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Status of vitamin D3 level and its co-relation with the glycaemic status in Indian population

Diabetes and vitamin D deficiency are global epidemics. Presently, around 285 million people have diabetes and this number is expected to reach 438 million by the year 2030. Given the burden of diabetes and its complications, researchers have long been exploring the role of potentially modifiable factors to identify at-risk individuals prior to diagnosis. Our focus has now shifted to prediabetes, which is an intermediate form of dysglycemia on a spectrum ranging from normal to overt diabetes. As per American Diabetes Association, a fasting glucose of 100 <126 mg/dL, a 2-hour plasma glucose of 140 <200 mg/dL after a 75-g OGT test, or HbA1c 5.7% (39mmol/mol) to <6.5% (48mmol/mol) defines prediabetes. Diabetes mellitus is diagnosed when fasting glucose >126mg/dL, 2-hour plasma glucose ≥200 mg/dL or HbA1c ≥6.5% (48mmol/mol). Fasting hyperglycemia indicates an increasing risk to development of cardiovascular disease, metabolic syndrome and mortality.


INTRODUCTION
Diabetes and vitamin D deficiency are global epidemics. Presently, around 285 million people have diabetes and this number is expected to reach 438 million by the year 2030. 1 Given the burden of diabetes and its complications, researchers have long been exploring the role of potentially modifiable factors to identify at-risk individuals prior to diagnosis. Our focus has now shifted to prediabetes, which is an intermediate form of dysglycemia on a spectrum ranging from normal to overt diabetes. 2 As per American Diabetes Association, a fasting glucose of 100 -<126 mg/dL, a 2-hour plasma glucose of 140 -<200 mg/dL after a 75-g OGT test, or HbA1c 5.7% (39mmol/mol) to <6.5% (48mmol/mol) defines prediabetes. Diabetes mellitus is diagnosed when fasting glucose >126mg/dL, 2-hour plasma glucose ≥200 mg/dL or HbA1c ≥6.5% (48mmol/mol). 2 Fasting hyperglycemia indicates an increasing risk to development of cardiovascular disease, metabolic syndrome and mortality. 2 Despite the advances in the diagnosis and management of diabetes, achieving normoglycemia or optimal glycemic control is still considered challenging. 4 This is because care of prediabetes and type 2 diabetes warrants intense life-style adaptations, polypharmacy and insulin centered regimens.
Conventional oral anti-diabetic medications are associated with hypoglycemia. Insulin treatment has been linked to poor compliance, weight gain and possibly adverse cardiovascular outcomes. In addition, progressive beta-cell dysfunction and insulin resistance can make anti-diabetic agents less effective. 5 Moreover, newer antidiabetic drugs such as incretin analogs and ultra-short acting insulin analogs are expensive and hence many patients in the developing world cannot afford these medications.
Vitamin D, a fat-soluble vitamin cum hormone, is synthesized in response to sunlight. It is a 9, 10-seco steroid and the most common forms in humans are vitamin D3 (cholecalciferol) and Vitamin D2 (ergocalciferol). Vitamin D undergoes two metabolic conversions, 25-hydroxylation in the liver and 1-αhydroxylation in the kidney. The active form, 1-α-25-(OH)2D, binds to the vitamin D receptor (VDR) to modulate gene transcription and regulate mineral-ion homeostasis.
Vitamin D plays several roles in the body influencing bone health as well as serum calcium and phosphate levels. Furthermore, vitamin D may modify cell proliferation, differentiation, apoptosis and immune function. Studies have shown that it may be useful as adjunctive treatment for tuberculosis, psoriasis, and multiple sclerosis or for the prevention of certain cancers. Vitamin D insufficiency may increase the risk of Type 1 diabetes mellitus, cardiovascular disease (insulin resistance, hypertension, or low-grade inflammation), or brain dysfunction (e.g., depression). 6 Many large studies have revealed a higher likelihood of progression of prediabetes to diabetes among Vitamin D deficient subjects. 7,8 Recent observational data reports a beneficial effect of vitamin D on preventing the onset of diabetes. 9 But the potential benefits of vitamin D supplementation on glycemic control are still debated.

