Download diabetic foot infections

INTRODUCTION

Deficiency of vitamin D is currently a major global health problem, in both
adults and children.

This problem is more prevalent in the northern part of India, with many studies
revealing a high prevalence of vitamin D deficiency (VDD) in otherwise normal
children and adolescents.

An association between diabetes mellitus and vitamin D metabolism has been
suggested by high prevalence of VDD in children with type 1 diabetes mellitus
(T1DM).

Cytokine production and lymphocyte proliferation, in susceptible persons, has
been hypothesized to be reduced by immunomodulatory actions of vitamin D,
thereby preventing destruction of beta-cells and subsequent development of
T1DM.
Daga RA, et al. Arq Bras Endocrinol Metabol. 2012;56(7):423-8.
INTRODUCTION

In studies related to supplementation of vitamin D during early childhood, it
has been found that vitamin D can prevent T1DM.1

The literature is also inclusive of suggestions about association of VDD and
the incidence of type 2 diabetes mellitus (T2DM), with low intake of total
vitamin D being associated with an increased risk of T2DM.1

Vitamin D deficiency in diabetic patients leads to immune cell dysfunction,
beta-cell damage and impaired production of insulin.2

Vitamin D deficiency, in addition to hyperglycaemia, has also been linked to
an altered immune system of patients with diabetes, making them
susceptible to foot infection and unfavourable prognosis.2
1.
2.
Daga RA, et al. Arq Bras Endocrinol Metabol. 2012;56(7):423-8.
Tiwari S, et al. British Journal of Nutrition.2013;109:99–102.
DIABETIC FOOT INFECTIONS: INDIAN PERSPECTIVE

In India, about 65.1 million people have been reported to be living with
diabetes.1

Foot ulcers are most common among diabetes-related complications, and
affect approximately 15% of diabetic patients during their lifetime.2

The main reasons for this high prevalence are several social and cultural
practices like walking barefoot, improper diabetes care and education
among masses and deprived socioeconomic conditions.2

Diabetic foot ulceration (DFU) has been associated with significant social
impact as patients suffer from stigma, social isolation, loss of a meaningful
role in society and unemployment.2
1.
2.
International Diabetes Federation. IDF Diabetes Atlas. 6th edn. Brussels, Belgium: International Diabetes Federation, 2013. Available from:
http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf. As accessed on March 9, 2015.
Shahi SK, et al. The Journal of Diabetic Foot Complications. 2012;4(3):83-91.
DIABETIC FOOT INFECTIONS: INDIAN PERSPECTIVE

In many previously published studies, the prevalence of DFUs has been
reported to be in the range of 5.3% ̶ 10.5% among diabetic patients.

It was observed by researchers that 71.13% of males and 28.86% of
females with a mean age of 55.25 years had DFUs.

Effective methods to prevent the devastating diabetic foot complications
include regular evaluations and early treatment.

The critical elements in the reduction of risk for complications of diabetes
include optimum levels of haemoglobin, blood pressure and lipid levels.
Shahi SK, et al. The Journal of Diabetic Foot Complications. 2012;4(3):83-91.
DIABETIC FOOT INFECTIONS: INDIAN PERSPECTIVE

The prevalence of diabetes has increased from around 1.9% to 3–12% in
India, as reported by studies conducted in rural areas of Kerala, Maharashtra
and Andhra Pradesh.

A recent study revealed that diabetic patients hailing from rural areas are
more prone to foot ulcers (70.10%) than those living in urban areas (29.90%)
(Table 1).

This could be due to the fact that rural Indians often sleep in huts, farm
houses or outdoors on the farm, and are prone to rodent bites, especially to
the feet that can lead to chronic ulcers.

Routine examination of 678 type 2 diabetic patients showed that diabetic foot
ulcers were present in 97 (14.30%) subjects.
Shahi SK, et al. The Journal of Diabetic Foot Complications. 2012;4(3):83-91.
DIABETIC FOOT INFECTIONS: INDIAN PERSPECTIVE
Shahi SK, et al. The Journal of Diabetic Foot Complications. 2012;4(3):83-91.
DIABETIC FOOT INFECTIONS: INDIAN PERSPECTIVE

A study by Viswanathan V et al., showed that:

Greater prevalence of foot infection was reported among rural than urban
patients (26% vs. 34%, P=0.0001), along with higher rates of amputation
among rural than urban patients (3% vs. 8%, P<0.05).

