The Impact of Vitamin D on Type 2 Diabetes Mellitus: Exploring Its Role in Glucose Metabolism and Insulin Sensitivity

Suhani Sharma , Sonali Karhana , Mohd. Ashif Khan ^*

1. Department of Translational & Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India

* Correspondence: Mohd. Ashif Khan

Academic Editor: Cristiano Capurso

Special Issue: Vitamin D and Human Health

Received: May 15, 2025 | Accepted: September 17, 2025 | Published: September 29, 2025

Recent Progress in Nutrition 2025, Volume 5, Issue 3, doi:10.21926/rpn.2503021

Recommended citation: Sharma S, Karhana S, Khan MA. The Impact of Vitamin D on Type 2 Diabetes Mellitus: Exploring Its Role in Glucose Metabolism and Insulin Sensitivity. Recent Progress in Nutrition 2025; 5(3): 021; doi:10.21926/rpn.2503021.

© 2025 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

1. Introduction

Type 2 Diabetes Mellitus (T2DM) is a growing global concern characterized by hyperglycemia due to insulin resistance and β-cell dysfunction. According to the International Diabetes Federation, there were about 537 million adults with diabetes globally in 2021, and estimates indicate that by 2045, there will be an estimated 783 million [1]. Over 90% of all occurrences of diabetes are type 2 diabetes mellitus (T2DM), resulting in the most prevalent form of the disease [2]. A major contributor to the pathogenesis of Type 2 Diabetes Mellitus (T2DM), vitamin D is essential for controlling insulin action and glucose metabolism.

According to recent findings, vitamin D deficiency (VDD) is common in the general population and is especially common in those with type 2 diabetes mellitus (T2DM). According to a systematic meta-analysis of 54 studies involving more than 38,016 individuals, vitamin D deficiency affected nearly two-thirds of T2DM patients (64.2%; 95% CI: 60.6–67.8%), with significant regional differences—70.9% in Africa and 57.1% in the Middle East. In addition to its prevalence, VDD is closely linked to several vascular and metabolic risk factors, such as female sex, obesity, hypertension, dyslipidaemia, and poor glycaemic management, as well as microvascular adverse effects such as retinopathy, nephropathy, and albuminuria [3].

In line with this, a case-control study involving 70 type 2 diabetic patients and 70 healthy controls showed vitamin D deficiency/insufficiency in 84.29% of people with diabetes versus 18.57% of the controls. Mean vitamin D levels were significantly lower in people with diabetes (25.73 ± 7.27) compared to controls (34.55 ± 5.17, p < 0.05). An inverse correlation was observed between HbA1C and serum vitamin D (r = -0.281, p < 0.001), with deficiency more common in uncontrolled diabetes. This shows Vitamin D deficiency is markedly prevalent in T2DM patients [4].

Since skeletal muscle, adipose tissue, and pancreatic β-cells all have vitamin D receptors (VDR), vitamin D can affect several metabolic processes, such as insulin production, secretion, and sensitivity. Over the past five years, recent studies have shown that it is linked to systemic inflammation, insulin resistance, and β-cell dysfunction—all of which are crucial for the development of type 2 diabetes. One of the most significant mechanisms is the impact of vitamin D on β-cell activity. Vitamin D inhibits oxidative stress and apoptosis in pancreatic β-cells, increasing insulin production and preventing β-cell failure, according to research by Zakhary et al. [5]. Likewise, Adriyan Pramono et al. [6] concentrated on how vitamin D can increase insulin sensitivity. According to their research, supplements can affect inflammatory pathways and lower insulin resistance indicators, which may be particularly beneficial for individuals with prediabetes [6]. The NF-κB signaling pathway and cytokine production are suppressed by vitamin D, which reduces chronic low-grade inflammation associated with metabolic dysfunction, according to Martínez-Moreno et al. [7], who further investigated inflammatory regulation [7]. There are also critical metabolic effects of vitamin D on muscle mitochondrial function. According to Latham et al. [8], it plays a crucial role in skeletal muscle mitochondrial function, which is a key factor in peripheral insulin sensitivity, and improves glucose uptake [8]. Furthermore, the synthesis and activation of vitamin D begin in the epidermis, where UVB rays transform 7-dehydrocholesterol to cholecalciferol (vitamin D₃). The active form, 1,25-dihydroxyvitamin D (1,25(OH)₂D), is created by hydroxylating this inactive form once in the liver to develop 25-hydroxyvitamin D (25(OH)D). This active form interacts with VDRs in different tissues to control calcium and other metabolic processes [8]. Furthermore, a meta-analysis conducted by Farahmand et al. [9] combined data from multiple clinical trials and came to the conclusion that vitamin D supplementation improves HbA1c and fasting blood glucose levels in people with type 2 diabetes [9]. These findings indicate the potential therapeutic benefit of vitamin D in the management of diabetes, despite the lack of agreement regarding the ideal dosage and length of treatment.

