/28 29/71
Type T2DM T2DM
Onset (<5 years), n 14 24
Onset (5−10 years), n 37 19
Onset (>10 years), n 20 57
BMI, kg/m2 23.1 24.3
Afarideh et al., 2016 [35] Cross-sectional (Iran) n 30 30 Medium
M/F 22/8 13/17
Age, year 59§12.61 54.5 § 13.62
HbA1c,% 8.5 § 1.71 7.9 § 1.4
BMI, kg/m2 28.9 § 1.32 26.4 § 3.5

lar et al., 2018 [41]
Çag Cross-sectional (Turkey) n 58 47 Low
M/F 42/16 27/20
Age, year 63.6 § 10.7 51.4 § 11.7
HbA1c 7.8 § 2.1 8.0 § 2.5
Onset, year 14.3 § 5.5 4.2 § 1.7
BMI, body mass index; HbA1c, glycated hemoglobin; F, female; M, male.
a
Converted from mmol/L.

[26,31,34−37,41]. Serum levels of inflammatory factors, namely could be positive. Both pooled analyses for TC and HDL are highly
interleukin (IL) 8, IL-10, IL-6, IL-1b, tumor necrosis factor (TNF)-a, heterogenous (p-X2<0.001; I2>90%).
and/or interferon (IFN)-g were reported [16,22,30,35,37].
The results from pooled estimates of SVD level (n = 19) with SMD Inflammatory parameters
as the outcome measure are presented in Fig. 2. The SMD was found
to be negative with 95% CI in the same direction (SMD= 1.2758 [95% Levels of CRP (n = 4) and ESR (n = 3) were meta-analyzed and the
CI: 2.0786 to 0.4730]). The averaged SMD was significantly differ- results are presented in Figs. 5S and 6S, respectively. Significantly
ent from zero with p-total=0.0037. Heterogeneity was considered higher levels of CRP (p-total=0.001; SMD=0.96; [95% CI: 0.58 to 1.35])
large in this pooled analysis with (p-X2<0.0001; I2=99.27%). and ESR (p-total<0.001; SMD=1.68 [95% CI: 0.95 to 2.41]) were found
in DFU group as compared to those in non-DFU group. The heteroge-
Lipid parameters neity is detected in both CRP (p-X2<0.027; I2=65.12%) and ESR (p-
X2<0.001; I2=86.12%).
Pooled analysis was performed on TC (n = 9), HDL (n = 8), LDL Meta-analysis was also carried out on pro-inflammatory cyto-
(n = 8), and TG (n = 8), where the forest plots are presented in Figs. kines, namely IL-6 (n = 3) and IL-8 (n = 2), and the results are pre-
1S, 2S, 3S, and 4S, respectively. The level of TC was significantly lower sented in Figs. 7S and 8S, respectively. Both biomolecules have
in DFU group as compared to non-DFU group (p-total= 0.017; SMD= significant total effect with p<0.01 and are found elevated in DFU
0.63 [95% CI: 1.14 to 0.11]). At the same time, HDL was also group (SMD=1.25 [95% CI: 0.69 to 1.8] and SMD=2.31 [95% CI: 1.95 to
found lower in DFU group than in non-DFU group (p-total=0.005; 2.68], respectively). The heterogeneities of the models were high in
SMD= 0.39 [95% CI: 0.67 to 0.12]), though the predicted SMD both IL-6 (p-X2=0.028; I2=72.02%) and IL-8 (p-X2=0.028; I2=72.02%).
5
M. Iqhrammullah, T.F. Duta, M. Alina et al. Diabetes Epidemiology and Management 13 (2024) 100175

Table 2
Different levels of serum vitamin D and other parameters between DFU patients and diabetic patients without DFU.
a
Author, Year [Ref.] Serum vitamin D (ng/mL) Other parameters