Foot infection recurrence rates were higher among rural than urban
patients (8% vs. 13%, P=0.003), with more number of rural patients
requiring surgical intervention as compared to urban patients (6% vs.
10%, P=0.04) [Table 2].
Viswanathan V, et al. Diabetes Care. 2006;29(3):701-3.
VITAMIN D DEFICIENCY IN PATIENTS WITH DIABETIC FOOT
INFECTION/ULCER

Vitamin D has a significant role in calcium and bone metabolism as well as in
immunomodulation.

The activated vitamin D receptors are found on pancreatic beta-cells and
immune cells.

Immunological defects in addition to neuropathy and vascular abnormality
are responsible for foot infections, accounting for 20% of hospitalisation of
diabetic patients annually.

Deficiency of vitamin D, as shown by many published studies, leads to
immune cell dysfunction, beta-cell damage and impaired insulin production.

Vitamin D deficiency, in addition to hyperglycaemia, could also be associated
with an altered immune system of patients with diabetes, making them
susceptible to foot infection and adverse prognosis.
Tiwari S, et al. British Journal of Nutrition.2013;109:99–102.
VITAMIN D DEFICIENCY IN PATIENTS WITH DIABETIC FOOT
INFECTION/ULCER

A recent study conducted by Tiwari S et al., showed that:

Vitamin D deficiency is more common and severe in patients with
diabetic foot infections.

25-hydroxyvitamin D [25(OH)D] was significantly lower in patients with
diabetic foot infection than in those without infection [40.25 (SD 38.35)
vs. 50.75 (SD 33.00); P<0.001].

Prevalence of vitamin D inadequacy at the three study cut-offs chosen,
i.e., <75, <50 and <25 nmol/L was 87.4%, 70% and 45.6%, respectively.

Risk of having severe vitamin D deficiency (25(OH)D <25 nmol/L) was
much higher in patients with diabetic foot infection (Table 3).

In cases of diabetic foot infections, the prevalence of severe
vitamin D deficiency (<25 nmol/L) was remarkably higher (46.4%) than
in controls (17.6%).
Tiwari S, et al. British Journal of Nutrition 2013;109:99–102.
VITAMIN D DEFICIENCY IN PATIENTS WITH DIABETIC FOOT
INFECTION/ULCER

Vitamin D deficiency is more prevalent and severe in diabetic foot infection.

In diabetics, vitamin D level, observed to influence calcium homeostasis is
possibly lower and thus enhances susceptibility to infection.

Vitamin D deficiency may be a possible risk factor for diabetic foot
infections and this suggests the need for vitamin D supplementation in
such patients to prevent or to adjuvant the antibiotic therapy for better
control of infection.
Zubair M, et al. Diabetes Metab Syndr. 2013;7(3):148-53.
VITAMIN D DEFICIENCY IN PATIENTS WITH DIABETIC FOOT
INFECTION/ULCER

A study by Zubair M et al., showed:

Diabetic foot ulcer subjects were reported to have lower median plasma
level of 25(OH)D [6.3 (4.2–11.1) vs. 28.0 (21.4–37.0)] ng/mL after
adjusting the age and BMI.

Lower vitamin D levels, regardless of the low levels of 25(OH)D in cases
and controls, were associated with neuropathy, sex (female), duration of
ulcer healing and smoking status, and were independent of confounding
factors, including BMI (kg/m2), HbA1c (%), hypertension, nephropathy,
foot ulcer, retinopathy, coronary artery disease, peripheral artery
disease, HDL-C (mg/dL) and LDL-C (mg/dL).
Zubair M, et al. Diabetes Metab Syndr. 2013;7(3):148-53.
VITAMIN D DEFICIENCY IN PATIENTS WITH DIABETIC FOOT
INFECTION/ULCER

Diabetic patients with foot ulcer in comparison with diabetics without
diabetic foot have low circulating levels of serum 25(OH)D (Table 4).

Prevalence of severe 25(OH)D deficiency was significantly higher in cases
than in controls.

Diabetic patients with foot infections reflected their poor immune status
compared to patients with diabetes.

An important role is played by lower serum 25(OH)D in the pathogenesis
of foot ulceration, independent of BMI, sex and age.

