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. 2023 Jan 17;20(6):2028–2036. doi: 10.1111/iwj.14066

Comparison of vitamin D levels in diabetes mellitus patients with and without diabetic foot ulcers: An analytical observational study in Jakarta, Indonesia

Mufqi Handaru Priyanto 1, Lili Legiawati 1, Siti Rizny F Saldi 2, Em Yunir 3, Eliza Miranda 1,✉
PMCID: PMC10333004  PMID: 36647686

Abstract

Diabetic foot ulcer (DFU) is a form of chronic wound which becomes a serious complication in diabetes mellitus (DM). Recently, the role of vitamin D on T cell‐mediated immunity, pancreatic insulin secretion, and its mechanism on cell growth and healing processes have been reported. This study aims to compare the vitamin D level of DM patients with DFU and without DFU to assess the duration and severity of DFU and its correlation with vitamin D levels. The sociodemographic characteristics and DFU duration were documented. The severity was examined in accordance with PEDIS classification. 25‐hydroxyvitamin D (25[OH]D) was analysed using in‐vitro chemiluminescent immunoassay (CLIA). Statistical analysis was performed and the P‐value <.05 was considered as statistically significant. The vitamin D levels in DM patients with and without DFU were 8.90 ng/mL (6.52–10.90) and 16.25 ng/mL (13–19.59), respectively, with P < .001. There was no correlation between the duration of DFU and DFU severity by PEDIS score with vitamin D levels. Vitamin D levels in DM patients with DFU are lower than those in patients without DFU. However, there was insufficient evidence to conclude that there is no correlation between the DFU duration and DFU severity by PEDIS score with vitamin D levels.

Keywords: DFU duration, DFU severity, diabetic foot ulcer, vitamin D

1. INTRODUCTION

Diabetes mellitus (DM) is a metabolic disease that epidemiologically shows an increasing incidence and prevalence in various parts of the world. 1 The World Health Organisation (WHO) in 2016 stated that people with DM reached 422 million worldwide, and estimates that the number of people with DM in Indonesia will increase from 8.4 million in 2000 to around 21.3 million in 2030. 2

In DM patients with uncontrolled blood sugar levels, various complications can occur with one of the most critical being diabetic foot ulcer (DFU). 3 Patients with DFU are reported to have a 2‐fold higher risk of mortality compared with DM patients without DFU. 4 The proportion of DM with complications in Indonesia is 6.9%, reaching 8.7% in the form of DFU. 5 The worsening prognosis of DFU is closely related to hyperglycaemia, which can stimulate oxidative stress, thereby resulting in immune dysfunction, persistent inflammatory conditions, microvascular complications, impairing wound healing. The severity of DFU can be assessed using PEDIS (perfusion, extend, depth, infection, sensation) score, ranging from 0 to 12. 6 , 7 , 8

There are various studies that mention the relationship between vitamin D with the occurrence of DM and its complications. Vitamin D is said to have a variety of non‐skeletal effects, including a major role in insulin action and differentiation of keratinocytes and fibroblasts through modulation of growth factors and cytokines. 7 , 9 Vitamin D is converted by the enzyme 25‐Hydroxyvitamin D hydroxylase, known to be the main non‐specific regulator of the immune system that triggers antimicrobial peptides (AMP) in monocytes or macrophages. 25‐Hydroxyvitamin D decrease pro‐inflammatory cytokines and increases anti‐inflammatory responses. 6 , 10 It was observed that longer DFU duration and vitamin D deficiency had a significant negative effect on the rate of DFU healing, indicating DFU patients with lower serum vitamin D levels may have a higher PEDIS score. 11 , 12 , 13

In recent years, more reports have been reported on the role of vitamin D on T cell‐mediated immunity, pancreatic insulin secretion, and its mechanism on cell growth and healing processes. 4 However, research on vitamin D in the Indonesian population is still limited. Oemardi et al 10 reported that the incidence of vitamin D deficiency in the female population aged 45–55 years in Indonesia reached 50%. 11 This figure roughly indicates that the rate of vitamin D deficiency in Indonesia is quite high. The aim of this study is to become the first to compare vitamin D levels in DM patients with and without DFU in Indonesia, which include three hypotheses: DM patients with DFU had lower levels of vitamin D 25(OH)D than DM patients without DFU; the longer the patient suffers from DFU, the lower the level of vitamin D 25(OH)D; the higher the PEDIS score, the lower the level of vitamin D 25(OH)D.

