Diabetes mellitus and vitamin D deficiency (VDD) represent significant global public health issues. Approximately 537 million adults have diabetes, with 90–95% diagnosed with type 2 diabetes mellitus (T2DM), and type 1 diabetes mellitus (T1DM) is rising by 3–5% annually [1]. The International Diabetes Federation projects that the global population aged 20–79 with diabetes will reach 700 million by 2045 [2]. Concurrently, about 1 billion people suffer from VDD, particularly prevalent in Asia and Africa due to limited sun exposure and dietary factors [3, 4]. Fu et al. [5] demonstrated that individuals with serum 25-hydroxyvitamin D [25(OH)D] levels ≥ 75 nmol/L had a multivariable-adjusted hazard ratio of 0.62 [95% confidence interval (CI): 0.56–0.70] for T2DM compared to those with levels < 25 nmol/L. Notably, within the sub-50 nmol/L range, increasing 25(OH)D concentration significantly reduces T2DM risk [5]. Khudayar et al. [6] demonstrated that 54.1% of patients with T2DM exhibited VDD, compared to 28.6% in the control group. This deficiency was significantly linked to the onset of T2DM (P < 0.0001) [6]. Vitamin D, a steroid hormone, plays a critical role in regulating bone mineral homeostasis and calcium metabolism. The predominant circulating form of vitamin D, 25(OH)D, determines an individual’s vitamin D status [7]. In this study, VDD was defined as 25(OH)D levels below 20 ng/mL (50 nmol/L) as deficient, levels between 20–29 ng/mL as insufficient, and levels equal to or greater than 30 ng/mL as adequate, consistent with Endocrine Society Clinical Practice Guideline [8]. Experimental and observational evidence indicates that vitamin D signaling plays a role in insulin secretion and sensitivity, suggesting that VDD may elevate the risk of diabetes [9]. Shared modifiable risk factors, such as obesity, physical inactivity, and advanced age, may confound the VDD-T1DM/T2DM relationship.

The available evidence suggests a bidirectional relationship between vitamin D and glucose homeostasis. Suboptimal vitamin D levels can impair pancreatic β-cell insulin secretion, a key process in regulating blood glucose. Additionally, VDD may diminish peripheral insulin sensitivity, thereby compromising glucose uptake by tissues, while chronic hyperglycemia and inflammation in diabetics can disrupt vitamin D metabolism [10]. Supporting this, Fu et al. [5] demonstrated a negative association between serum 25(OH)D levels and T2DM risk, even below the diabetes diagnostic threshold, and Nóvoa-Medina et al. [11] observed seasonal vitamin D variations and a higher deficiency prevalence in T1DM patients.

Prior meta-analyses were limited by their emphasis on one-way relationships. Dominguez et al. [12] focused solely on the impact of VDD on the onset of T2DM in older individuals, neglecting the occurrence of VDD in those already suffering from diabetes. Similarly, Yu et al. [13] exclusively investigated the effect of VDD on the development of T1DM across different populations, without taking into account the prevalence of VDD in individuals already diagnosed with diabetes. Recent clinical studies have expanded this understanding: Khudayar et al. [6] identified a 2.95-fold increased VDD risk in T2DM patients (95% CI: 2.28–3.80; P < 0.0001), while Chen et al. [14] found a 2.04-fold increased risk in the T1DM population (95% CI: 1.31–3.15; P = 0.001). This meta-analysis synthesizes data from 53 studies (n = 552,032) to systematically evaluate the bidirectional association between VDD and diabetes mellitus, stratified by subtypes (T1DM vs. T2DM) and phenotypic subgroups.

The bidirectional relationship between diabetes mellitus and VDD has become a significant focus in metabolic disease research. Salih et al. [47] identified a substantial prevalence of vitamin D insufficiency and deficiency in individuals with T2DM (71%), especially in those with inadequate glycemic control and prolonged disease duration. This was established through a study involving 155 patients with T2DM and 155 non-exposed control subjects [47]. Similarly, Majeed et al. [62] observed a high prevalence of 25(OH)D deficiency among children and adolescents in the United Arab Emirates, with rates decreasing with age. Pittas et al. [71] reported that daily supplementation with 400 International Unit (IU) of vitamin D₃ did not significantly lower the risk of diabetes in high-risk populations not screened for VDD. Furthermore, they noted a higher prevalence of VDD in females compared to males, and a greater risk of VDD in obese individuals compared to those with normal weight [62]. Chen et al. [72] reported a negative correlation between serum 25(OH)D levels and the homeostatic model assessment of insulin resistance, specifically in females with VDD. This indicates a gender-specific effect of VDD on insulin resistance [72].

