Type 1 diabetes mellitus (T1DM) is characterized by high blood sugar levels secondary to low blood insulin levels due to the autoimmune destruction of pancreatic beta islet cells (1). T1DM is commonly preceded by a pre-clinical phase of islet autoimmunity (IA), defined by the presence of circulating glutamic acid decarboxylase, insulin and protein tyrosine phosphatase-2 autoantibodies. Individuals with IA are at high risk of progression to T1DM (2).

The prevalence of T1DM is set to rise 0.34% annually, with an estimated 8.4 million people living with the condition in 2021, and a projected 13.5-17.4 million in 2040 (3). Long-term complications include diabetic retinopathy, neuropathy and nephropathy, the avoidance of which entails rigorous blood sugar monitoring and control (4). Individuals with type 1 diabetes mellitus experience a lower health-related quality-of-life (5) and psychological distress (6). Beyond the individual level, the cost to public health imposed by the condition is onerous. Individuals with type 1 diabetes mellitus, although fewer in number, have significantly higher mean total medical costs per patient per year compared with individuals with type 2 diabetes mellitus (7). Therefore, there is merit in investigating factors that may be protective against the development of T1DM, the development of IA, and the progression of IA to T1DM.

Vitamin supplementation has been studied in association with the development of IA and T1DM (8). Carakushansky et al. demonstrated a significantly high prevalence of vitamin D insufficiency in a cohort of children with T1DM (9). Similarly, Koshy et al. reported a 45% prevalence of vitamin B12 deficiency in a cohort of individuals with T1DM. T1DM develops at an early age, with the first peak in incidence at 4-7 years old. Therefore, early intervention is of particular interest to preventing its occurrence. In vitro, vitamin D acts as an immunosuppressant to reduce lymphocyte proliferation and cytokine production which are components of IA seen in T1DM (10). Other vitamins have also been investigated in association with T1DM and IA (11, 12). For example, niacin, vitamin B12 and riboflavin are components of a dietary pattern linked to a metabolomic profile negatively associated with the progression of T1DM (13) and have been demonstrated to reduce progression to T1DM (11). A systematic review of the effect of vitamin supplementation on the prevalence and progression of IA to T1DM may help provide evidence-based guidance for mothers on supplementing with antenatal and postnatal vitamins. This systematic review aims to investigate the relationship between vitamin supplementation on the development of IA, T1DM or progression of IA to T1DM. Secondary outcomes include evaluating the prognostic factors affecting maternal usage of vitamin supplementation.

The systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our protocol is registered on PROSPERO (CRD42024540524).

15 studies were included from 2,721 records ( Figure 1 ) (8, 11, 12, 17–28). 2,704 records were excluded after removing irrelevant studies with the wrong population, design, outcomes and duplicates. Out of the 15 studies, four were from the United States (11, 18, 22, 28), three from Finland (8, 19, 29), two from Europe (23, 27), one each from Sweden (25), Denmark (30), Egypt (26), Algeria (24), Norway (12) and Italy (17). Nine studies were cohorts (11, 18–21, 25, 27, 28, 31), five were case-controls (12, 17, 22, 24, 26) and one was a randomized controlled trial (23). 386,116 total participants were studied. The overall characteristics of the studies can be found in Table 1 .

This systematic review and meta-analysis aimed to investigate the modifiable risk of developing IA, T1DM, progression of IA to T1DM with supplementation of vitamins. Overall, our results demonstrated that supplementation of vitamin D and B may not have any modulatory effect on disease risk but demographic factors such as a higher maternal education level increased levels of supplementation among mothers. Meta-analyses demonstrated that vitamin D supplementation might not have any effect on modifying the risk of developing IA or T1DM. Systematic review revealed that vitamin B supplementation did not influence the risk of T1DM and progression of IA to T1DM. Additionally, there was an association between higher maternal education levels and higher levels of vitamin D supplementation in their offspring. Despite this being a systematic review and meta-analysis of the available literature, there is considerable heterogeneity among the studies, complicating the ability to draw a definitive conclusion regarding the efficacy of vitamin supplementation in modifying the risk of developing IA, T1DM or progression of IA to T1DM.

It is important to note that the studies included in our analysis demonstrated considerable heterogeneity in their design, methodology and results. For instance, while the EURODIAB study demonstrated a protective role of vitamin D supplementation in reducing T1DM risk (27), other studies failed to replicate these findings. These discrepancies could be attributed to several factors. This includes differences in demographics in study populations, as the studies are carried out in different countries. The dosage and duration of supplementation, timing of intervention, and methods of measuring vitamin D status also varied across different studies. Furthermore, the definition and assessment of outcomes (IA, T1DM) was defined differently across studies, potentially contributing to the inconsistent results.

