European Journal of Cardiovascular Medicine

Vitamin D, traditionally recognized for its role in calcium and phosphate homeostasis and skeletal health, has emerged as a pleiotropic hormone with significant influence on extra-skeletal functions [1]. Among these, its role in glucose metabolism and insulin sensitivity has attracted considerable attention. Vitamin D receptors (VDRs) are expressed in pancreatic β-cells and peripheral tissues involved in glucose utilization, suggesting a mechanistic link between vitamin D status and glycaemic control. Deficiency of vitamin D has been associated with impaired insulin secretion, increased insulin resistance, and a heightened risk of type 2 diabetes mellitus (T2DM) [2]. Given the rising global burden of diabetes, particularly in low- and middle-income countries, understanding modifiable risk factors such as vitamin D deficiency is of paramount importance.

India is often referred to as the “diabetes capital of the world,” with an estimated 77 million adults living with diabetes as of 2019, projected to rise to over 100 million by 2030. The prevalence of prediabetes and metabolic syndrome is also alarmingly high, reflecting a population at risk of early onset and complications [3]. Parallel to this, vitamin D deficiency is widespread in India, despite abundant sunlight. Studies have reported deficiency rates ranging from 50% to 90% across different age groups and regions. Factors such as darker skin pigmentation, cultural clothing practices, limited outdoor activity, urbanization, and dietary insufficiency contribute to this paradoxical deficiency [4]. The coexistence of two major public health challenges—diabetes and vitamin D deficiency—raises the possibility of a synergistic relationship that may worsen metabolic outcomes in the Indian population.

Several international studies have demonstrated associations between vitamin D deficiency and poor glycaemic control, higher HbA1c levels, and adverse lipid profiles. Interventional trials have shown mixed results, with some reporting improvements in insulin resistance and lipid parameters following vitamin D supplementation, while others found no significant benefit [5, 6]. In some studies, supplementation was shown to improve insulin resistance and lipid profile, whereas some studies have reported variable outcomes. A few cross-sectional studies have observed higher fasting plasma glucose and HbA1c levels in patients with low vitamin D, but robust evidence remains limited [7-13]. The Institute of Medicine (IOM) guidelines classify serum 25-hydroxyvitamin D (25OHD) levels into sufficient (≥30 ng/ml), risk of inadequacy (12–20 ng/ml), deficiency (<12 ng/ml), and potentially harmful (>50 ng/ml) [14]. Despite these standardized thresholds, the clinical translation of vitamin D status into diabetes management strategies remains underexplored in the Indian context.

While global literature suggests a potential link between vitamin D status and glycaemic control, there is a paucity of well-designed studies from India that specifically address this association. Importantly, there is limited evidence from Bihar and eastern India, where both diabetes prevalence and vitamin D deficiency are significant but under-researched.

This study seeks to address the research question of whether there is an association between vitamin D levels and glycaemic control in patients with type 2 diabetes mellitus in the Indian population. The central hypothesis proposes that patients with low serum vitamin D levels (<20 ng/ml) will demonstrate significantly higher HbA1c, fasting blood sugar (FBS), postprandial blood sugar (PPBS), and adverse lipid profiles compared to those with sufficient vitamin D levels (≥20 ng/ml). To test this, the primary objective is to compare mean HbA1c levels between cases with low vitamin D and controls with adequate levels, while the secondary objectives are to compare mean FBS and PPBS values, as well as lipid profiles, between the two groups.

This investigation was designed as a cross-sectional study conducted over a period of three months within the Department of General Medicine at a tertiary care teaching hospital in eastern India that caters to a diverse patient population from both urban and rural backgrounds.

Sample Size: 75 cases and 75 controls were taken in our study. With anticipated HbA1c in cases to be 7.5 ± 0.5 and 7.2 in control group, the required sample size required to achieve 95% power with 0.05 alpha is found to be 144 with 72 patients in each group. So, 75 patients were enrolled in each group to manage for any attrition.

Study Population: The study included adult patients above 18 years of age of either gender, diagnosed with T2DM and receiving metformin monotherapy at a daily dose of 1000 mg. Cases were defined as those with serum vitamin D levels <20 ng/ml, while controls comprised T2DM patients on the same treatment regimen, matched for age, gender, diet, and lifestyle, but with serum vitamin D levels ≥20 ng/ml. Patients with chronic kidney disease or other chronic illnesses, those with conditions or medications known to affect calcium homeostasis, as well as pregnant and lactating women, were excluded.