2. Vitamin D Metabolism and Physiology

Vitamin D, an essential nutrient, is important for maintaining calcium and phosphate homeostasis in the body. The synthesis of vitamin D begins in the skin, where ultraviolet B (UVB) rays convert 7-dehydrocholesterol into vitamin D₃ (cholecalciferol). This inactive form of vitamin D is then transported to the liver, where it undergoes hydroxylation to form 25-hydroxyvitamin D (25(OH)D), or calcidiol, which is the primary circulating form of vitamin D. This form is typically measured in blood tests to assess vitamin D status [10]. Both vitamin D₃ from sunlight and vitamin D₂ from dietary sources are converted into 25(OH)D in the liver. Still, the liver’s ability to convert vitamin D is influenced by factors such as age, liver function, and the availability of enzymes like Cytochrome P450 family two subfamily R member 1 (CYP2R1) [11]. The conversion of 25(OH)D to its active form, 1,25-dihydroxyvitamin D (1,25(OH)₂D), occurs in the kidneys through the action of the enzyme 1-α-hydroxylase. This active form of vitamin D, known as calcitriol, plays a vital role in regulating calcium and phosphate absorption in the intestines and the reabsorption of calcium in the kidneys. The regulation of 1,25(OH)₂D production is controlled by several factors, including parathyroid hormone (PTH), which stimulates the kidneys to increase the conversion when calcium levels are low, and fibroblast growth factor 23 (FGF23), which inhibits its production [12]. Additionally, calcitriol is involved in regulating immune function. It has been shown to reduce the production of pro-inflammatory cytokines while enhancing the release of anti-inflammatory cytokines, which is essential for maintaining immune system balance [13].

The physiological roles of Vitamin D are not limited to bone and mineral metabolism. Its active form, calcitriol, helps modulate immune responses and influences insulin sensitivity and secretion. For example, vitamin D can improve insulin sensitivity in peripheral tissues by promoting insulin receptor expression and by stimulating insulin secretion from β-cells in the pancreas [14]. This effect on glucose metabolism has made vitamin D a vital area of research in conditions such as Type 2 Diabetes (T2DM). The deficiency of vitamin D has been associated with several metabolic disorders, including osteoporosis, cardiovascular diseases, and increased risk of diabetes [15]. Therefore, ensuring adequate vitamin D levels through sun exposure or supplementation is critical for maintaining overall health, particularly for bone integrity, immune function, and glucose metabolism.

3. Role of Vitamin D in β-Cell Function and Insulin Secretion

Vitamin D plays a crucial role in maintaining pancreatic β-cell function and regulating insulin secretion, both of which are vital for glucose homeostasis (Table 1). Pancreatic β-cells possess vitamin D receptors (VDRs) and the enzyme 1α-hydroxylase, enabling the local production of the active form of vitamin D, 1,25-dihydroxyvitamin D₃ (1,25D₃). This active form influences β-cell function through genomic and non-genomic pathways. For instance, 1,25D₃ enhances glucose-stimulated insulin secretion (GSIS) by modulating calcium influx via voltage-gated calcium channels, thereby affecting insulin release [16]. In addition to its effects on insulin secretion, vitamin D influences β-cell survival and function through various mechanisms. It modulates the expression of genes involved in insulin synthesis and secretion, thereby enhancing β-cell function. Vitamin D also regulates intracellular calcium levels, which are essential for insulin exocytosis. Furthermore, vitamin D has been shown to protect β-cells from apoptosis by modulating inflammatory pathways, thereby contributing to β-cell survival [17].

Table 1 Studies reporting the Role of Vitamin D in β-Cell Function and Insulin Secretion.

