INTRODUCTION

2. 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.

3. 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 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.

4. 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 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.

5. 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.

6. 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.

7. DIABETIC FOOT INFECTIONS: INDIAN PERSPECTIVE Shahi SK, et al. The Journal of Diabetic Foot Complications. 2012;4(3):83-91.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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 above-mentioned cytokines and the following results were noted: • 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. • 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. DIABETES AND VITAMIN D: CLINICAL EVIDENCE • Prospective case control study ‒ North India (102 new-onset T2D patients vs. 102 healthy controls) • 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. • 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. • In 16.2% of patients and 2.5% of control subjects severe VDD (25(OH)D <5 ng/mL) was observed • 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. IMPORTANCE OF VITAMIN D SUPPLEMENTATION IN DIABETIC FOOT INFECTIONS Zubair M, et al. Diabetes Metab Syndr. 2013;7(3):148-53.

29. 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

30. 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

31. 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.

32. Thank you