2. MATERIALS AND METHODS

2.1. Study design

This study is an analytical observational study with a cross‐sectional design, to compare vitamin D (25(OH)D) levels in DM patients with and without DFU, and to find out whether the duration of suffering from DFU and the severity of DFU based on the PEDIS score correlated with levels of 25(OH)D in DM patients with DFU. Patients with a diagnosis of DM both with DFU and without DFU will be checked for 25(OH)D levels and other examinations. In the DM group with DFU, additional data will be collected including the duration and severity of DFU based on the PEDIS score to see the correlation with vitamin D levels. The characteristics of the subjects were not analysed in the comparison of the two unpaired groups because they were only used as additional descriptive data, not the primary purpose of the study. In terms of sample size, only sample size was counted for comparison of vitamin D levels of DM patients with DFU and without DFU; and the correlation of vitamin D with DFU duration and severity.

2.2. Research population

Patients attending Internal Medicine Outpatient Clinic and Dermatology‐Venereology Outpatient Clinic, Cipto Mangunkusumo National Hospital, also Pasar Rebo District Health Center from November 2020 until May 2021 who were willing to take part in the study, signed the research consent form, aged >18 years old, met the diagnostic criteria for type 2 DM according to the Indonesian Society for Endocrinologist consensus in 2021, with and without DFU were included. 1 , 3 On the other hand, patients who were taking vitamin D supplementation in the last 1 month and had comorbidities: systemic infection, autoimmune and rheumatism, malignancy, end stage renal failure (haemodialysis), and severe liver disease were excluded. During this period, 81 subjects were obtained, consisting of 41 DM patients with DFU, and 40 DM patients without DFU. Subjects with total PEDIS score of 2 to 6 were selected: Perfusion (no PAD, normal ABI, scored 0); Extent (intact skin, scored 0; <1 cm2, scored 1; 1–3 cm2, scored 2; >3 cm2, scored 3); Depth (intact skin, scored 0; superficial, scored 1); Infection (none, scored 0; superficial or mild according to IDSA/IWGDF, scored 1); Sensation (no loss, scored 0; loss, scored 1). 6 , 7 , 8 The PEDIS score range of 2 to 6 was chosen to standardise wound conditions; therefore, the degree of severity does not vary too much and can be used to predict the effect of vitamin D levels on non‐healing wounds even in mild and superficial DFU.

2.3. Materials and workflow

Initial examination began with subject data collection through history taking and medical records including age, sociodemographic, smoking history, duration of DM, history of DM and cholesterol treatment, duration of DFU in subjects with DFU, as well as the latest random blood sugar (RBS) laboratory results. and in the last 3 months in the form of HbA1c, creatinine, and total cholesterol. Then, a physical examination is carried out including vital signs, body mass index (BMI), and wound measurements as well as an assessment of the severity of the DFU based on the PEDIS score for subjects with DFU. If the data regarding the laboratory parameters are complete, then the patient will be immediately taken peripheral venous blood, and then sent to the laboratory of Southeast Asian Ministers of Education Organisation Regional Centre for Food and Nutrition (SEAMEO RECFON)—Department of Nutrition, Faculty of Medicine Universitas Indonesia for examination of vitamin D 25(OH)D levels, otherwise the researcher would first take peripheral venous blood to check the level of vitamin D 25(OH)D. The content of vitamin D 25‐OH in serum/plasma determined by direct competitive chemiluminescence immunoassay (CLIA) with LIASON® DiaSorin.

2.4. Research ethics

This study was approved by the Health Research Ethics Committee of Universitas Indonesia (number KET‐1074/UN2.F1/ETIK/PPM.00.02/2020). Informed consents were obtained from all subjects.