Method DFU Non-DFU

Todorova et al., 2020 [25] ECLIA 11.88§5.29 15.68§7.82 Ca2+

Todorova et al., 2020 [25] ECLIA 11.88§5.29 12.92§6.22 Ca2+
Zubair et al., 2013 [32] RIA 8.38§0.39 29.81§5.37 LDL, HDL, TC, TG
Tang et al., 2023 [37] CLIA 11.67§9.65 16.33§12.04 LDL, HDL, TC, TG, CRP, ESR, Ca2+, IL-6, IL-10
Tsitsou et al., 2021 [36] LC-MS/MS 17.9 § 6.7 19.8 § 8.7 CRP, Ca2+
b b
Wang et al., 2022a [28] ECLIA 30.49§14.69 38.14§20.11 LDL, HDL, TC, TG
b
Wang et al., 2022b [29] ECLIA 28.28§13.51 37.78§19.93 LDL, HDL, TC, TG
Priyanto et al., 2023 [27] CLIA 8.86 § 1.01 16.26 § 1.53 TC
b b
Tang et al., 2022 [26] ECLIA 35.8 § 3.59 45.5 § 3.94 LDL, HDL, TC, TG, Ca2+
Tiwari et al., 2022 [30] RIA 16.1 § 1.48 19.76§1.28 IL-8, MIF
Tiwari et al., 2014 [16] RIA b
40.2 § 3.7 b
49.4 § 3.2 IL-6, IL-1b, TNF-a, IFN-g
b b
Tiwari et al., 2013 [33] RIA 40.25§38.35 50.75§33
c c
Qasim et al., 2013 [22] ELISA 6.7 15.91 IL-8, IL-10
Darlington et al., 2019 [38] ELISA 23.19§11.49 29.59§11.24
Dai et al., 2020 [31] RIA 11.21 § 5.20 17.73 § 3.20 LDL, HDL, TC, TG, CRP, ESR
Feldkamp et al., 2018 [39] RIA 11.8 § 11.3 19.0 § 14.4
Najafipour et al., 2019 [34] ECLIA 16.86§10 23.9 § 15.24 LDL, HDL, TC, TG, ESR
Greenhagen et al., 2019 [24] Not stated 18.7 23.6
b b
Xiao et al., 2020 [40] CLIA 36.96 § 18.03 40.97§ 17.82
b b
Kanwal et al., 2022 [23] RIA 35.4 43.2 LDL, HDL, TC, TG, Ca2+
Afarideh et al., 2016 [35] ELISA 16.8 § 18.68 16§10.98 LDL, HDL, TC, TG, CRP, MCP-1, IL-6, IL-8

lar et al., 2018 [41]
Çag ECLIA 7.9 § 6.3 11.6 § 6.5 CRP, Osteoprotegerin
CLIA, chemiluminescence immunoassay; ECLIA, electrochemiluminescence immunoassay; RIA, radioimmunoassay; LC-MS/MS, liq-
uid chromatography-tandem mass spectrometry; ELISA, enzyme-linked immunosorbent assay.
a
Otherwise stated, the value is presented in ng/mL. Presented in b nmol/L and c pg/mL.

Serum Ca2+ respectively, showing statistical significance at p<0.001 based on Stu-

dent t-test [24]. In another study, the levels of SVD were 40.2 § 3.7
Based on the pooled analysis, the difference of serum Ca2+ level versus 49.4 § 3¢2 nmol/L (DFI versus non-DFI, respectively), having
between DFU group and non-DFU group was not statistically signifi- no statistical significance (p = 0.06) [16]. However, among patients
cant (p-total=0.166; SMD= 0.58 [95% CI: 1.39 to 0.24]) (Fig. 9S). With with severe hypovitaminosis D (<25 nmol/L), DFI prevalence were
I2 exceeding 50% (97.99%), this pooled analysis model is considered highly pronounced (48.2% versus 20.5% for DFI and diabetic control,
to have high heterogeneity (p-X2<0.001) (Fig. 9S). respectively) [16]. Using logistic regression and SVD <25 nmol/L as
the cut-off value, the study revealed significant positive correlations
between lower SVD and IL-1b (p<0.001) or IL-6 (p = 0.04) [16].
Diabetic foot infection (qualitative)

Of the included studies, two specifically reported significant dif- Publication bias
ference of SVD level between diabetic foot infection (DFI) patients
and diabetic controls [16,24]. A meta-analysis could not be carried Begg’s funnel plot for the pooled analysis of the SVD level is
out considering one study did not report standard deviations [24]. presented in Fig. 3. Both the rank correlation and the regression
Levels of SVD in DFI and non-DFI groups were 23.9 and 16.3 ng/mL, test indicated potential funnel plot asymmetry (p = 0.0066 and

Fig. 2. Forest plot of SDV. Size effect: 3.34; p-tot=0.004; SME: 1.28 ( 2.8 to 0.47). Heterogeneity: I2=99.27%; p-X2<0.001.