Specific and non-random lower levels of serum 25(OH)D are seen in
patients with foot ulcers.
Zubair M, et al. Diabetes Metab Syndr. 2013;7(3):148-53.
ROLE OF VITAMIN D DEFICIENCY IN PATHOGENESIS OF
DIABETIC FOOT INFECTIONS ‒ INFLAMMATORY CYTOKINES

Vitamin D, in addition to its endocrine role, has been shown to have potent
immunomodulatory activity.

Deficiency of vitamin D is common in normal population as well as
diabetics, and has been shown to be associated with an increased
incidence of infections directly or indirectly.

The major mediators of the host’s response to infection are cytokines and
thus play an important role in the differentiation of macrophages,
eradication of infection and progression of wound-healing process.
Zubair M, et al. Diabetes Metab Syndr. 2013;7(3):148-53.
ROLE OF VITAMIN D DEFICIENCY IN PATHOGENESIS OF
DIABETIC FOOT INFECTIONS ‒ INFLAMMATORY CYTOKINES

Cytokines are regulated by counter-regulatory mechanisms including
production of anti-inflammatory cytokines such as IL-10 to avert a
hyperinflammatory state necessary for infection control and effective wound
healing.

Wound healing abnormalities in diabetics result from decreased growth
factor production, angiogenic response and macrophage function, and
impaired cytokine production.

Basic abnormality of hyperglycaemia in diabetes also disrupts the normal
process of cytokine production. All these factors combined further lead to
the development of a chronic wound where persistent and elevated
inflammatory cell activities are considered to be critical.
Tiwari S, et al. Br J Nutr. 2014;112(12):1938-43.
ROLE OF VITAMIN D DEFICIENCY IN PATHOGENESIS OF
DIABETIC FOOT INFECTIONS ‒ INFLAMMATORY CYTOKINES

Vitamin D deficiency in addition to hyperglycaemia in diabetes has been
proposed as a risk factor for diabetic foot infection probably via immune
dysregulation.

A study by Tiwari S et al. (2014) aimed to evaluate the circulating
concentrations of IL-1b, TNF-, IFN- and IL-6 in patients with diabetic foot
infection and assess the influence of vitamin D deficiency on the abovementioned cytokines and the following results were noted:
o
The study recognised vitamin D as a potent immunomodulator and found
that its deficiency is common in different population groups including
patients with diabetic foot infection.
o
Severe vitamin D deficiency was found to be associated with elevated
inflammatory cytokine concentrations in diabetic patients, particularly in
those with foot infection.
Tiwari S, et al. Br J Nutr. 2014;112(12):1938-43.
ROLE OF VITAMIN D DEFICIENCY IN PATHOGENESIS OF
DIABETIC FOOT INFECTIONS ‒ INFLAMMATORY CYTOKINES

Severe vitamin D deficiency (25(OH)D concentration <25 nmol/L) was more
common in DFI cases than in controls (48.2% vs. 20.5%).

Although age, duration of diabetes, HbA1C concentration and BMI were
similar, cases had significantly higher concentrations of IL-6
(P≤0.001), IL-1 (P≤0.02) and TNF- (P≤0.006) than controls.

A significant difference in IL-1 (P≤0.007) and IL-6 (P≤0.02) concentrations
was observed in patients with severe 25(OH)D deficiency compared with
patients with 25(OH)D concentration >25 nmol/L, and this difference was
remarkable for TNF- (Figure 1).
Tiwari S, et al. Br J Nutr. 2014;112(12):1938-43.
ROLE OF VITAMIN D DEFICIENCY IN PATHOGENESIS OF
DIABETIC FOOT INFECTIONS ‒ VASCULAR CALCIFICATION

Vascular calcification (VC) is a complex biomineralisation process
resembling osteogenesis. VC has long thought to be the result of passive
degeneration.

In progression of vasculopathy in diabetes mellitus (DM), VC is an important
development and contributes to significantly high prevalence of peripheral
vascular disease and lower extremity amputation in these subjects.

Other manifestations of cardiovascular diseases like hypertension, coronary
insufficiency and increased mortality in patients with DM are also associated
with VC.