2.5. Data analysis

All data obtained from the examination were recorded. The collected data were edited, verified, and coded using Microsoft Excel 2017 and SPSS version 20 software. Data with a numerical scale is presented in mean or median. Independent t‐test or Mann–Whitney was used for the first hypotheses analysis while for the second and third hypotheses used the Pearson or Spearman. The P value <.05 is considered statistically significant. Normality test used was Kolmogorov–Smirnov as the total sample size was larger than 50.

3. RESULTS

3.1. Research subjects characteristics

In this study, the sociodemographic characteristics are presented in Table 1, while clinical characteristics along with kinds of treatment and laboratory parameters of DM subjects with and without DFU are presented in Table 2. The most common DM treatment found in the DM group with DFU was a single oral anti‐diabetic drug (OAD), while in the DM group without DFU, it was a combination of oral OAD and insulin. Anti‐cholesterol treatment was more common in the group of DM patients without DFU. The levels of GDS, HbA1C, creatinine, and cholesterol in the DM group with DFU were higher than the DM group without DFU.

TABLE 1.

Sociodemographic characteristics of DM patients with and without DFU

Variable DM with DFU, n = 41 DM without DFU, n = 40
Gender; n (%)
Female 25 (60%) 24 (60%)
Male 16 (40%) 16 (40%)
Age (years) a 56.93 (8.09) 54.98 (8.96)
BMI (kg/m2) a 25.42 (4.09) 27.74 (4.57)
Occupation; n (%)
Unemployed 32 (78%) 27 (67.5%)
Employee 3 (7.3%) 9 (22.5%)
Entrepreneur 5 (12.2%) 4 (10%)
Others 1 (2.4%) 0 (0%)
Educational background; n (%)
No school 4 (9.8%) 2 (5%)
Elementary school 7 (17.1%) 3 (7.5%)
Junior high school 11 (26.8%) 6 (15%)
Senior high school 11 (26.8%) 14 (35%)
Educational background; n (%)
Diploma 7 (17.1%) 9 (22.5%)
Bachelor 1 (2.4%) 6 (15%)
Financing status; n (%)
National health insurance 31 (75.6%) 34 (85%)
Other health insurance 0 (0%) 2 (5%)
Private 10 (24.4%) 4 (10%)
Smoking history; n (%)
Yes 19 (46.3%) 15 (37.5%)
No 22 (53.7%) 25 (62.5%)
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a

Data in mean (standard deviation).

TABLE 2.

Clinical characteristics, treatment, and laboratory parameters in DM patients with and without DFU

Variable DM with DFU, n = 41 DM without DFU, n = 40
DM duration (years) a 6 (3.5–14) 7 (3.25–10)
DM treatment; n (%)
Single OAD 23 (56.1%) 5 (12.5%)
Combination OAD 5 (12.2%) 11 (27.5%)
Single insulin 2 (4.9%) 1 (2.5%)
Combination insulin 4 (9.8%) 6 (15%)
Combination of OAD and insulin 7 (17.1%) 17 (42.5%)
Cholesterol treatment; n (%)
Yes 13 (31.7%) 34 (85%)
No 28 (68.3%) 6 (15%)
RBS (mg/dL) a 230 (169.5‐369) 203 (167‐254.5)
HbA1C (%) a 8.9 (6.2‐11.15) 7.4 (6.11‐8.85)
Cholesterol (mg/dL) b 202.93 (46.66) 194.48 (43.59)
Creatinine (mg/dL) a 1.20 (1‐–1.45) 1.00 (0.8‐1.3)
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Abbreviations: OAD, oral antidiabetics; RBS, random blood sugar.

a

Data in median (Q1‐Q3).

b

Data in mean (standard deviation).

Characteristics of DFU in subjects based on size, duration, location, presence of deformity, ABI, and severity of DFU using the PEDIS assessment are presented in Table 3. The median duration of DFU in subjects was 8 weeks, and the location of the most common ulcers was in the forefoot area.

TABLE 3.