6
M. Iqhrammullah, T.F. Duta, M. Alina et al. Diabetes Epidemiology and Management 13 (2024) 100175

Fig. 3. Begg’s funnel plot diagram of the pooled analysis for SVD level between DFU and non-DFU group.

p = 0.0125, respectively). According to studentized residual test al. [27] the values remain negative (SMD= 1.018 [95% CI: 1.49
and Cook’s distance, two studies might act as outliers in this anal- to 0.55] and SMD= 1.053 [95% CI: 1.58 to 0.53], respectively).
ysis [27,32].

Meta-Regression
Sensitivity test
To observe the heterogeneity contributors, a meta-regression was
Results from the leave-one-out analysis has been presented in performed on age, BMI, study locations (based on continent), and
Fig. 4. The results suggest that the SDV level is significantly higher in HbA1c, where the bubble plots are presented in Fig. 5. Of these varia-
non-DFU group, and none is significantly influential that suggest the bles, statistical significance was found in age (p = 0.026) and conti-
contrary trend. Even when removing Zubair et al. [32] or Priyanto et nent (p = 0.001). As for TC, LDL, and HDL the bubble plots were

Fig. 4. Forest plot for leave-one-out analysis of pooled estimate of SVD level differences between DFU and non-DFU group.

7
M. Iqhrammullah, T.F. Duta, M. Alina et al. Diabetes Epidemiology and Management 13 (2024) 100175

Fig. 5. Bubble plots for the effects of age (A), BMI (B), continent (C) and HbA1c (D) on the heterogeneity of the SVD level differences between DFU and non-DFU group.

constructed based on their respective size effect (SMD), presented in alterations in sunlight exposure duration, skin thickness, and dietary
Fig. 6. Statistical significance is only achieved by the SVD versus TC pattern. In the case of continent effect, the heterogeneity is attributed
regression model with p = 0.001. to sunlight exposure (due to distance to the equator and/or skin
color), lifestyle and cultural practices, dietary pattern, genetic factors,
Discussion and socioeconomic factors.
We found a significant correlation with serum level Ca2+.
Serum vitamin D Though the level difference of Ca2+ was insignificant between the
two groups, it was strongly correlated with the level difference of
We found that SVD was significantly lower in DFU group as com- SVD. It is no wonder since vitamin D is primarily known to main-
pared to non-DFU group. Individually, almost all included studies tain skeletal health by binding with its receptor and subsequently
herein supported the fact of lowered SVD in DFU, except one [35]. promote Ca2+ absorption in intestine. Furthermore, it functions to
This is in line with the findings from previous meta-analyses mediate Ca2+ reabsorption in renal tubules and Ca2+ mobilization
[17,18,42]. Further, a meta-analysis had concluded that vitamin D from bone [43].
deficiency is associated with a higher incidence of DFU than that of Interestingly, lower level of TC was positively correlated with the
with sufficient vitamin D [17]. A study reported raised vitamin D level lower level of SVD, but no significance correlation was observed for
in individuals with active DFU, but the robustness of its findings is HDL and LDL. As evidenced by previous studies, vitamin D could
questionable since it recruited individuals with extreme vitamin D reduce the level of cholesterol (especially the LDL) [44,45]. We sus-
deficiency as control (< 12 ng/L) [35]. Regardless, the study did not pect the contradictory results is due to statin therapies, as they are
affect the body of evidence established in the present study as indi- the first-line therapy for patients with PAD [46]. There is suspicion on
cated by the sensitivity test. the competitive inhibitory effect of statins against vitamin D metabo-
The regression model generated using HbA1c level as the predic- lism [47]. Nevertheless, the current scientific findings suggest the
tor had low statistical significance suggesting that the state of glyca- otherwise, where several statins in fact increase the level of SVD [48].
tion control does not affect the SDV level. Similarly, nutritional status Moreover, vitamin D is suggested to exert higher efficacy of simva-
did not affect the heterogeneity in the pooled analysis. Age and conti- statin while reducing its adverse effects [49]. Therefore, it is safe to
nent, however, contributed to heterogeneity. Aged individuals might treat lower levels of TC and SDV in DFU group as confounding. How-
have lower nephrotic and hepatic ability to convert vitamin D to its ever, a strong correlation in the meta-regression suggests that the
active form, in which this relationship is also correlated with comor- difference in TC level contributes to the different level of SVD
bidities and medication use. Other than the physiological factor, other between DFU and non-DFU group. It is worth noting that patients
contributing factors to age-related change of SVD include the undertaking statins but having vitamin D deficiency may suffer from
8
M. Iqhrammullah, T.F. Duta, M. Alina et al. Diabetes Epidemiology and Management 13 (2024) 100175