Outcome Measures: The primary outcome measure of this study was the glycated hemoglobin (HbA1c) level, chosen as the most reliable indicator of long-term glycaemic control in patients with type 2 diabetes mellitus. In addition, several secondary outcome measures were evaluated to provide a broader metabolic profile, including fasting blood sugar (FBS), postprandial blood sugar (PPBS), and key lipid parameters such as total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels.

Methodology: Serum Vitamin D levels were assessed with the CLIA method and levels lower than 20 ng/mL were accepted as vitamin D deficiency. Fasting blood sugar levels was determined using glucose-oxidase peroxidase using “Beckman Coulter 700AU (Brea, CA)”. “A Tosoh HLC-723 G8 (Tosoh G8, variant-mode) ion-exchange high-performance liquid chromatography (HPLC) system (Tosoh, Tokyo, Japan)” were used for HbAlc measurements. Fasting plasma, total cholesterol, HDL and LDL cholesterol, and triglyceride concentrations were determined using “spectrophotometry based on Beer-Lambert law by the Beckman Coulter 5800AU machine (Brea, CA).” Blood samples for fasting blood sugar were taken before breakfast and uptake of anti-diabetic drugs.

Statistical Analysis: Data from cases and control were represented in tabular form and analysed using graph-pad version 8.4.3. Normality distribution of continuous data such as HbA1c, FBS, PPBS, and lipid profile was evaluated using Shapiro-Wilk test. Comparison of normally distributed continuous data were done using unpaired t test. Categorical variables like gender were compared using Fisher’s Exact Test. A p-value of less than 0.05 was taken as measure of statistical significance.

Table 1 compares baseline demographic and clinical characteristics between cases (Vitamin D <20 ng/ml) and controls (Vitamin D ≥20 ng/ml). The results show no statistically significant differences between the two groups in terms of age, gender distribution, BMI, or duration of diabetes, as all p-values were greater than 0.05. This suggests that the groups were well-matched in these baseline characteristics, allowing for a more valid comparison of other outcome measures such as glycemic and lipid parameters.

Table 1: Comparison of Baseline Demographic and Clinical Characteristics between Cases (Vit D <20 ng/ml) and Controls (Vit D ≥20 ng/ml)

 *Unpaired t-test, **Fisher’s Exact Test

Table 2 presents a comparison of HbA1c levels between the two groups. The mean HbA1c was significantly higher in the cases (7.29%) compared to the controls (6.97%), with a p-value of 0.0497. This indicates that individuals with Vitamin D deficiency had worse glycemic control, and the difference, though modest, is statistically significant at the 5% level.

Table 2: Comparison of HbA1c between Cases (Vit D <20 ng/ml) and Controls (Vit D ≥20 ng/ml)

Figure 1: Comparison of Proportion of Patients with HbA1c < 7.0% between Cases (Vit D <20 ng/ml) and Controls (Vit D ≥20 ng/ml)

27 (36%) patients had HbA1c less than 7.0% in cases as compared to 39 (52%) in controls (Figure 1).

Table 3: Comparison of Fasting Blood Glucose and Post-Prandial Blood Glucose between Cases (Vit D <20 ng/ml) and Controls (Vit D ≥20 ng/ml)

Table 3 compares fasting and post-prandial blood glucose levels between cases and controls. Both fasting and post-prandial glucose levels were significantly higher in the Vitamin D deficient group (p = 0.0048 and p < 0.0001, respectively). This reinforces the finding that low Vitamin D levels are associated with poorer glucose control in diabetic patients.

Table 4: Comparison of Lipid Profile Parameters between Cases (Vit D <20 ng/ml) and Controls (Vit D ≥20 ng/ml)

Table 4 examines lipid profile parameters between the groups. Total cholesterol and LDL levels were significantly higher in the cases compared to controls (p = 0.0221 and p = 0.0380, respectively), while HDL and triglycerides did not show statistically significant differences. This suggests that Vitamin D deficiency may be associated with adverse lipid profiles, particularly higher total cholesterol and LDL

The scientific premise linking vitamin D to glucose metabolism is robust. The vitamin D receptor (VDR) is expressed in pancreatic beta-cells, and vitamin D is involved in the transcription of the insulin gene and in promoting insulin sensitivity in peripheral tissues like muscle and fat. Furthermore, vitamin D modulates systemic inflammation and immune function, both of which are implicated in the pathogenesis of insulin resistance and type 2 diabetes (T2DM).