Ulcer characteristics in DM patients with DFU

Variable DM with DFU, n = 41
Area (cm2) a 2.20 (0.61‐6.56)
Ulcer duration (weeks) a 8 (4‐17)
PEDIS score a 4 (3‐5)
Ulcer location; n (%)
Ankle 7 (17.1%)
Dorsal of foot 5 (12.2%)
Hallux 6 (14.6%)
Digits 3 (7.3%)
Forefoot 9 (22.0%)
Midfoot 6 (14.6%)
Hindfoot 5 (12.2%)
Deformity; n (%)
Yes 12 (29.3%)
No 29 (70.7%)
Ankle‐brachial index b 1.04 (0.08)
Neuropathy; n (%) 33 (80.48%)
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a

Data in median (Q1‐Q3).

b

Data in mean (standard deviation).

3.2. Vitamin D levels comparison

It was found that vitamin D levels in DM patients with DFU (8.90 [6.52–10.9] ng/mL) were significantly lower than in patients without DFU (16.25 (13–19.59) ng/mL) (P < .001, using Mann–Whitney test). In both groups, vitamin D deficiency was found according to the classification of vitamin D levels from the Endocrine Society Guideline. 1

3.3. Correlation between Vitamin D levels and DFU duration and PEDIS score

The analysis to determine the correlation between the duration of experiencing DFU and vitamin D levels in the DM patients with DFU is presented in Table 4. The results showed that there was no correlation between the duration of experiencing DFU and vitamin D levels, and it was not statistically significant (P = .703). No correlation was found either between the severity of DFU based on the PEDIS value and vitamin D levels, and it was not statistically significant (P = .528).

TABLE 4.

Correlation analysis between vitamin D levels and DFU duration and PEDIS score

Independent variable Vitamin D levels (ng/mL) (n = 41)
Spearman's rho P
DFU duration (weeks) −0.061 .703
PEDIS score 0.102 .528
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4. DISCUSSION

In the sociodemographic characteristics of the subjects, it was found that the female sex was more numerous in both the group with and without DFU, each by 60%. The mean age of the subjects in the DM group with DFU was similar as the DM group without DFU, namely 56.93 and 54.98 years. These results indicate that the age group in both groups is the 5th decade, with a tendency to be older in the DFU group. This age characteristic is in accordance with two other studies in Indonesia which states that DM patients with DFU are more commonly found in populations aged >50 years. 14 , 15 Body mass index (BMI) in the obesity category is a major factor in type‐2 DM, but this does not have a significant role in the formation of DFU complications. 16 In terms of lifestyle, more than 50% of subjects in both groups of DM patients with and without DFU admitted to having no history of smoking.

The duration of developing DM in DM group subjects with and without DFU was similar, with median values ​​were 6 and 7 years, respectively. The history of DM treatment in the two groups showed quite different results. In the DFU group, it was found that the highest percentage was in patients who received a single OAD (56.1%), while in the group without DFU, the highest percentage was actually found in the combined OAD and insulin group (42.5%). The use of insulin in DM patients is mostly given to patients with underlying conditions of severe DM, whose blood glucose levels cannot be controlled by lifestyle changes or the use of OADs such as metformin alone. 16 However, in this study, it seems that combination therapy with insulin actually shows that blood sugar levels in the subjects group without DFU were well controlled, compared with the DFU group, the majority of whom were still receiving treatment with a single OAD alone. This emphasises the importance of paying attention to blood sugar control in patients with DM, especially those with complications, such as DFU, therefore, the wound healing process can take place properly. The median HbA1C value in the DFU group was higher than in the group without DFU, namely 8.9% versus 7.4%. This was also evident from the RBS levels in both groups, which were also found in the DFU group to be higher than in the group without DFU with a median value of 230 mg/dL versus 203 mg/dL. In this study, it was found that in the DM group subjects with DFU, more than 50% of subjects did not receive cholesterol treatment. Creatinine levels were also found higher in the group with DFU than without DFU with a median value of 1.2 mg/dL versus 1.00 mg/dL, although the median creatinine level in the group with DFU was just slightly higher compared with normal creatinine levels.