Recent studies have provided further insights into the role of vitamin D in β-cell function and insulin secretion. Wang et al. [19] studied the role of vitamin D in pancreatic β-cell function using an in vivo streptozotocin (STZ)-induced diabetic mouse model and in vitro MIN6 β-cell cultures. The study reported that vitamin D treatment improved insulin secretion, reduced pancreatic inflammation, and increased the expression of autophagy-related proteins LC3 and Beclin 1 [19]. Additionally, it was observed that vitamin D elevated the levels of the anti-apoptotic protein Bcl-2 and decreased β-cell apoptosis. Histopathological analysis showed reduced insulitis, while apoptosis was measured using annexin V/V/V/propidium iodide staining. Insulin secretion was quantified through ELISA, confirming a positive effect on β-cell function [19]. These results show a protective role of vitamin D in maintaining β-cell survival. Vitamin D also exerts immunomodulatory effects, reducing cytokine-induced β-cell damage by promoting an anti-inflammatory state. This is particularly significant in the development of type 2 diabetes mellitus (T2DM), where chronic inflammation contributes to β-cell dysfunction and insulin resistance.

Epidemiological studies have also observed associations between vitamin D deficiency and an increased risk of T2DM. Supporting this, Palomer et al. [22] reviewed multiple epidemiological studies linking vitamin D to improved insulin function. A study involving 5,677 individuals with impaired glucose tolerance found that vitamin D supplementation increased insulin sensitivity by 54%. Another study with 126 healthy participants reported that lower vitamin D levels correlated with reduced insulin function and β-cell health [22]. Additionally, a 20-year longitudinal study following 4,843 individuals with T2DM showed that those with higher vitamin D intake had a lower risk of developing diabetes, reinforcing the idea that vitamin D plays a role in preventing metabolic dysfunction.

While these studies show the benefits of vitamin D, others present mixed findings. Parekh D et al. [18] conducted a randomized, placebo-controlled trial in 81 South Asian women with vitamin D deficiency and insulin resistance. Over a six-month period, participants received either 4,000 IU of vitamin D₃ daily or a placebo. The study observed a significant improvement in insulin sensitivity, particularly in those whose vitamin D levels exceeded 80 nmol/L. However, it found no effect on insulin secretion, as measured by C-peptide levels, and other metabolic markers such as lipid profiles and inflammation remained unchanged [18]. Similarly, a meta-analysis of 19 randomized controlled trials with 1,374 individuals (747 in the intervention group and 627 in the placebo group) was carried out by Hu et al. [23] to evaluate the impact of vitamin D supplementation on glycemic management in patients. A decrease in insulin resistance shows that short-term vitamin D treatment significantly increased insulin sensitivity, according to the study. Additionally, it caused a little but noteworthy drop in fasting insulin and HbA1c readings. Supplementing with vitamin D, however, did not result in long-term changes in glycemic indicators. Therefore, as per the report, Vitamin D is not a stand-alone treatment for glycemic management, but it may be helpful as an adjuvant therapy in people who are vitamin D deficient [23].

Some studies have also questioned the effectiveness of vitamin D supplementation in diabetes management. Wu et al. [21] reviewed multiple studies and acknowledged vitamin D’s role in insulin secretion, inflammation reduction, and β-cell preservation. However, they noted inconsistencies in clinical outcomes, emphasizing that genetic, metabolic, and environmental factors may influence its effectiveness [21]. Furthermore, Hu et al. [20] examined 75 participants (25 with T2DM, 25 with prediabetes, and 25 healthy individuals) and found a significant negative correlation between vitamin D levels and insulin resistance (p < 0.05). While their results suggested that low vitamin D levels contribute to poor β-cell function and higher insulin resistance, the study found that individual variability could affect outcomes [20].

Overall, while evidence supports the role of vitamin D in insulin sensitivity and β-cell preservation, its effects on glycemic control and diabetes prevention remain inconclusive. The variability in clinical results suggests that vitamin D may benefit specific populations more than others, highlighting the need for further research to determine its precise role in diabetes management.

Concluding these, results show that having enough vitamin D is essential for maintaining healthy blood sugar levels, though individual differences may influence its effects. The complete influence of vitamin D on diabetes management requires more research.

4. Vitamin D and Insulin Sensitivity in T2DM

Type 2 diabetic mellitus (T2DM) treatment and insulin sensitivity are both affected by vitamin D. Studies reveal that vitamin D deficiency has been associated with elevated insulin resistance and is common in people with type 2 diabetes. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), fasting plasma glucose, and insulin levels all significantly improved in T2DM patients who took vitamin D supplements. This shows that vitamin D supplementation may help lower insulin resistance in T2DM patients [24].

The connection between serum vitamin D levels and insulin resistance has been thoroughly studied in recent studies. A cross-sectional study by Xu et al. [25] assessed the relationship between serum vitamin D₃ levels and insulin resistance by using data from the National Health and Nutrition Examination Survey (NHANES). Serum vitamin D₃ levels and insulin resistance were found to be significantly inversely correlated in the study, which involved 9,298 people. Higher vitamin D₃ levels have been associated with lower risks of insulin resistance, according to multivariate logistic regression analysis (OR 0.82, 95% CI 0.72–0.93) [25].