The clinical significance of our study's results lies in their strong, consistent demonstration of the association between vitamin D deficiency (<20 ng/ml) and poorer metabolic control in T2DM patients. Our findings reveal a statistically significant detrimental impact on key clinical parameters. Higher HbA1c, higher fasting and post-prandial blood glucose, and a lower proportion of patients achieving the HbA1c target of <7.0%. Significantly higher Total Cholesterol and LDL ("bad" cholesterol) levels.

This pattern suggests that vitamin D deficiency in diabetic patients is not an isolated finding but is integrally linked to a more adverse cardiometabolic phenotype. For clinicians, this reinforces the importance of screening for and treating vitamin D deficiency as a potential modifiable factor in the comprehensive management of T2DM, aimed at improving both glycemic and cardiovascular risk profiles.

Our results align with a significant body of observational evidence but also highlight the ongoing controversy surrounding the therapeutic efficacy of vitamin D supplementation, as seen in interventional trials.

Our findings are in clear agreement with Kostoglou-Athanassiou et al. (2013) and Salih et al. (2021), who also reported a high prevalence of vitamin D deficiency in T2DM patients and a significant inverse correlation between vitamin D levels and HbA1c [15, 16]. This consistency across different geographic populations strengthens the evidence for a strong association between low vitamin D and poor glycemic control.

However, our results appear to contradict studies like Kumar et al. (2019) and Olt (2015), which found no significant link between vitamin D levels and glycemic markers [17, 18]. This discrepancy could be due to several factors.  Our study had a well-defined, larger case group (n=75 with deficiency) compared to some smaller studies, providing greater statistical power to detect differences.  The critical factor seems to be the severity of deficiency. Our study specifically compared a deficient group (<20 ng/ml) to a sufficient group (≥20 ng/ml), which may have amplified the observable effect, whereas other studies may have included patients with less severe insufficiency.

The most complex comparison is with randomized controlled trials (RCTs) on supplementation. Our observational data suggest a strong relationship, yet RCTs like Krul-Poel et al. (2015) and Ryu et al. (2014) found that correcting the deficiency did not improve glycemic control. This creates a key paradox in the field [19, 20]. The meta-analyses by George et al. (2012) and Wu et al. (2017) help resolve this by showing that any benefit from supplementation is likely modest and predominantly confined to specific subgroups—particularly those with established vitamin D deficiency and/or glucose intolerance [21, 22].

Our study's cohort fits precisely this putative "responsive" subgroup. Patients with T2DM and clear vitamin D deficiency. The findings of Wu et al. (2017) directly support this, showing a stronger HbA1c reduction (SMD -0.39) in deficient individuals [22]. Similarly, the Kawahara et al. (2022) trial, which used a potent vitamin D analog, showed a significant reduction in diabetes risk after multivariable adjustment, especially in a high-risk subgroup [23].

In summary, our study provides compelling observational evidence that adds weight to the existing link between vitamin D deficiency and worse metabolic health in T2DM. While interventional trials have been mixed, the collective literature indicates that the relationship is likely real but that the therapeutic window for vitamin D supplementation may be narrow. The benefit is most probable in clearly deficient populations, like the one you studied, and may be influenced by other factors such as baseline glycemic status, BMI, and the dose and form of vitamin D used. Therefore, our results reinforce the clinical value of screening for deficiency in diabetic patients and support the rationale for further targeted research on supplementation in this specific, high-risk subgroup.

A key limitation of this study is its case-control design, which can identify associations but cannot establish a causal relationship between vitamin D deficiency and poorer glycemic or lipid control. Additionally, the single-center nature and modest sample size may limit the generalizability of the results to broader populations.

In conclusion, this study demonstrates a significant association between vitamin D deficiency (serum levels <20 ng/ml) and poorer metabolic control in patients with type 2 diabetes, as evidenced by significantly higher HbA1c, fasting and post-prandial blood glucose, and adverse lipid profiles compared to sufficient controls. These findings strengthen the existing observational evidence linking low vitamin D status to worsened glycemic and cardiovascular risk parameters in diabetes. While interventional trials on supplementation remain mixed, our results, consistent with subgroup analyses from major meta-analyses, suggest that patients with established deficiency represent a key population where this relationship is most clinically apparent. Therefore, this study underscores the importance of routine vitamin D status screening in the management of type 2 diabetes, as identifying and correcting deficiency may represent a valuable adjunctive strategy for improving overall cardiometabolic outcomes.

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