The most common DFU locations in this study were found in the following four locations, namely the forefoot (22%), ankle (17.1%), then hallux, and midfoot (14.6% each). The location of DFU on the forefoot was also found to be the most common location of DFU in studies conducted in China, Jordan, and Saudi Arabia. 17 , 18 , 19 In another study, it was stated that the pressure on the soles of patients with DFU in the forefoot area was higher than in the midfoot and hindfoot areas. 17 , 20 In terms of duration, the median duration of experiencing DFU was found to be 8 weeks. Until now, there are no clear boundaries regarding when a wound in DM patients is called a DFU. However, a study states that the condition of wounds in DM patients is referred to as DFU if there is no significant improvement after 2 to 8 weeks. 21 Peripheral neuropathy was found in 80.48% of the subjects. Reiber et al 22 stated that peripheral neuropathy was the most common component found in 78% of patients who subsequently developed foot ulcers.

The comparison of vitamin D levels in DM patients with and without DFU in this study was statistically significant (P < .001), with the result that vitamin D levels were lower in the DM group with DFU, namely 8.9 versus 16.25 ng/dL, so the first hypothesis in this study is accepted. These results are consistent with studies conducted in Asian and European countries, which state that DM patients with DFU have significantly lower vitamin D levels than DM patients without DFU. 6 , 7 , 8 , 9 , 23 , 24 , 25 A meta‐analysis states that severe vitamin D deficiency is associated with an increased risk of developing DFU. In addition, on the analysis of independent factors also found a relationship between increased incidence of UKD along with decreased levels of vitamin D. 4 Low vitamin D levels are associated with insulin resistance, impaired beta cell function, and contribute to DM. 9 The active form of vitamin D can stimulate phagocytosis and is a potent suppressor of interferon‐γ. Coupled with hyperglycemia conditions, vitamin D deficiency will increase the risk of infection in DFU because of reduced immune response. 8 , 9

Conditions with DFU reflect an immunocompromised condition, resulting in the occurrence of a systemic 25(OH)D production defect is greater in patients with chronic DFU. A meta‐analysis showed that severe vitamin D levels <10 ng/mL significantly increase the risk of DFU (OR 3.22; 95% CI 2.42–4.28). 4 Adequate vitamin D levels, which are 30 ng/mL (75 nmol/mL) or more, is said to be adequate to trigger the performance of the 1‐OHase substrate, which it can convert 25(OH)D into the active form of 1,25(OH)D. This active form will then move to the cell nucleus, increase the expression of catelicidin, activating natural immunity, and triggers the eradication of infectious pathogens. 4

25‐hydroxyvitamin D also plays a role in increasing insulin sensitivity and secretory transcription factors through the effect of vitamin D receptors present on the surface of pancreatic beta cells, adipocytes, and peripheral skeletal muscle cells; hence, 25(OH)D deficiency is considered to have a major role in the pathogenesis of DFU which causes the elimination of excessive glucose in the circulation inefficient. 26 In addition, the role of vitamin D in DM by influencing insulin sensitivity and secretion is also through the effect of intracellular calcium, which is crucial to be balanced. 27

Vitamin D supplementation in DM patients can improve insulin secretion through the mechanism of calcium regulation by 1,25(OH)D thereby increasing the amount of glucose into the tissues. Vitamin D indirectly reduces high levels of circulating glucose and maintains glucose absorption into tissues, thereby preventing complications of DFU that occur because of prolonged exposure to high blood glucose levels, such as nerve damage, peripheral neuropathy, and subsequent formation of DFU. 26 Hyperglycemia conditions result in impaired cytokine production, decreased production of growth factors, reduced macrophage function, and susceptibility to infection; hence, it has a significant contribution to the wound healing process. 25 , 28

Infectious conditions in DFU reflect changes in the state of host immunity because of changes in immune function mediators. Cytokines are the main mediators of the host response to infection and play an important role in macrophage differentiation, eradication of infection, and wound healing processes. 29 , 30 Infection will trigger an inflammatory response to release inflammatory cytokines including IL‐1β, IL‐6, IFN‐γ, and TNF‐α or the chemokine IL‐8, which is regulated by counter‐regulatory mechanisms such as the production of the anti‐inflammatory cytokine IL‐10 to prevent hyperinflammation, therefore controlling infection and effective wound healing. 24