Fig. 6. Bubble plots for the effects of TC (A), LDL (B), and HDL (C) on the heterogeneity of the SVD level differences between DFU and non-DFU group.

higher risk of statins adverse effects (such as myalgia and myopathy) inhibiting the expression of pro-inflammatory cytokines and activa-
[50,51]. tion of nuclear factor-kappa b (NF-kb). Moreover, vitamin D has
been revealed to interact with renin-angiotensin-aldosterone system
Role of vitamin D in the pathomechanism of DFU (RAAS) by suppressing the production of renin and angiotensin-con-
verting enzyme (ACE) and regulate oxidative stress by acting as reac-
In the present study, we found significantly increased inflamma- tive oxygen species (ROS) scavenger and enhancing the activity of
tory markers in patients with DFU and lowered SVD. Our findings antioxidant enzymes [70,71].
suggest that the role of vitamin D in DFU involves its anti-inflamma- Evidence of vitamin D as anti-inflammatory agent in preclinical
tory activities. and clinical settings is well-established [53]. In an animal study, SVD
Patients with diabetes are likely to develop chronic inflammation has been reported to maintain the stability of NF-kB, thereby inhibit-
concomitant to the impaired balance between pro- and anti-inflam- ing its activation [54]. Ex-vivo experiment using monocytes isolated
matory factors. Moreover, diabetes-induced oxidative stress imbal- from type 2 diabetic patients suggests that the addition of 1,25-dihy-
ance is common and further initiates the inflammatory response droxyvitamin D3 (the active form of vitamin D) could reduce the
cascades. Inflammatory conditions induce cell and tissue damage expressions of IL-1, IL-6, IL-8 and TNF-a [55]. Six-month vitamin D
that essentially reduces the wound healing process. This pathologic supplementation has been reported to increase SVD level and conse-
inflammation also contributes to the development of neuropathy and quently suppress the serum levels of pro-inflammatory cytokines
ischemia through endothelial dysfunction, vasodilation impairment, namely IL-18, TNF-a, and IFN-g [56]. A recent meta-analysis suggests
disrupted neovascularization, and atherosclerotic plaque formation significant attenuations of CRP and ESR among DFU patients as the
which also act as the positive feedback loop. results of vitamin D supplementation [45]. Taken altogether, vitamin
Targeting inflammatory factors (i.e. IL-6 and CRP) have been the D deficiency might contribute to DFU development concomitant to
interest of researchers in developing treatment modalities for DFU the worsening of the chronic inflammation in diabetic patients.
[52]. Significantly elevated level of IL-6 is reported as the confound- Two studies investigated the association between vitamin D in
ing of lowered SDV in DFU patients [16,35,37]. Higher levels were DFU patients with culture positivity for infection [16,24]. Patients
also found in other inflammatory markers, namely CRP, ESR, CCL2, IL- with diabetic foot infection (DFI) were found to be likely having
1b, TNF-a, and IFN-g [31,35−37]. The pooled analysis in the present lower SVD as compared to their non-DFI counterpart [24]. In severe
study suggests that the IL-6, CRP, and ESR levels are significantly vitamin D deficiency cases, prevalence of DFI was reported the high-
higher in DFU patients than in diabetic patients without DFU. Vitamin est [16]. These findings corroborate the role of low SVD in increasing
D has been reported to downregulate inflammatory reaction by the susceptibility of diabetic patients to develop foot infection. Some
9
M. Iqhrammullah, T.F. Duta, M. Alina et al. Diabetes Epidemiology and Management 13 (2024) 100175