METHODS
The present study was a cross-sectional observational study done on randomly selected adult patients from medicine department, GSVM MC, Kanpur from January 2015 to September 2016. Participants were categorized into control, pre-diabetic group and diabetic group. Patients with acute illnesses, pancreatic disease, hepatic disease, renal disease, bone diseases, malignancy, pregnant females, familial hyperlipidemia, and those who were taking medication that altered vitamin D metabolism were excluded from the study.
Detailed history and physical examination including fundoscopy were done. Venous sample for fasting and post prandial blood sugar, serum HbA1c, Serum vitamin D (measured by chemiluminence method by Architect i1000SR Machine {Abbott Laboratories, Abbott park, IL 60064 USA}) and fasting lipid profile were collected. Serum vitamin D3 values were categorized as: <20 ng/mL: deficient, 20-30 ng/mL: insufficient, 30-100 ng/mL: sufficient, >100 ng/mL: toxic. 6 Serum uric acid, serum calcium, CRP, complete blood count, serum creatinine, liver function test was measured by automated analyzers. USG abdomen was done wherever feasible and indicated.
The statistical co-relation between vitamin D levels and glycosylated hemoglobin has been done using Pearson chi-square test. They share significant inverse co-relation as affirmed by the 'p' value <0.003 ( Figure 1 and Table  8).

DISCUSSION
The present study was a cross-sectional observational study with an aim to find out serum vitamin levels in normal subjects, prediabetics and in diabetes patients with good and poor glycemic status. Among controls we found majority of them had normal levels of serum vitamin D3 (37.9%) followed by 32.4% of controls with deficient levels and 29.7% of controls with insufficient vitamin D3 levels. No subject was found to have toxic levels of vitamin D3 levels. In a study by Gupta et al, vitamin D deficiency is no less than an epidemic in India, with an overwhelming prevalence of 70-100%. They identified that in India, widely consumed food items such as dairy products are fortified with vitamin D. Indian socio-religious and cultural practices limit sun exposure, thereby negating potential benefits of plentiful sunshine. 10 In the present study, mean value of vitamin D3 among controls was found to be 26.53±11.99 ng/ml. This is a worrisome scenario as it implies that Indians in general do not have sufficient levels of vitamin D. According to a study, Harinarayan et 13 The above-mentioned study did not take into consideration the glycemic status of the diabetics.
The mean value of vitamin D3 for diabetics with good glycemic control was 21.93±9.00 whereas with poor glycemic control was 13.09±7.34. This could be a subtle indicator that higher vitamin D3 levels have a role in maintaining good glycemic status. Similar findings are seen in a study by Bayani MA et al. Out of 120 diabetics and 120 control group, mean concentration of vit D in the case group was 18.7±10.2 and in the control group was 24.6±13.5 ng/dl (p=0.002). In diabetic patients vit D was deficient in 77 (64.2%), insufficient in 30 (25%) and sufficient in 13 (10.3%) patients. 14 Second objective of the present study was to find out the correlation between Vit D3 Levels and glycated haemoglobin. Statistical evaluation using Pearson chisquare test clearly shows an inverse co-relation between vitamin D levels and glycosylated haemoglobin as affirmed by the 'p' value <0.003. Kostoglou-Athanassiou I et al also found the similar co relation in their study. Glycosylated hemoglobin and 25(OH)D3 levels were measured in 120 diabetes mellitus type 2 patients and 120 controls. 25(OH)D3 levels were lower in the diabetics than in the control group, being 19.26±0.95 ng/ml and 25.49±1.02 ng/ml respectively (p < 0.001, Student's ttest). 25(OH)D3 levels were found to have inverse corelation with HbA1c when the patient and control groups were analysed together (p < 0.001, r (2) = 0.086). 15

CONCLUSION
People with Indian ethnicity have high prevalence of vitamin D3 deficiency/ insufficiency. Only 37.9% healthy controls had vitamin D3 levels above 30 ng/ml, with 26.53±11.99 ng/ml as the mean vitamin D level. Vitamin D3 deficiency was prevalent in 46.3% pre-diabetics, 41.7% diabetics with good glycemic control and 84.2% diabetics with poor glycemic control. HbA1c and serum vitamin D3 share a significant inverse correlation (p<0.003).
The sparse vitamin D3 levels in pre-diabetics and diabetics hint towards its role in the patho-physiology of worsening glycemic status. The present study provides the rationale for conducting interventional trials to evaluate the effect of vit D3 supplementation on glycemic control in Indian population.