JUSINDO, Vol. 7 No. 1, Januari 2025

p-ISSN: 2303-288X, e-ISSN: 2541-7207

Jurnal Sehat Indonesia: Vol. 7, No. 1, Januari 2025 | 125

Association of Vitamin D Deficiency and Diabetic Foot Ulcer Patients

in Dr Mohammad Hoesin General Hospital Palembang

Kemas Dahlan

, Fahmi Jaka Yususf

, Irfannuddin

, Krisna Murti

Akhmadu Muradi

, Iche Andriyani Liberty

RSUP Dr. Mohammad Hoesin Palembang, Indonesia

1,6

Universitas Sriwijaya, Palembang, Indonesia

2,3,5

Universitas Indonesia, Depok, Indonesia

Email: dokterdahlanspb@gmail.com

ABSTRACT

Keywords:

Vitamin D; Diabetes

Mellitus; Diabetic Foot

Ulcers

Vitamin D plays a role in the healing process of diabetic foot ulcers

(DFU); it can improve the immune system, regulate inflammation

function, and regulate growth factors in diabetes mellitus (DM). The

immunomodulatory effects of vitamin D include reduced production

of IL-2, IL-6, and TNF-alpha and increased production of IL-10. It

also increases the activity of antimicrobial peptides (AMP) such as

cathelicidin, and it promotes the differentiation of monocytes into

macrophages, phagocytosis, and the production of lysosomal

enzymes. Furthermore, vitamin D stimulates growth factors

including vascular endothelial growth factor (VEGF) and

transforming growth factor beta (TGF-β). In this study, the incidence

of DM and DFU in DM patients at RSUP Dr. Mohammad Hoesin

Palembang will be compared to serum vitamin D levels. This

research uses quantitative methods with an analytical observational

design. The Mean vitamin D serum level was 11,727 ng/mL, and

there was a significant association between serum vitamin D

deficiency and DFU (p-value; 0.036 < 0.05). There was a significant

association between serum vitamin D deficiency and DFU

occurrence (p-value; 0.036 < 0.05) in Mohammad Hoesin General

Hospital Palembang. Based on the results of this study, we proposed

that patients with diabetic foot ulcers should have their serum

vitamin D levels checked, and that vitamin D should be given to them

as part of their therapy.

Coresponden Author: Kemas Dahlan

Email: [email protected]

Artikel dengan akses terbuka dibawah lisensi

Introduction

One chronic consequence of diabetes mellitus (DM) is diabetic foot ulcers (DFU). The

prevalence rate of DFU in the DM population is quite high, about 4-15% and (Harrisa et al., 2020;

Ji et al., 2021; Yunir et al., 2022). The immune system and growth factors, which are crucial to

the healing of wounds, perform less well in people with diabetes. In hyperglycemic conditions,

proinflammatory mediators increase, leading to chronic inflammation and delayed wound healing

time in DM patients (Cimmino et al., 2013). As an inflammatory marker, fibrinogen promotes the

expression of some protease enzymes such as matrix metalloproteinases-9 (MMP-9) (Giatsidis et

al., 2018).

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DFU patients had higher blood sedimentation rate (ESR) and C-reactive protein (CRP)

levels. Elevation of CRP and ESR in DFU can be used as indicators of wound severity (Muller et

al., 2008). The higher the CRP or ESR of DFU patients, the worse the wound. Defense systems

are unable to create an initial response to damage as a result of decreased immune function,

growth factor, and inflammatory system activity. Formation of granulation tissue will be delayed

in DFU (Lobmann et al., 2002).

MMP-9 plays a role in the degradation of the extracellular matrix in the wound-healing

process. TIMP-1 is an inhibitor of several protease enzymes including MMP-9. High levels of

MMP-9 and low TIMP-1 are predictors of obstacles to DFU healing in DM patients (Caley et al.,

2015; López-López et al., 2014; Shin et al., 2019). Based on research conducted by Lopez et al.

(2014), vitamin D3 could regulate MMP gene expression from keratinocyte cells in DFU patients

(Ross et al., 2011).

In addition to controlling calcium metabolism to preserve bone health, vitamin D can help

diabetic foot ulcers (DFU) heal more quickly because it strengthens the immune system, controls

inflammatory cytokines, and modifies the activity of growth factors, proteolytic enzymes like

MMPs, and their inhibitors in diabetic mellitus (DM) (Dai et al., 2019; Ghezel et al., 2019;

Kamble & Swarnkar, 2019; Kinesya et al., 2023; Ross et al., 2011; Yammine et al., 2020).