Similarly, Wang et al. [26] studied how vitamin D affects insulin sensitivity, focusing on how it lowers low-grade inflammation. According to their study results, increased vitamin D levels may reduce the likelihood of insulin resistance by reducing inflammatory reactions, which are a significant contributing factor to the development of this condition [26]. Furthermore, Sung et al. [27] analyzed the molecular pathways by which vitamin D influences insulin sensitivity and pointed out that taking vitamin D supplements may improve insulin sensitivity by lowering low-grade inflammation [27].

A randomized controlled trial conducted by Dutta et al. [28] found that vitamin D supplementation in individuals with prediabetes significantly reduced the progression to Type 2 Diabetes Mellitus (T2DM). The intervention was also associated with a significant increase in the reversion to normoglycemia. Improvements in insulin resistance (HOMA-IR), systemic inflammation indicators (e.g., hs-CRP, TNF-α), and dyslipidemia parameters (e.g., serum triglycerides, HDL-C levels) were seen.

The study's goal was to assess vitamin D's independent influence by supplying Group A with vitamin D and calcium, whereas Group B received calcium alone. Group A had significant improvements in glycemic management, insulin resistance, and inflammatory markers. These modifications were associated with increasing serum 25(OH)D levels. Group A also showed higher insulin sensitivity and lower inflammation than Groups B and C. This suggests a potential metabolic advantage of treating vitamin D insufficiency in individuals with prediabetes.

These findings contribute support to Vitamin D's possible involvement as a preventative agent along the pathophysiological spectrum from prediabetes to overt diabetes [28].

Furthermore, A double-blind, placebo-controlled randomized clinical trial by Niroomand et al. [29] evaluated the effect of high-dose vitamin D on insulin sensitivity and the risk of progression to diabetes.

The study also revealed that supplementing with vitamin D for individuals with glucose intolerance and hypovitaminosis D can reduce the progression to overt diabetes.

The findings concluded that supplementation with high-dose vitamin D₃ in patients with prediabetes and hypovitaminosis D can improve insulin sensitivity and reduce the rate of progression toward diabetes [29].

A study by Talaei et al. [24] investigated the effect of vitamin D on insulin resistance in patients with type 2 diabetes. The results indicated that vitamin D administration significantly decreased serum Fasting Plasma Glucose (FPG), insulin, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in patients with T2DM.

There was an interesting observation in this study that there was an inverse relationship between final FPG and basal 25(OH) D concentrations. In other words, higher serum basal 25(OH) D resulted in lower final FPG. This suggests that individuals with a greater blood basal 25(OH) D concentration benefited more from vitamin D supplementation in terms of lowering final FPG. This could be due to the non-skeletal effects of vitamin D, which are evident in higher vitamin D concentrations. In contrast, the effects of lower vitamin D concentrations are primarily limited to the bones and muscles.

This study stated that vitamin D could improve diabetes control, and vitamin D supplementation must be included in the treatment of type 2 diabetes [24].

All of these outcomes point to the possibility that, through modifying inflammatory processes, sustaining appropriate vitamin D levels may be essential for enhancing insulin sensitivity and lowering the risk of insulin resistance.

5. Mechanisms of Vitamin D in Insulin Regulation

Vitamin D is involved in insulin regulation by influencing multiple cellular mechanisms that support glucose homeostasis and pancreatic β-cell function. It exerts its effects through calcium-dependent signaling, gene regulation, and protection against apoptosis, all of which contribute to improved insulin sensitivity and secretion (Figure 1).

Figure 1 Molecular Mechanisms of Vitamin D in Glucose Homeostasis and Insulin Sensitivity.

5.1 Calcium-Dependent Signaling

Vitamin D modulates intracellular calcium levels, which are necessary for insulin signaling and glucose uptake. Vitamin D promotes calcium homeostasis in skeletal muscle and adipose tissue by increasing the availability of calcium ions. This is essential for activating the insulin receptor and triggering downstream signaling pathways that promote glucose absorption into cells. For example, vitamin D-induced calcium influx enhances insulin receptor sensitivity, increasing total insulin activity in these peripheral tissues. The activation of calcium-sensitive signaling pathways improves glucose metabolism and insulin efficiency, especially in people with type 2 diabetes (T2DM).