studies have reported the possible connection between vitamin D DFU could have significantly lower SVD, and it is of importance to
with bacterial infections in clinical settings such as methicillin-resis- investigate the pathophysiological pathway. True experimental
tant Staphylococcus aureus [57,58]. design using animal models could assist researchers in investigating
There is growing body of evidence supporting vitamin D signaling these currently unexplained phenomena.
as the promoter of innate immune response as suggested by labora-
tory-based and epidemiological studies [59]. Upon infection, macro- Strength and limitations
phages induce the expression of 25-hydroxyvitamin D 1a-
hydroxylase to produce 1,25-dihydroxyvitamin D3 which subse- This is the first meta-analysis with meta-regression to investigate
quently promotes the expression of genes encoding antimicrobial the association between SVD and DFU. This is also the first study to
peptides [59]. Moreover, vitamin D has a role in determining the life- elaborate the possible pathomechanism of SVD involvement in DFU
cycle stages and function of keratinocytes [60]. Along with other epi- development. Unfortunately, we still faced language barrier, which
dermal cells, keratinocytes has been known to produce antimicrobial prevented us to gather more findings from articles written in non-
peptides and this activity is increased by SVD [61,62]. Additionally, English or non-Indonesian language. Manual search by contacting
vitamin D is suggested to prevent DFU development by attenuating the renown experts in this field was not performed, and there were
immune dysregulation (i.e. by reducing IL-1b and IL-6 production) some databases that were not used to identify the record, contribut-
[16]. ing to the selection bias.
More compelling hypothesis about the role of vitamin D is its con-
tribution in improving insulin sensitivity and glycemic control [6−8]. Conclusions
There are several mechanisms proposed to explain the role of vitamin
D in attenuating insulin resistance. Firstly, the vitamin could enrich Level of SVD is lower in patients with DFU as compared to diabetic
cytoplasmic Ca2+ in pancreatic b-cells by inhibiting the expression of patients without DFU, irrespective to the presence of other complica-
l-type Ca2+ channels resulting in higher release of insulin [63]. Sec- tions. Involvement of vitamin D in the development and progression
ondly, vitamin D increases insulin-mediated glucose transport con- of DFU might be correlated with the systemic inflammation and
comitant to the intensified translocation of glucose transporter 4 in infection susceptibility. Clinicians should pay attention to diabetic
skeletal muscle by regulating intracellular Ca2+ concentrations [64]. patients who are developing lowered SVD and increased inflamma-
Thirdly, interaction of vitamin D with RAAS has been proposed as one tory markers. In the future, it is also interesting to investigate the effi-
of the mechanisms as angiotensin II induces skeletal muscle insulin cacy of vitamin D supplementation in reversing the pathologic
sensitivity [65]. Other mechanisms involving epigenetic pathway, conditions during DFU.
lipid metabolism, and anti-inflammatory properties of vitamin D
have been discussed thoroughly in a previously published review Funding
[66].
Improved insulin sensitivity mediated by vitamin D might explain The authors received no funding from an external source.
the significantly lower SVD level in PAD patients than in diabetic
patients without PAD [24]. Unfortunately, collective findings in this Data availability
present systematic review have yet shown any supportive evidence.
Previously, supplementation of vitamin D has been reported to have
no effect on insulin resistance [56,67]. Therefore, it is unlikely that All underlying data have been presented.
the DFU development is affected by vitamin D deficiency owing to
the worsening of insulin resistance. Nonetheless, more evidence is
required to observe the effect of vitamin D since its glycemic control- Declaration of Competing Interest
related activity is dependent on ethnicity and genetic factors [68].
There is still uncertainty about the systemic effect of diabetes on The authors declare that they have no known competing financial
reduced SVD level. A study argued that impaired renal function interests or personal relationships that could have appeared to influ-
induced by the diabetic conditions is the cause of low SVD since the ence the work reported in this paper.
organ is the primary location of the vitamin D hydroxylation [24].
Another study associated their findings with different vitamin D Supplementary materials
intake and sunlight exposure [36], which have been reported as the
great influence to SVD level [69]. In addition, a study stipulated that Supplementary material associated with this article can be found,
lack of SVD in DFU patients was caused by restricted mobility of the in the online version, at doi:10.1016/j.deman.2023.100175.
DFU patients which resulted in less sunlight exposure and physical
exercise [26]. References

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