This study systematically examined the complex interaction between VDD and diabetes mellitus, including its subtypes (T1DM/T2DM), by analyzing 53 observational studies (n = 552,032). The findings revealed a 53% increased risk of T2DM (OR = 1.53) in individuals with VDD. This association is likely mediated by vitamin D’s influence on pancreatic β-cell function and insulin signaling pathways. Studies show that vitamin D enhances insulin secretion by binding to vitamin D receptors (VDRs) on β-cells, which regulate insulin gene transcription [41]. VDD, meanwhile, promotes insulin resistance by upregulating inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) and impairing glucose transporter type 4 (GLUT4) activity in skeletal muscle and adipose tissue [73, 74]. Conversely, the risk of VDD was elevated by 2.02-fold in patients with T1DM and 2.62-fold in those with T2DM. These results corroborate previous studies by Lucato et al. [75] and Yang et al. [76], underscoring the pivotal role of disrupted vitamin D metabolism in diabetes development. Importantly, this bidirectional relationship exhibited significant heterogeneity across populations. For instance, the risk of VDD was notably higher in T1DM patients in Asia (OR = 2.21) compared to European populations (OR = 1.65), while the risk in T2DM patients in Africa showed greater variability (OR = 4.75, 95% CI: 0.55–41.06). This suggests that genetic factors, environmental exposures, and healthcare access may contribute to these geographical differences [77]. Socioeconomic factors, including limited access to vitamin D-rich foods, healthcare disparities, and cultural practices (e.g., sun avoidance), may contribute to the observed geographic heterogeneity in VDD risk [78]. Polymorphisms in vitamin D metabolism genes, like the BsmI variant, are linked to a heightened risk of T1DM, especially prevalent in Asian populations, and may impact 25-hydroxylation and vitamin D binding [79]. Cultural practices, including skin-whitening norms and indoor lifestyles, along with high urban air pollution, further limit cutaneous vitamin D synthesis in these regions [78]. In contrast to Europe, where vitamin D management is often integrated into diabetes care, many Asian healthcare systems lack standardized screening and supplementation for VDD [78, 80].

Study design differences significantly influenced the results. Prospective cohort studies demonstrated a stronger effect of VDD on T2DM (I² = 66%), while retrospective case-control studies indicated a higher estimated risk of VDD in T2DM patients (OR = 2.71) but exhibited substantial heterogeneity (I² = 90%). The bidirectional analysis primarily relied on retrospective case-control studies (47 out of 53), whereas only 6 prospective cohort studies were included. It is important to highlight that the relationship between VDD and the development of T2DM was predominantly based on data from 5 prospective cohorts. Conversely, the reverse association, where diabetes mellitus leads to VDD, was mainly supported by retrospective data. This disparity in study designs could impact the ability to establish causality, given that case-control studies are susceptible to recall bias and residual confounding. Analysis of follow-up duration revealed a critical insight: the T2DM risk associated with VDD increased 1.66-fold (I² = 0%) when follow-up exceeded 5 years. This finding aligns with the ‘cumulative metabolic damage’ hypothesis by Schöttker et al. [81], which posits that persistent VDD can irreversibly impair islet function via chronic inflammation and oxidative stress. Conversely, short-term studies (< 5 years) showed negligible and non-significant effect sizes, implying that earlier vitamin D interventions might be necessary to prevent pathological processes.

The metabolic intricacy is further underscored by BMI stratification results: obese (BMI ≥ 30 kg/m²) T2DM patients exhibit a lower VDD risk (OR = 5.21) compared to their normal-weight counterparts (OR = 7.68). This paradox may arise from vitamin D accumulation in subcutaneous adipose tissue in obese individuals, leading to seemingly lower circulating 25(OH)D levels [82], while lean patients might have an inherent defect in vitamin D absorption or metabolism. In obesity, excess subcutaneous adipose tissue may sequester lipid-soluble vitamin D, creating a “sink effect” that lowers circulating 25(OH)D levels despite adequate systemic availability [82]. This hypothesis is supported by studies showing serum vitamin D elevation following weight loss without supplementation [83]. The CI for the OR in the obese group was wide (0.08–332.64), with a non-significant P value (P = 0.44), possibly due to the small sample size (n = 2) or outliers. Interpretation of this result should be approached with caution. Conversely, the significantly increased VDD risk in lean T2DM patients suggests intrinsic metabolic defects, potentially involving genetic polymorphisms in vitamin D hydroxylating enzymes, such as CYP2R1 variants impairing hepatic 25-hydroxylation [84], gut dysbiosis-mediated suppression of intestinal VDR expression [85]. These findings advocate for personalized supplementation strategies: higher doses to counteract adipose sequestration in obesity [86] and targeted therapies for absorption or metabolism defects in lean patients.