By boosting the action of antimicrobial peptides (AMP) like cathelicidin, stimulating

monocyte differentiation into macrophages, enhancing phagocytosis function, and elevating

lysosomal enzyme synthesis, vitamin D modulates the immune system. Vitamin D also affects the

action of the inflammation system for several interleukins and growth factors by reducing the

production of IL-2, IL-6, and TNF-α and increasing the production of IL-10. TGF-β and VEGF

are two examples of growth factors that are activated by vitamin D (Kamble & Swarnkar, 2019).

Numerous MMP genes that are generated by keratinocyte cells are influenced by vitamin

Furthermore, increased blood vitamin D levels have been demonstrated in recent research to

upregulate MMP-1 expression, which is considered a trustworthy marker of DFU wound healing

8, 10

Sunlight's ultraviolet B rays cause the skin to spontaneously create the prohormone vitamin

D. The activation of vitamin D's effect in the skin is attributed to vitamin D receptors (VDR) in

the skin. The relationship between vitamin D and VDR affects the control of basal cell

keratinocyte growth, which acts as a physical barrier. Vitamin D also helps to regulate cell

differentiation in the skin, which in turn helps to synthesise keratin, involucrin, transglutaminase,

loricrin, and filaggrin (Tiwari et al., 2014).

By affecting the function of the Matrix Metalloproteinase (MMPs) enzymes and the activity

of the Tissue Inhibitor Matrix Metalloproteinase (TIMP), vitamin D also plays a part in the

proteolysis of the extracellular matrix (ECM), which is generated during the remodeling phase of

DFU wound healing. In DM patients, there are high glucose levels in blood serum; this condition

increases macrophage infiltration, increasing TNF-α in the wound. Increased levels of TNF-α

cause more expression of MMP produced by keratinocyte cells and delay wound healing in DFU

patients, as in invitro research conducted by Huang et al. (2019), Elevated glucose levels trigger

M-1 macrophage polarization, which hinders keratinocyte migration through TNF-α. This is a

crucial mechanism that postpones the healing of diabetic wounds.

For DFU among other

disorders, vitamin D supplementation treatment is an option (Dadaei et al., 2015; Holick et al.,

2011).

A level of vitamin D less than 50 nmol/mL (<20 ng/mL) is considered a deficiency of

vitamin D. Serum Vitamin D level more than 50 nmol/L (20 ng/mL) is recommended. In healthy

Jurnal Sehat Indonesia: Vol. 7, No. 1, Januari 2024 | 127

people, daily requirement for vitamin D is 15 mcg (600 IU) (Masood et al., 2015; Rastogi et al.,

2022).

The Endocrine Society states that people need a daily vitamin D supplement of at least

37.5 to 50 mcg (1,500–2,000 IU) in order to maintain blood 25(OH)D levels above 75 nmol/L (30

ng/mL). High-dose vitamin D is more effective in promoting wound healing in DFU

(Marcinowska-Suchowierska et al., 2018; Rastogi et al., 2022).

Based on other studies, it has also been proven that low levels of Vitamin D3 have a close

relationship with the occurrence of LKD due to prolonged inflammation and infection processes

28–30. Studies such as the Randomized Double-blinded Clinical Trial by Halschou-Jensen et al.

in Denmark in 2021 and the study by Razzaghi et al. in Iran in 2017 have demonstrated that

administering additional high-dose vitamin D3 therapy to patients with LKD improves the wound

healing process more than administering low doses.

Further research is required to determine the relationship between serum vitamin D levels

and the incidence of diabetes mellitus and DFU, as there is still a dearth of information in

Indonesia, particularly in South Sumatra, regarding vitamin D levels and the degree of DFU and

the high risk of disability due to DFU.

Research Methods

This study used quantitative methods with an analytical observational design to determine

the relationship between serum vitamin D levels in DM patients with DFU. The research was

conducted at the Mohammad Hoesin Palembang General Hospital (RSMH) from January to

September 2023. The study population included all patients at RSMH who underwent blood

sampling to examine serum vitamin D levels. Retrieving, inputting, and collecting data were

carried out using medical record data stored in e-Medical Records (EMR). The data collection

period that satisfied the inclusion and exclusion criteria was used for data collection. Data

recorded included the subject's identity, serum vitamin D levels, current blood sugar values, and

whether the patient had diabetes mellitus with diabetic foot ulcers (DFU) or not.

Before analyzing research data, determine the data type to be processed based on each

research variable. In each study, the data obtained were converted into ordinal form before

bivariate analysis. All calculations of the results of this research were done using SPSS software.

This research was conducted with approval from the Dr. Mohammad Hoesin General Hospital

Health Research Ethics Committee No. DP.04.03/ D.XVIII.6.11/ ETIK/ 99/ 2023.