In pancreatic β-cells, calcium signaling is directly involved in insulin secretion. Vitamin D enhances calcium influx through voltage-gated calcium channels, which are critical for insulin granule release. This influx of calcium ions into β-cells triggers insulin exocytosis, a process necessary for insulin release in response to elevated blood glucose. The ability of vitamin D to regulate intracellular calcium concentrations in β-cells ensures efficient insulin secretion and aids in the maintenance of blood glucose levels. Disruption of calcium signaling, often due to vitamin D deficiency, can impair β-cell function, leading to reduced insulin release and an increased risk of insulin resistance and type 2 diabetes mellitus (T2DM) [30]. Furthermore, vitamin D's role in calcium-dependent signaling extends to the liver, where it influences glucose metabolism. Studies have shown that calcitriol, the active form of vitamin D, increases cytosolic calcium concentration in hepatocytes. This elevation activates the Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ) pathway, leading to the phosphorylation of AMP-activated protein kinase (AMPK). Activation of AMPK results in reduced hepatic triglyceride accumulation and glucose output, thereby improving insulin sensitivity [31].

The function of 1,25-dihydroxyvitamin D₃ (1,25D₃) in promoting glucose-stimulated insulin secretion (GSIS) in mouse and human pancreatic islets was examined in the study by Kjalarsdottir et al. [16]. The researchers observed that preincubating islets with 1,25D₃ boosted both glucose-stimulated calcium influx and GSIS. They discovered the R-type voltage-gated calcium channel gene (Cacna1e) as a new target of the vitamin D receptor (VDR) using microarray analysis and in silico research. In both mouse and human islets, 1,25D₃ markedly increased the expression of this gene, which has a conserved VDR response region in intron 7. According to these results, 1,25D₃ influences β-cell activity via modifying calcium influx through the R-type VGCC, which in turn increases insulin production [1,2].

5.2 Gene Regulation

Vitamin D influences insulin sensitivity by regulating specific genes involved in glucose metabolism, including GLUT4, an insulin-responsive glucose transporter in skeletal muscle. Studies have demonstrated that vitamin D increases GLUT4 expression, which increases glucose uptake into muscle cells. This increase in GLUT4 helps to improve insulin sensitivity and glucose homeostasis. The effects of cholecalciferol (vitamin D₃) supplementation on the expression of glucose transporter 4 (GLUT4) in diabetic rat adipocytes were studied in the Sari et al. [32] study. For 14 days, 19 male Wistar strain diabetic rats were split up into four groups and given cholecalciferol doses of 6.25 μg/kg (X₁), 12.5 μg/kg (X₂), and 25 μg/kg (X₃) per os, once daily. The control group (K) was given a placebo. There were no discernible variations in adipocyte diameter or fasting blood glucose (FBG) levels across the groups, according to the study. In contrast to the control group, the treatment groups' adipocytes exhibited a notable uptick in GLUT4 expression. These results imply that cholecalciferol can increase GLUT4 expression in adipocytes in diabetic rats without changing adipocyte size or FBG levels [33].

A study found that vitamin D supplementation boosted GLUT4 expression in skeletal muscle, leading to improved insulin action [34]. Beyond GLUT4, vitamin D also influences the transcription of other genes involved in glucose metabolism. It has been observed that vitamin D modulates the expression of genes involved in mitochondrial function and energy production. By influencing these genes, vitamin D enhances mitochondrial energy generation, which is crucial for efficient glucose utilization and overall metabolic health. A review also showed that vitamin D's effect on gene expression extends to various metabolic pathways, including those involved in insulin sensitivity [21].

Furthermore, the impact of Vitamin D on gene regulation extends to adipose tissue. Research suggests that vitamin D receptor (VDR) expression in adipose tissue is linked to obesity and may be influenced by 1,25-dihydroxyvitamin D₃. This regulation shows that vitamin D influences adipocyte function and insulin sensitivity through gene expression modulation. e-Postigo et al. [35] conducted a study to investigate the relationship between serum 25-hydroxyvitamin D levels, vitamin D receptor (VDR) expression in adipose tissue, and glycemic status. The study included 118 participants, categorized based on their glucose tolerance status: standard glucose tolerance, impaired glucose regulation, and type 2 diabetes mellitus (T2DM). Through biopsy samples, researchers studied serum vitamin D levels, insulin sensitivity (using the HOMA-IR index), and VDR expression in adipose tissue. Their results showed a favorable relationship between serum vitamin D levels and VDR expression, with higher VDR expression associated with better insulin sensitivity. Also, people with T2DM had considerably decreased VDR expression in adipose tissue, implying that vitamin D signaling in fat tissue affects glucose metabolism. Reduced VDR expression was identified as an independent predictor of insulin resistance (p < 0.05). These findings suggest a potential biochemical mechanism by which vitamin D influences insulin sensitivity, underscoring the importance of maintaining optimal vitamin D levels for metabolic health [35].