In addition to hyperglycemia, severe vitamin D deficiency is also a risk factor for infection in DFU through immune dysregulation. 24 , 25 This is evidenced by a study in India which found a negative correlation between concentrations of pro‐inflammatory cytokines IL‐1β, IL‐6, and TNF‐α with vitamin D levels. The concentration of inflammatory cytokines was significantly increased in patients with DFU who had infection compared with the control group, and severe vitamin D deficiency was more common in patients with DFU who had infection than the control group. In addition, the study also found significant differences between the concentrations of IL‐1, IL‐6, and TNF‐ in patients with severe vitamin D deficiency (levels of 25(OH)D < 10 ng/mL) compared with patients with levels of 25(OH)D > 10 ng/mL. These results suggest that an increased cytokine response occurs as a result of vitamin D deficiency in patients with DFU. 24

The active form of vitamin D, 1,25(OH)2D, acts to regulate the expression of cathelicidin (LL‐37), an antimicrobial peptide (AMP) as a mediator of natural immunity in the skin to accelerate the process of wound healing and tissue repair. 31 , 32 Cathelicidin encodes the propeptide human cationic antimicrobial peptide (hCAP18), inactive cathelicidin, which then releases the c‐terminal 37 amino acid peptide chain LL‐37 as the active catelicidin. 33 Studies in humans showed increased expression of cathelicidin in the early process of normal wound healing. 34 Other studies have shown that catelicidins modulate inflammation in the skin, induce angiogenesis, and improve re‐epithelialization. 35 , 36 The active form of vitamin D and its analogues have shown upregulation of catelicidin expression in cultured models of keratinocytes. 34 , 37 If vitamin D levels are inadequate, the catelicidin expression is not optimal and its role in wound healing is impaired. 16 Research in a population with healthy adult study subjects stated that there was a positive correlation between plasma hCAP18 levels and serum 25(OH)D levels; therefore, vitamin D status is one of the main regulators of systemic hCAP18/LL‐37 levels. 38

Gonzales‐Curiel et al conducted an in vitro study of DFU by taking tissue from the wound margin of the DFU, compared with a control group taken from the wound margin in surgical patients with orthopaedic cases. The results of the study stated that patients with DFU had lower cathelicidin levels compared with the control group. This reinforces the notion that elevated glucose levels are associated with decreased AMP production. 39 In addition, preliminary studies conducted on the wound margins of DFU showed low or even absent cathelicidin expression. 40 Furthermore, the researchers provided the active form of vitamin D, namely 1,25(OH)D in keratinocyte cultures from DFU and showed that 1,25(OH)D was able to increase catelicidin expression by 2 to 125‐fold, especially in tissues obtained from patients with good glycaemic control. This study showed that administration of 1,25(OH)D was able to induce gene expression and catelicidin production in keratinocyte cultures from DFU, and showed increased keratinocyte proliferation and migration. 39

The levels of vitamin D obtained in all subjects in this study were overall insufficient and deficient. The result is greater than a study in Qatar, which stated that 64% of the total subjects with metabolic syndrome had vitamin D deficiency. 41

Several studies have shown the relationship between vitamin D deficiency and the occurrence of bacterial infection in DFU which contributes 20% of hospitalizations in DM patients. 42 , 43 Immune cells, beta cell damage, impaired insulin production, and vitamin D deficiency are associated with susceptibility to infection in DFU. 11

Low circulating levels of vitamin D cause an increase in the concentration of inflammatory cytokines in DFU patients, resulting in a prolongation of the wound healing process. 9 A study in United States found that an increase in DFU duration was significantly associated with the likelihood of DFU failure to heal. The study also stated that vitamin D deficiency was more dominant in infected DFU. The optimal form of the active metabolite of vitamin D, 1,25(OH)D, is required to induce AMP production in keratinocytes in DFU. 11

The longer the duration of DFU indicates the inflammatory condition is continuing and is associated with lower vitamin D levels because of vitamin D deficiency or insufficiency so that wound healing is not optimal. However, in this study, there was insufficient evidence to explain the correlation between DFU duration and vitamin D levels, and it was not statistically significant; therefore, the second hypothesis in this study was not validated. This may be caused by several factors, including the role of micronutrient elements other than vitamin D, growth factors, and oxidative stress which were not investigated further on their effect on DFU in this study. In addition, vitamin D levels in all subjects with DFU are deficient and insufficient. 44