Studies indicated that experimentally higher 25(OH)D levels are associated
with increased VC.
Swain J, et al. Indian Journal of Endocrinology and Metabolism. 2012;16(Suppl 2):S450-S452.
ROLE OF VITAMIN D DEFICIENCY IN PATHOGENESIS OF
DIABETIC FOOT INFECTIONS ‒ VASCULAR CALCIFICATION

A study by Swain J et al., showed:

Vascular calcification was present in 42% of diabetic patients

Significant difference in the mean (±SD) levels of vitamin D, HbA1c, and
eGFR in VC +ve compared to VC –ve patients

Severe vitamin D deficiency was more common in VC +ve (51.6%)
compared to in VC –ve (18.6%) patients

The risk of VC was significantly higher (RR=2.4, P<0.05, 95% CI=0.058–
2.88) in patients with vitamin D<10 ng/mL compared to others, as shown
by sub-group analysis

High prevalence of peripheral VC in diabetic foot patients with relatively
preserved renal function was observed

There is a possibility of its contribution in development of VC in diabetic
foot as suggested by the higher incidence of severe vitamin D deficiency
in VC +ve diabetic foot patients.
Swain J, et al. Indian Journal of Endocrinology and Metabolism. 2012;16(Suppl 2):S450-S452.
VITAMIN D STATUS IN PATIENTS WITH DIABETIC FOOT
INFECTIONS AND POTENTIAL ROLE OF ITS SUPPLEMENTATION

Vitamin D deficiency and its association with type 1 diabetes (T1D) is
widely reported.

Importantly, supplementation with vitamin D has been shown to improve
and even prevent T1D in human models.

In some studies, the definite role of vitamin D in pancreatic beta-cell
function and insulin sensitivity too has been shown.

On the other hand, there is ambiguity regarding the association between
vitamin D and type 2 diabetes (T2D) in humans, with several studies
revealing a link between vitamin D receptor (VDR) gene polymorphism
and T2D.
Laway BA, et al. Indian Journal of Endocrinology and Metabolism. 2014;18(5):726-730.
VITAMIN D STATUS IN PATIENTS WITH DIABETIC FOOT
INFECTIONS AND POTENTIAL ROLE OF ITS SUPPLEMENTATION

An inverse association between vitamin D status and T2D has been
shown by a large number of cross sectional and longitudinal studies.

Clinical data favours supplementation of vitamin D in deficient patients to
rectify the abnormalities of impaired insulin secretion and glucose
intolerance.

Vitamin D supplementation has reported inconsistent results in presence
of normal vitamin D status in patients with T2D or impaired glucose
tolerance (IGT).

Some Indian studies have also reported hypovitaminosis D in a significant
number of people with T1D and in youth-onset T2D.
Laway BA, et al. Indian Journal of Endocrinology and Metabolism. 2014;18(5):726-730.
DIABETES AND VITAMIN D: CLINICAL EVIDENCE

Prospective case control study ‒ North India (102 new-onset T2D patients
vs. 102 healthy controls)
ʘ
Data analysis showed that serum level of 25(OH)D had a significant
negative correlation with FPG and HbA1c and positive correlation with
24-hour dietary calcium intake.
ʘ
81% of T2D patients had VDD or insufficient vitamin D, taking a
25(OH)D cut-off of 30 ng/mL, while around 67% of healthy control
subjects also had either deficiency or insufficiency.
ʘ
In 16.2% of patients and 2.5% of control subjects severe VDD (25(OH)D
<5 ng/mL) was observed
ʘ
The study researchers observed that a significantly lower level of
25(OH)D is present in patients with diabetes compared to healthy
controls.
Laway BA, et al. Indian Journal of Endocrinology and Metabolism. 2014;18(5):726-730.
DIABETES AND VITAMIN D: CLINICAL EVIDENCE

In a Korean study, HbA1c was reported to be high in T2D patients as
compared to controls, and this study showed significant correlation of
diabetes with 25(OH)D.

Significantly higher intake of dietary calcium was reported in healthy
control subjects as compared to T2D patients.

In one Italian study, diabetic patients were shown to have lower dietary
calcium intake as compared to controls.

Vitamin D and calcium supplementation can be helpful in diabetic patients
as well as its complications like diabetic foot infections.
Laway BA, et al. Indian Journal of Endocrinology and Metabolism. 2014;18(5):726-730.
IMPORTANCE OF VITAMIN D SUPPLEMENTATION IN DIABETIC
FOOT INFECTIONS

Zubair M et al., in recent study showed that diabetic patients with foot ulcer in
comparison with patients without diabetic foot have an low circulating levels
of serum 25(OH)D.

Severe 25(OH)D deficiency prevalence was remarkably higher in cases than
in controls.

Diabetics patients with foot infection reflect their poor immune status
compared to diabetic patients without foot infection.