Results and Discussion

Result

The connection between blood vitamin D levels and DFU patients at Mohammad Hoesin

General Hospital Palembang was investigated using a retrospective analytical observational

design from January to September 2023. 658 patients satisfied the inclusion criteria.

Table 1 Patient Demographic Characteristics and Health Status

Variable

Gender

Man

Woman

166

492

25.2

74.8

Age

≥ 60 Years

50 – 59 Years

≤ 49 Years

302

275

45.9

41.8

12.3

Jurnal Sehat Indonesia: Vol. 7, No. 1, Januari 2024 | 128

Vitamin D levels

Deficiency

Insufficiency

Sufficient

555

84.3

12.8

2.9

Diabetes Mellitus Status

DM + DFU

Non-DM

111

517

4.6

16.9

78.6

In this study, 658 samples of patients were treated at RSUP Dr. Mohammad Hoesin

Palembang. 166 (25.2%) samples were male and 492 (74.8%) were female. The highest age group

of the sample was in the group aged more than 60 years with 302 (45.9%) samples. In this study,

there were 555 (84.3%) samples who had Vitamin D deficiency, there were 111 (16.9%) samples

suffering from DM, and there were 30 (4.6%) samples with DFU (Table 1).

Table 2 Serum Vitamin D Levels of Patients at RSMH (ng/mL) (n=658)

Mean

Min

Max

DM + DFU

Non-DM

All Patients

11.727

24.736

22.849

22.660

5.5

4.9

5.1

4.9

23.3

156

151.3

156

DM= Diabetes Mellitus, DFU= Diabetic Foot Ulcer

The average vitamin D level across all patients in this research is 22,66 ng/mL; in the DM

group, it is 24,736 ng/mL; and in patients with DFU (30), the average blood vitamin D level is

around 11,727 ng/mL (Table 2).

Table 3 Association Between Serum Vitamin D Concentration and Diabetes Mellitus

Patients in Mohammad Hoesin Hospital Palembang (n=658)

Variable

Deficiency

Insufficiency

Sufficient

Total

P-

Value

DM + DFU

100%

0,026

81.1%

12.6%

6.3%

111

100%

Non-DM

435

84.1%

13.5%

2.3%

517

100%

Total

555

84,3%

12,8%

2,9%

658

100%

DM= Diabetes Mellitus, DFU= Diabetic Foot Ulcer

The association between each hospital patient's vitamin D level and the Chi-Square test

was examined. The study demonstrated a strong connection (p-value of 0.026) between the

occurrence of diabetes mellitus (DM) in patients at Mohammad Hoesin General Hospital in

Palembang and serum vitamin D deficiency (Table 3).

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Table 4 Association Between Serum Vitamin D Concentration and DFU Patients in

Mohammad Hoesin Hospital Palembang (n=120)

Variable

Deficiency

Insufficiency

Sufficient

Total

P-

Value

DM + DFU

100%

0,036

81.1%

12.6%

6.3%

111

100%

Total

120

85,1%

0,9%

0,5%

141

100%

DM= Diabetes Mellitus, DFU= Diabetic Foot Ulcer

The chi-square test was used to look at the connection between vitamin D levels and

diabetes mellitus with DFU. The Chi-Square test produced a p-value of 0.036 <0.05, indicating a

possible correlation between the frequency of DFU patients in RSMH and the blood vitamin D

level (Table 4).

Discussion

In this study, we analyzed 658 samples. The samples were divided into two groups DM

and Non-DM. The samples consisted of 492 (74.8%) females and 166 (25.2%) males; in this

study, we found females more than males. The largest sample age in the age group is over 60

years, with a total of 302 (45.9%) samples. A complication of DM is more frequently found in

elderly patients because in the elderly group, there is more atherosclerosis of the vessels,

especially in the lower extremity, and the immune system's capacity is declining, along with the

body's resistance to infection and the inflammatory response.

From all of the 658 samples in this study, there were 517 (78.6%) samples without DM,

111 (16.9%) samples with DM, and 30 (4.6%) samples DM with DFU. Out of all the samples, we

discovered that 555 (84.3%) had inadequate levels of vitamin D, 84 (12.8%) had inadequate

levels, and 19 (2.9%) had appropriate levels. Many samples had vitamin D deficiency, both from

patients. Diabetes Mellitus patients and patients who do not suffer from Diabetes Mellitus. It is

well recognized that type 2 diabetic mellitus (T2DM) and vitamin D insufficiency have combined

to become a contemporary epidemic

(Vijay et al., 2023). A growing amount of evidence suggests

that vitamin D deficiency may contribute to the onset and consequences of diabetes. Numerous

studies have shown that a drop in 25(OH)D (25-hydroxy vitamin D) levels is linked to a forty

percent higher risk of developing diabetes, while an increase in 25(OH)D concentration is linked

to a twenty-four percent lower risk of developing diabetes (Bleizgys, 2021).