In recent years, emerging research has suggested that vitamin D supplementation in early childhood could play a pivotal role in modifying the risk of developing T1DM later in life, due to its potential anti-inflammatory and immunomodulatory effects (32). The EURODIAB study demonstrated the potential protective role of vitamin D supplementation in significantly reducing the risk of developing T1DM (27). Significantly, a study by Janner et al. revealed a high prevalence of vitamin D deficiency in children or adolescents with T1DM, suggesting an association between vitamin D levels and the risk of developing T1DM (33). Despite the prior hypotheses from existing literature, our results showed that vitamin D supplementation does not significantly affect the odds and RR of developing T1DM. While vitamin D might play a role in the immune system (34), it is important to recognize that T1DM is a multifactorial disease with a complicated pathogenesis (35). Other genetic, epigenetic, environmental and immunological factors contribute to disease development and progression (36), and might undermine the protective abilities of vitamin D. Another possibility is that only specific subgroups, for example those with severe vitamin D deficiency, may benefit from supplementation. As our included studies mainly looked at broad populations, this might not have been adequately captured in the analyses. As mentioned above, the heterogeneity of the studies must be considered as well. Firstly, the timing and duration of supplementation varied across studies, with some focusing on early infancy while others extended into childhood. Secondly, the dosage of vitamin D supplementation differed, ranging from 400 IU to over 2000IU daily. Additionally, the baseline vitamin D levels of participants varied across studies, which might have affected the efficacy of supplementation. These variations in intervention protocols could significantly impact the efficacy of supplementation Our results underscore the need for more targeted research, focusing on high-risk groups and considering other confounding factors to fully elucidate the relationship between vitamin D supplementation and T1DM risk.

Other than T1DM, our results further indicate that vitamin D supplementation does not seem to significantly affect the odds of developing IA or its progression to T1DM. Prior research has drawn possible links between vitamin D supplementation and a decreased risk of developing IA later in life, such as the study by Norris et al. (37 ), which determined that increased childhood plasma 25-hydroxyvitamin D concentration was associated with a decreasing IA risk. Similar to T1DM, it is imperative to realize that IA is also a multifactorial disease that can be influenced by environment, genetics, epigenetics, disease phenotypes and many other factors (38). The lack of a significant effect in our meta-analysis could be attributed to this, or variations in the physiology of the participants of each study. The heterogeneity of the studies included in the meta-analysis should also be kept in consideration, with variations in study design and population characteristics leading to limited ability to detect sub-group specific effects.

The role of vitamin B supplementation in modulating the risk of developing IA, T1DM or progression of IA to T1DM was also considered in our analysis. Our results concluded that vitamin B supplementation does not seem to significantly affect the odds. While the role of vitamin B in modulating immune responses is less well researched than vitamin D, vitamin B is postulated to have anti-inflammatory effects (39). The Boston Puerto Rican Health Study demonstrated that low vitamin B6 concentrations are associated with inflammation, higher oxidative stress, and metabolic conditions in older adults (40). Out of all the studies included in our meta-analysis, only two reported on vitamin B supplementation and the risk of developing IA or T1DM. The lack of significant findings could be attributed to the insufficient data and the variability in study designs, which may have obscured potential effects. While the current evidence from our study does not support a significant role for vitamin B in preventing T1DM or IA, further research with larger sample sizes and more robust study designs is necessary to explore this potential relationship more comprehensively.

Our results also revealed an association between demographic factors and disease risk, namely maternal education levels. Higher maternal education levels were correlated with higher supplementation of vitamin D in their offspring. This finding demonstrates how socio-economic and educational disparities can directly influence health literacy (41). Significantly, a study by Viinikainen et al. affirmed that individuals with higher educational levels were not only less prone to risky health behaviors such as smoking, but also allocated more attention to healthy habits, for instance the consumption of fruit and vegetables (42). In the context of this study, more educated mothers potentially had greater access to health information and resources, leading to higher rates of supplementation. This finding emphasizes on the importance of public health initiatives to tackle educational and socio-economic barriers to increase health literacy in the general population, particularly in underprivileged communities. This finding emphasizes that maternal education levels, which influence vitamin D supplementation in offspring, may play a critical role in shaping early-life health outcomes that affect the risk of developing T1DM. Several studies have demonstrated an association between lower maternal education level and higher risk of developing T1DM (43, 44). Andersson et al. found that in a cohort of 16,365 Swedish parents, lower maternal education level was associated with an increased risk of developing T1DM (43). Similarly, in a cohort of 4647 Norwegian children, Ruiz et al. demonstrated that the children of mothers with a master’s degree had a lower risk of type 1 diabetes mellitus than children of mothers with only a completed upper secondary education (44). Adequate vitamin D levels during critical developmental periods could contribute to immune system modulation, potentially reducing the likelihood of autoimmune conditions like T1DM, particularly in populations with higher maternal health literacy. Additionally, stratification for socio-economic factors that could directly affect health outcomes should also be highlighted in future studies.

The inconsistencies in our findings compared to some previous studies highlight the complex nature of vitamin D’s role in T1DM and IA. Future research should aim to address these discrepancies by conducting large-scale, long-term randomized controlled trials with standardized protocols for vitamin supplementation and outcome assessment. Additionally, studies should consider stratifying participants based on baseline vitamin D status, genetic risk factors, and other relevant variables to identify subgroups that may benefit most from supplementation. A majority of studies included in our review examined vitamin D. Further studies of other vitamins which have an immunomodulatory or antioxidative effect would be beneficial to elucidate the role of micronutrients in the pathophysiology of T1DM and IA (45–49).

Our study demonstrated that the available literature presents inconsistent findings, likely due to substantial heterogeneity which complicates the ability to draw definitive conclusions regarding the efficacy of vitamin B and D supplementation in modifying the risk of developing IA, T1DM or progression of IA to T1DM. The data suggests that demographic factors can have an impact on T1DM risk. Vitamin D deficiencies are linked to a higher risk of developing T1DM. Vitamin D deficiency may be less likely in children to mothers with higher educational levels and health literacy, due to higher rates of vitamin D supplementation. This finding has important implications for public health initiatives, particularly when considering implementing prophylactic supplement programs. Our study provides a foundation for future research by contributing to the evolving landscape of nutritional immunology.