Diabetic foot ulcer severity based on University of Texas was associated with
circulating levels of serum 25(OH)D.
Zubair M, et al. Diabetes Metab Syndr. 2013;7(3):148-53.
IMPORTANCE OF VITAMIN D SUPPLEMENTATION IN DIABETIC
FOOT INFECTIONS

Vitamin D has been linked with several other immunological changes that
are associated with increased susceptibility towards infection.

Vitamin D has also been known to stimulate phagocytosis and killing of
bacteria by macrophages and is a potent suppressor of interferon-
mediated macrophage activation.

Vitamin D deficiency in diabetic foot patients, in addition to
hyperglycaemia, might also increase the risk of infection by further
depleting the immune cells’ response against infection.
Zubair M, et al. Diabetes Metab Syndr. 2013;7(3):148-53.
IMPORTANCE OF VITAMIN D SUPPLEMENTATION IN DIABETIC
FOOT INFECTIONS

Vitamin D supplementation has been shown to delay the onset of diabetes.

An increased risk of pressure ulcers exists with malnutrition and vitamin D
deficiency being highly probable factors in ulcer development.
Supplementation with vitamin D can help prevent DFU.

Low circulating levels of vitamin D might actually be one of the causes for
development of DFU in diabetic patients (Table 5).

The research in last few decades has already shown that patients with
diabetes have become vitamin D deficient over a period of time.

Vitamin D supplementation is generally given as an add-on therapy in order
to avoid any complications.
Zubair M, et al. Diabetes Metab Syndr. 2013;7(3):148-53.
IMPORTANCE OF VITAMIN D SUPPLEMENTATION IN DIABETIC
FOOT INFECTIONS

Vitamin D may influence insulin sensitivity and secretion via its effects on
intracellular calcium and aid in treating diabetes patients.

Improvement in insulin secretion and increase in the amount of glucose
entering the tissues (including skeletal muscles) has been reported with
supplementation of vitamin D to diabetic patients.

Vitamin D supplementation also helps to fight complications like DFU that
occur due to prolonged exposure to high glucose levels, which causes
damage to the nerves, resulting in peripheral neuropathy and ultimately
DFU.
Zubair M, et al. Diabetes Metab Syndr. 2013;7(3):148-53.
IMPORTANCE OF VITAMIN D SUPPLEMENTATION IN DIABETIC
FOOT INFECTIONS
Zubair M, et al. Diabetes Metab Syndr. 2013;7(3):148-53.
VITAMIN D SUPPLEMENTATION: POSITIVE EFFECT ON
ULCER HEALING

Supplementation with vitamin D has been observed to have a role in
improving and even preventing type1 DM.

Vitamin D binds to its hormone receptor (VDR) in skin, increasing the
secretion of cathelecidin.

Vitamin D has become an important pharmacologic agent in DFU due to the
importance of cathelecidin during wound healing.

Studies have shown a good effect of vitamin D3 supplementation on healing
of DFU.
Rahman NMA, et al. IJAPBC. 2013;2(4):600-604
VITAMIN D SUPPLEMENTATION: POSITIVE EFFECT ON
ULCER HEALING

In a recent study in Iraq, vitamin D3 and zinc were administered to separate
groups to evaluate their effectiveness in accelerating healing process in
DFU in diabetic patients in comparison with placebo administering group.

The study researchers observed significant effect of both zinc and
vitamin D3 on percentage of healing (Table 6).
Rahman NMA, et al. IJAPBC. 2013;2(4):600-604
SUMMARY

Around 15% of diabetics in India have diabetic foot ulcers, with most of them
amenable to treatment with proper care.

Vitamin D deficiency is more prevalent and severe in patients with diabetic foot
infection. Vitamin D levels in diabetics, observed to influence calcium
homeostasis, is possibly lower and thus enhances susceptibility to infection.

Severe vitamin D deficiency is associated with elevated inflammatory cytokine
concentrations in diabetic patients, particularly in those with foot infection.

Supplementation of vitamin D in diabetic patients helps fight complications like
DFU that basically arise due to prolonged exposure to higher than normal
glucose levels which damage the nerves, causing peripheral neuropathy and
ultimately resulting in DFU.

Vitamin D becomes an important pharmacologic agent in DFU and
supplementation of vitamin D has a good effect on healing of DFU.

Vitamin D deficiency should be recognised as a possible risk factor for diabetic
foot infections. There is a need for vitamin D supplementation in such patients
to prevent or to adjuvant the antibiotic therapy for control of infection.
Thank you