5.3 Protection Against Apoptosis

Pancreatic β-cells can undergo apoptosis (programmed cell death) due to factors like oxidative stress, inflammation, and metabolic dysfunction—standard features in Type 2 Diabetes Mellitus (T2DM) [21]. Vitamin D exhibits protective effects on pancreatic β-cells by modulating apoptotic pathways, thereby preserving insulin secretion capacity and enhancing insulin sensitivity. One of the key mechanisms involves the vitamin D receptor (VDR), which, upon activation by vitamin D, can inhibit apoptosis in β-cells. When vitamin D binds to the Vitamin D Receptor (VDR) in pancreatic β-cells, it triggers a series of protective responses that prevent apoptosis and support insulin secretion. The active form of vitamin D (1,25-dihydroxyvitamin D₃) binds to VDR, which then forms a complex with Retinoid X Receptor (RXR) and translocates into the nucleus, regulating gene expression [36]. A study demonstrated that overexpression of VDR protected β-cells from apoptosis induced by Forkhead box class O1 (FOXO1), a transcription factor associated with cell death. This protection was linked to the reduction of reactive oxygen species (ROS) and the maintenance of mitochondrial membrane potential, both critical factors in cell survival [36]. Additionally, vitamin D influences the expression of anti-apoptotic proteins, further safeguarding β-cell integrity. Research published in Endocrinology highlighted that 1,25-dihydroxyvitamin D₃ (the active form of vitamin D) upregulated the expression of A20, an anti-apoptotic protein. A20 inhibits NF-κB activation, a pathway known to promote inflammation and cell death. By modulating this pathway, vitamin D reduces β-cell apoptosis, thereby supporting insulin production and secretion [20]. Furthermore, vitamin D has been shown to induce autophagy in pancreatic β-cells, a process that removes damaged cellular components and supports cell survival. A study found that vitamin D treatment increased the expression of autophagy-related genes, such as LC3 and Beclin 1, in β-cells. This induction of autophagy not only protected β-cells from apoptosis but also enhanced insulin secretion, contributing to improved glucose homeostasis [19].

6. Emerging Mechanisms of Vitamin D in T2DM

Emerging evidence suggests that gut microbiota composition can influence vitamin D absorption, and conversely, vitamin D status can modulate gut microbial communities, potentially impacting T2DM pathophysiology. Dysbiosis, or an imbalance in the gut microbial community, may impair the intestinal barrier function, leading to reduced absorption of nutrients, including vitamin D.

Vitamin D, through its nuclear receptor (VDR), influences the gut microbiota composition by promoting the growth of beneficial bacteria such as Bifidobacterium and Lactobacillus, while suppressing pathogenic species. This modulation enhances intestinal barrier integrity, reducing systemic inflammation and improving insulin sensitivity, thereby mitigating T2DM progression.

In a recent randomized controlled experiment, Wyatt et al. [37] assessed the effects of vitamin D₃ supplementation on gut microbiota in healthy adults. Participants in this trial were given a moderate dosage of vitamin D (4,000 IU per day) as an intervention, and controls were given a placebo. The results revealed that the stability of the gut microbiota and related metabolite networks was dramatically impacted by vitamin D administration. This suggests that modifying micronutrients can alter microbial ecology and, consequently, impact host metabolic pathways [37].

Similarly, Singh et al. [32] conducted a randomized, double-masked, placebo-controlled trial on 80 healthy adults to investigate the effect of vitamin D supplementation on the gut microbiota. Participants received either vitamin D or a placebo for 12 weeks, and outcomes were assessed using 16S rRNA sequencing. The results showed that taking vitamin D supplements improved the gut microbiota's overall diversity, specifically increasing the relative abundance of Bacteroidetes and decreasing that of Firmicutes, which is associated with improved gut health [32].

Expanding on these findings on gut microbiota regulation, probiotics have also been explored for their possible contribution to type 2 diabetes patients' glycaemic management.

The meta-analysis and systematic review conducted by Liu et al. [38] evaluated the impact of probiotic supplementation on glycaemic control in patients with type 2 diabetes by combining data from 30 RCTs, involving 1,827 participants. The results indicated that probiotic supplementation dramatically reduced T2DM patients' HOMA-IR scores as well as their FBG, insulin, and HbA1c levels. Additional subgroup analyses revealed that the benefit was greater in the following subgroups: food-type probiotics, Bifidobacterium probiotics, high baseline BMI (≥30.0 kg/m²), and Caucasians. The idea that probiotics aid in the glycaemic management of T2DM patients was validated by this study [33].