A complex interaction network links VDD and diabetes mellitus through multiple pathophysiological mechanisms. The high expression of the VDR in pancreatic β-cells and its regulatory role in insulin gene transcription underlie VDD’s direct impact on insulin secretion [87–89]. Norman et al. [90] found that insulin secretion from pancreatic islets in rat models decreased by 40–50% in the VDD group. This function was partially restored after supplementation with 1,25(OH)₂D₃. In the endocrine pathway, vitamin D directly influences β-cell function by maintaining intracellular calcium homeostasis. It regulates L-type calcium channels and calcium-binding proteins, essential for glucose-stimulated insulin secretion [91]. Deficiency in vitamin D can disrupt calcium signaling, diminishing β-cell sensitivity to glucose and impairing insulin synthesis and release [91]. Furthermore, vitamin D activates VDR, enhancing GLUT4 expression and membrane transport capacity in skeletal muscle and adipose tissue [74, 91]. VDD leads to compromised glucose uptake in peripheral tissues. VDR gene polymorphisms, including BsmI, FokI, and ApaI loci, influence receptor activity [74]. Pro-inflammatory T helper 1 (Th1) and Th17 cells are critical in mediating autoreactivity against β-cells [92]. In animal models, 1,25(OH)₂D, the active form of vitamin D, enhances regulatory T (Treg) cell activity and inhibits Th17 and Th1 cells via VDR [93, 94]. VDD disrupts the balance between Th17 and Treg cells [95]. It reduces pro-inflammatory Th17 cell differentiation by inhibiting the STAT3/RORγt pathway, thereby decreasing cytokine-mediated autoimmune attacks, such as IL-17, on pancreatic islet β-cells, notably in T1DM. Conversely, deficiency leads to excessive IL-12 and IL-23 secretion by dendritic cells, promoting Th1/Th17 polarization and weakening Treg cells’ immunosuppressive effects, exacerbating chronic low-grade inflammation [96]. This state upregulates inflammatory factors like TNF-α and IL-6 via nuclear factor kappaB (NF-κB) and Jun N-terminal kinase (JNK) pathways, disrupts insulin receptor substrate-1 (IRS-1) phosphorylation, and induces insulin resistance in skeletal muscle and adipose tissue [97]. Vitamin D supplementation can inhibit the NF-κB pathway, reducing pro-inflammatory factors, and may more effectively prevent and treat diabetes mellitus [73, 98], as demonstrated by Mohammad et al. [99] who observed a dose-dependent positive correlation between 25(OH)D levels and insulin sensitivity. Conversely, diabetes mellitus exacerbates VDD via several pathways: obesity-related fat accumulation decreases vitamin D bioavailability [82], diabetic nephropathy impairs 1,25(OH)₂D activation [100], and autonomic neuropathy limits outdoor activity, reducing skin synthesis of vitamin D.

While this study confirmed the robustness of its findings through sensitivity analyses and the trim and fill method, several limitations persist. The observational design cannot fully account for confounding factors like sunshine duration and dietary intake. Additionally, the predominance of studies from Asia (70%) may limit the global applicability of the results. Despite efforts to harmonize VDD diagnostic thresholds through data conversion, variations in 25(OH)D measurement methods across original studies may introduce residual bias. These limitations underscore the need for more prospective cohort studies, particularly standardized ones in underrepresented regions such as Africa and South America.

This study examines the integrated management of diabetes mellitus and VDD through clinical transformation. For Asian patients with T1DM and chronic VDD, routine clinical procedures should include regular monitoring of serum 25(OH)D levels, with intervention thresholds raised from the standard < 20 ng/mL to < 30 ng/mL. At the public health level, promoting vitamin D-fortified foods, such as dairy products, is suggested as an effective prevention strategy in regions with high prevalence, like South Asia and the Middle East. This study underscores the heightened risk of VDD in normal-weight T2DM patients, prompting clinicians to focus on lean individuals and tailor vitamin D supplementation plans. Gender differences, particularly in postmenopausal women with reduced estrogen affecting vitamin D binding protein function, should also be considered [72, 101]. Maintaining 25(OH)D levels at or above 25 ng/mL is recommended to enhance insulin sensitivity. Future research should investigate the metabolic benefits of VDR agonists in specific populations and determine the optimal timing and dosage of supplementation through randomized controlled trials to develop an evidence-based strategy for addressing the “metabolism-vitamin D disproportionation cycle”.