In this study, all DM patients with DFU (30; 4.6%) have vitamin D deficiency, with an

average serum level of vitamin D 11.727 ng/mL. Samples from DM without DFU group have an

average serum vitamin D level of 24.736 ng/mL. The average value of serum vitamin D levels in

patients who do not suffer from diabetes mellitus is 22.849 ng/mL

We used the Pearson chi-square test to examine the relationship between blood vitamin

D levels and the prevalence of DM. A p-value of 0.026 indicated a significant relationship

between vitamin D levels and the occurrence of diabetes mellitus. According to research by Arafat

et al. (2020), vitamin D deficiency has been associated to poor control and outcomes in T2DM

patients, and it is commonly observed in DFU patients. Furthermore, vitamin D has been shown

by Mousa et al. (2018) to lessen persistent low-grade inflammation in people with type 2 diabetes

(Arafat et al., 2020).

The relationship between blood vitamin D levels and DFU's Diabetes Mellitus status was

examined using the chi-square test. With a p-value of 0.036 (<0.05), the findings indicated a

Jurnal Sehat Indonesia: Vol. 7, No. 1, Januari 2024 | 130

significant relationship between blood vitamin D levels and DM with DFU. Serum vitamin D

levels and DFU with infection have been linked in several studies. For instance, vitamin D

administration has been shown in the research by Karonova et al. (2020) to improve clinical

symptoms and decrease indicators of inflammation in individuals with type 2 diabetes.

Vitamin D plays a role in immune system regulation as well as in the generation of genes

that code for two antimicrobial peptides (AMP) that fight infections and keep the right balance of

skin flora: cathelicidin and β-defensin (Benson et al., 2023).

Vitamin D is associated with the control of infections and immune responses because it

is a critical regulator of the innate immune response to the threat of bacterial infection. This has

been stated in a number of papers. Decreased immune ability against microbial infections and

excessive inflammatory response are the causes of delayed wound healing in DFU patients

(Furtado et al., 2020). In DFU patients, there is a decrease in levels of Antimicrobial Peptides

(AMP) such as cathelicidin (LL-37), an increase in inflammatory cytokines, and excessive biofilm

formation

(Wang et al., 2022).

According to Irma Gonzalez-Curiel et al., patients with DFU showed reduced

antimicrobial peptides (AMP) levels in the lesion region, which may have impeded the healing

process of their wounds. It showed the potential for vitamin D as supplementation therapy in

treating DFU (Afonso et al., 2021; Gonzalez-Curiel et al., 2014; Mendoza-Marí et al., 2022;

Miranda et al., 2023).

Several other studies found that patients with DM and DFU tended to have low serum

vitamin D levels (Mozaffari-Khosravi et al., 2016; Wang et al., 2022). Thus, it is postulated that

in individuals with diabetes mellitus and DFU, persistent inflammation and infections that are

hard to cure are linked to vitamin D insufficiency

(Lin et al., 2023; Y. Tang et al., 2023). The use

of vitamin D can be considered as an additional therapy for DFU to reduce infection (Macido,

2018; W. Tang et al., 2022).

According to Dai et al. (2019), there is a strong correlation between severe vitamin D

deficiency and a high incidence of diabetic foot ulcers, as well as a large drop in vitamin D levels

in diabetic foot ulcers. According to Zubair et al. (2013), low levels of 25(OH)D are correlated

with the ulcer's grade and have a major influence in the etiology of foot ulcers. According to

Tiwari et al. (2014), patients with diabetes who also had ulcer infection had substantially lower

25(OH)D levels.

Conclusion

The average vitamin D level in 658 samples was 11.727 ng/mL. Of them, 492 (74.8%)

were female, 302 (45.9%) were over 60, 555 (84.3%) had vitamin D insufficiency, 120 (85.1%)

had DM, and sample DM had DFU 30 (100%). Every patient in the study had significant

associations between their serum vitamin D levels and diabetes mellitus (p-value of 0.026 < 0.05)

and between their serum vitamin D levels and DFU (p-value of 0.036 < 0.05). This suggests that

individuals with Diabetes Mellitus, both those with and those without DFU, have low blood levels

of Vitamin D.

Our research led us to conclude that, in order to effectively treat individuals with diabetic

foot ulcers, vitamin D must be given and blood vitamin D levels must be monitored.

Jurnal Sehat Indonesia: Vol. 7, No. 1, Januari 2024 | 131

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