A recent study demonstrated that in mice subjected to elevated vitamin D₃ levels during pregnancy and lactation, a decrease in vitamin D led to a reduction in vitamin D receptor expression and an increase in pro-inflammatory gene expression in the colon at 3 months. Additionally, there was a lower abundance of colonic Bacteroides/Prevotella on postnatal day 21 and elevated serum LPS levels in adulthood [39]. In addition, a genome-wide association study (GWAS) involving a combined cohort of 2029 individuals revealed two VDR polymorphisms as significant factors contributing to variations in the microbiota [19]. These human VDR polymorphisms were consistently found to affect the genus Parabacterioides (phylum: Bacteroidetes). Further analysis of VDR^-/- mice revealed a corresponding increase in the abundance of Parabacteroides compared to wild-type (WT) mice [40]. VDRs also regulate the production of antimicrobial peptides, such as cathelicidin and defensin, with the active form of vitamin D stimulating their output at the macrophage level [41]. These antimicrobial peptides are crucial for maintaining microbial balance. Additionally, existing evidence suggests that vitamin D and VDRs contribute to the regulation and preservation of gut integrity and microbiota functions by suppressing beta-catenin, which promotes cell proliferation, and enhancing the expression of tight junction proteins such as E-cadherin, Occludin, and ZO-1 [42].

A recent study has demonstrated that early-life vitamin D deficiency (VDD) results in impaired glucose tolerance in both adult and offspring rats. In a rat model, vitamin D deficiency from weeks 0 to 8 resulted in altered gut microbiota composition, including an increase in general species like Desulfovibrio and Bilophila, and impaired glucose tolerance observed at both 8 and 18 weeks. These effects were linked to significant metabolic changes, suggesting that early-life VDD may impact adult diabetes risk through alterations in the gut microbiota and their metabolites [38]. In a recent study, VD deficiency in zebrafish led to impaired glucose regulation, marked by altered expression of intestinal peptide hormones and increased sodium glucose cotransporter-1. The study further revealed that VD-regulated glucose metabolism is dependent on gut microbiota, as germ-free zebrafish transplanted with microbiota from VD-deficient zebrafish developed hyperglycemia. Supplementation with acetate or Cetobacterium somerae, a potent acetate producer, alleviated hyperglycemia, demonstrating that VD modulates the gut microbiota-SCFAs-gastrointestinal hormone axis to maintain glucose homeostasis [43]. The gut microbiota produces short-chain fatty acids (SCFAs), such as butyrate, acetate, and propionate, during fiber fermentation. These metabolites enter systemic circulation and act as signaling molecules, activating pathways that improve glucose metabolism and reduce inflammation [43]. However, more clinically based studies are required to understand the underlying mechanisms fully and to evaluate the potential for microbiota-targeted therapies in the management of T2DM.

7. Clinical Trials and Vitamin D Supplementation in T2DM

Clinical trials have been conducted to investigate the effect of vitamin D supplementation on type 2 diabetes mellitus (T2DM), including critical metabolic parameters such as fasting blood glucose, HbA1c, and insulin sensitivity (Table 2).

Table 2 Clinical Trials and Vitamin D Supplementation in T2DM.

The D2d Study [47], a randomized, placebo-controlled trial involving 2,423 adults with prediabetes, examined the effects of 4,000 IU/day of vitamin D₃ over 2.5 years. The results showed no significant reduction in diabetes incidence (HR: 0.88; 95% CI: 0.75–1.04; p = 0.12), indicating that vitamin D did not substantially lower the risk of T2DM [44]. In contrast, a 2019 meta-analysis of over 2,000 individuals with T2DM, analyzing various vitamin D supplementation doses, found significant improvements in fasting blood glucose (-0.36 mmol/L, p < 0.05), HbA1c (-0.39%, p < 0.01), and HOMA-IR (-0.63, p < 0.05), suggesting a positive effect on insulin sensitivity [45]. Similarly, a 2023 study on 60 T2DM patients with vitamin D deficiency, supplementing with 2,000 IU/day of vitamin D₃ for 12 weeks, reported notable reductions in fasting plasma glucose (-8.7 mg/dL, p = 0.01) and HbA1c (-0.3%, p = 0.04) [9]. Another randomized controlled trial in 2020, involving 8 individuals with prediabetes who received 4,000 IU/day of vitamin D₃ for a year, observed an increased rate of reversion to normoglycemia and a reduced risk of developing type 2 diabetes (T2DM) [46]. Additionally, a 2022 study on 200 participants with T2DM, which supplemented with 4,000 IU/day of vitamin D₃ for six months, found no significant difference in adverse events between the vitamin D and placebo groups, supporting its safety profile [47].