Assessment with PEDIS includes perfusion, extent, depth, infection, and sensation variables. 8 , 12 A study conducted by Lawrence et al showed that there was an association between the depth of infection in DFU and the occurrence of amputation. 45 Furthermore, the study conducted by Oyibo et al stated that blood flow, infection, depth, and area of the ulcer were associated with the healing process of DFU. 46 , 47 , 48

One study showed that the higher the PEDIS value, especially if the value was more than 7, the significantly associated with impaired healing process of DFU. 12 Loss of protective sensation has an important role in the pathogenesis of DFU. 49 , 50 Vitamin D deficiency in several studies is associated with the incidence and severity of neuropathy. It has also been suggested that vitamin D hypovitaminosis is an independent risk factor for peripheral neuropathy in DM patients. 51 , 52 , 53 , 54 , 55 , 56 The biologic effects of vitamin D on the nervous system include a role in the synthesis of enzymes for neurotransmitters as well as an ingredient used in brain detoxification mechanisms. 57

Research conducted in Iran stated that giving high doses of vitamin D per week in DM patients was able to improve peripheral neuropathy. 58 Research conducted by Zubair et al stated that decreased vitamin D levels were associated with increased severity of DFU as assessed by the University of Texas system (P = .002). 26 Similar to that study, a study conducted in Indonesia by Harris et al showed that vitamin D levels were negatively and significantly correlated with the severity of DFU based on the Wagner classification. 59

From these several studies, although using different DFU severity assessments, they showed a negative correlation between vitamin D levels and the severity of DFU. Whereas in this study, the DFU severity assessment used was the PEDIS value, because of the better sensitivity and specificity of the PEDIS score, namely 93% and 82%, respectively. 8 Unfortunately, the results of this study did not show sufficient evidence between the correlation between PEDIS values and vitamin D levels, and it was not statistically significant so that the third hypothesis in this study could not be rejected. This may be because of the narrow acceptance criteria for the DFU group, so the value of the number of PEDIS obtained is relatively not much different, namely the minimum and maximum values range from 2 to 6, of the total score that can be obtained is between 0 and 12.

This study has some strengths and limitations. This is the first study in Indonesia to determine the comparison of vitamin D levels in DM patients with and without DFU, to analyse the correlation between DFU duration and vitamin D levels, and to analyse the correlation between the severity of DFU based on the PEDIS assessment and vitamin D levels. However, because of the strict acceptance criteria for DFU conditions in this study, not all DFU conditions, especially severe ones, could be included in this study to be able to see further relationship with vitamin D levels at various degrees of DFU severity.

5. CONCLUSION

Vitamin D levels in DM patients with DFU were lower and statistically significant compared with vitamin D levels in DM patients without DFU. However, there is insufficient evidence to conclude correlation between the duration of having DFU and vitamin D levels also the severity of DFU by PEDIS score and vitamin D levels.

FUNDING INFORMATION

This research was conducted using the International Indexed Publication (Publikasi Terindeks Internasional/PUTI) Saintekes 2020 research grant from the Directorate of Research and Development Universitas Indonesia, number NKB‐4748/UN2.RST/HKP.05.00/2020.

CONFLICT OF INTEREST

The authors have no conflicts of interest to declare.

ACKNOWLEDGEMENTS

The authors would like to express highest gratitude to the Directorate of Research and Development Universitas Indonesia for the research grant. Special thanks to Wound Clinic at Internal Medicine and Dermatology‐Venereology Outpatient Clinic Dr. Cipto Mangunkusumo National Hospital, and Pasar Rebo District Health Centre.

Priyanto MH, Legiawati L, Saldi SRF, Yunir E, Miranda E. Comparison of vitamin D levels in diabetes mellitus patients with and without diabetic foot ulcers: An analytical observational study in Jakarta, Indonesia. Int Wound J. 2023;20(6):2028‐2036. doi: 10.1111/iwj.14066

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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