While these studies indicate that vitamin D may play a role in improving insulin sensitivity and glucose metabolism, the inconsistencies in findings show the need for further research to establish its impact on diabetes management and its potential as a therapeutic intervention.

7.1 Reconciling Conflicting Evidence

The variability in outcomes across clinical trials investigating the effects of vitamin D supplementation on type 2 diabetes (T2DM) can be attributed to several factors. One major contributor is the differences in study populations, including variations in ethnicity and baseline vitamin D status, which may influence how individuals respond to supplementation. Studies involving populations with lower baseline vitamin D levels often show more pronounced benefits compared to those with adequate levels. Additionally, variations in supplementation protocols—such as differences in dosage, treatment duration, and the form of vitamin D (e.g., D₂ vs. D₃)—can lead to inconsistencies in results. Another critical factor is the presence of genetic variations, specifically VDR polymorphisms, which may affect the responsiveness to vitamin D supplementation. Individuals with specific VDR gene variants may experience a different magnitude of effect on insulin sensitivity and glucose metabolism. Furthermore, environmental factors, including sunlight exposure and dietary intake, play a significant role in determining vitamin D status and could modulate the outcomes of supplementation. To reconcile conflicting evidence, future research should focus on standardizing supplementation protocols, such as dose, duration, and form of vitamin D, while considering factors like ethnicity, baseline vitamin D status, and genetic variations. Additionally, personalized approaches that incorporate genetic and environmental factors, such as VDR polymorphisms and sunlight exposure, may help clarify the inconsistent findings in current studies.

8. Limitations

One of the primary limitations is the variability in study designs, with some studies relying on observational and cross-sectional data, which can only establish associations rather than causality. Additionally, there is considerable heterogeneity in the dosages of vitamin D administered, ranging from low to high doses, and the duration of supplementation varies from a few weeks to several months. This inconsistency in dosing and duration makes it difficult to determine the optimal vitamin D dosage for improving insulin sensitivity and glycemic control. Furthermore, many studies fail to control for confounding factors such as baseline vitamin D levels, lifestyle factors (e.g., diet, physical activity), and genetic predispositions, which may influence the observed effects. These limitations highlight the need for more large-scale and long-term studies to conclusively establish the role of vitamin D in managing type 2 diabetes.

9. Conclusions

Vitamin D has been shown to influence multiple pathways related to insulin sensitivity, β-cell function, and inflammation. The active form of vitamin D enhances insulin secretion by modulating calcium influx in pancreatic β-cells, reduces inflammation, and improves insulin sensitivity in peripheral tissues. Vitamin D regulates calcium signaling in pancreatic β-cells, enhancing insulin secretion by increasing calcium influx, and helps maintain blood glucose levels. It also influences glucose metabolism in the liver by activating the CaMKKβ/AMPK pathway, improving insulin sensitivity, and reducing hepatic triglyceride accumulation. Vitamin D also increases the expression of the GLUT4 gene, which enhances glucose uptake in skeletal muscle, thus increasing insulin sensitivity. Vitamin D influences adipose tissue function through vitamin D receptor (VDR) expression, with higher VDR expression linked to better insulin sensitivity, especially in individuals with type 2 diabetes. Additionally, Vitamin D protects pancreatic β-cells from apoptosis induced by oxidative stress, inflammation, and metabolic dysfunction in type 2 diabetes by modulating apoptotic pathways, enhancing insulin secretion, and promoting autophagy. It activates the vitamin D receptor (VDR) to reduce cell death and support β-cell function, improving glucose homeostasis.

Despite the promising evidence, variability in clinical outcomes suggests the need for targeted research to optimize supplementation protocols, including the ideal dosages and duration of treatment. By addressing these gaps, future research could refine the role of vitamin D as an adjunctive therapy in T2DM, leading to improved management strategies for patients.

Author Contributions

Suhani Sharma contributed to data curation and the preparation of the original draft. Sonali Karhana was responsible for visualization, conducting the investigation, and reviewing and editing the manuscript. Dr. Mohd Ashif Khan contributed to the conceptualization and methodology of the study, provided supervision throughout the research process, and validated the findings.

Competing Interests

The authors have declared that no competing interests exist.