Effects of vitamin D and exercise on glycemic control and circulating 25(OH)D in adults with metabolic disorders: A systematic review and meta-analysis with GRADE assessment

Effects of vitamin D and exercise on glycemic control and circulating 25(OH)D in adults with metabolic disorders: A systematic review and meta-analysis with GRADE assessment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Effects of vitamin D and exercise on glycemic control and circulating 25(OH)D in adults with metabolic disorders: A systematic review and meta-analysis with GRADE assessment Mohammad Javad Pour Ahmadi, Maryam Sharifi, Shiva Shokri, Ghazal Mehranpour, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8122833/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background However, vitamin D and exercise are both key factors in regulating glycemic control; no previous study has examined their combined effects in adults with metabolic disorders. Hence, the current systematic review and meta-analysis aimed to evaluate the impact of vitamin D supplementation and exercise, both individually and in combination, on glycemic control and circulating 25(OH)D levels in adults with metabolic disorders. Methods This systematic review and meta-analysis followed PRISMA guidelines. SCOPUS, PubMed, Web of Science, and Google Scholar were searched until August 2025 for randomized controlled trials examining combined vitamin D supplementation and exercise in adults with metabolic disorders. Data extraction and risk of bias assessment were performed independently using the Cochrane RoB 2.0 tool, and evidence certainty was graded via GRADE. Random-effects models were applied using Comprehensive Meta-Analysis (version 3). Results Fifteen randomized controlled trials were analyzed. Vitamin D supplementation plus exercise significantly improved fasting blood glucose (FBG) (WMD: −16.59 mg/dL, 95% CI: −20.69 to − 12.48, P < 0.001), fasting insulin (WMD: −1.54 µU/mL, 95% CI: −2.34 to − 0.73, P < 0.001), HbA1c (WMD: −0.97%, 95% CI: −1.46 to − 0.48, P < 0.001), HOMA-IR (WMD: −0.98, 95% CI: −1.54 to − 0.42, P = 0.001), vitamin D (WMD: 14.39 ng/mL, 95% CI: 10.39 to 18.38, P < 0.001) compared to control. Vitamin D increased significantly in the aerobic group, while FBG, HOMA-IR, and fasting insulin declined in both aerobic and anaerobic subgroups. FBG, HOMA-IR, and vitamin D improved after 8- and 12-week interventions, whereas fasting insulin decreased only after 8 weeks. Conclusion The results of this study indicated that vitamin D supplementation alongside exercise can reduce FBS, fasting insulin, HbA1c, and HOMA-IR more effectively than either intervention alone or the control group. Furthermore, vitamin D supplementation combined with exercise, aerobic exercise can increase circulating 25(OH)D levels more than the other comparison groups. Nevertheless, additional well-designed studies are needed to strengthen and confirm these findings. Trial registration: PROSPERO, registration number CRD420251131187, retrospectively registered on 24 August 2025. metabolic disorders vitamin D exercise glycemic control Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Metabolic disorders are mainly considered as metabolic syndrome and type 2 diabetes mellitus, affecting approximately 25% worldwide population (1). They are defined by central obesity, hyperglycemia, insulin resistance, hypertension, and dyslipidemia (2). The pathophysiology of metabolic disorders is complex and involves interactions between genetic predisposition and environmental factors, including sedentary lifestyle, high-calorie dietary patterns, excess adiposity, and, in some cases, vitamin D deficiency. Furthermore, chronic inflammation and atherogenic lipid profiles resulting from excess adiposity and insulin resistance exacerbate the condition (3). Metabolic disorders encompass a wide range of chronic diseases, such as overweight and obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, and polycystic ovary syndrome (PCOS), which have substantially increased the global health burden. This indicated the necessity for developing effective approaches to prevent or manage these disorders (4). Vitamin D is a fat-soluble vitamin that is primarily synthesized in the epidermis of the skin and can be obtained through dietary intake. It plays several critical roles in the body, such as calcium homeostasis regulation, anti-inflammatory effects, and insulin-sensitizing effects (5). Vitamin D status is determined by serum 25-hydroxy vitamin D (25OHD) concentration, and levels below 50 nmol/L are defined as deficiency based on Endocrine Society guidelines, and it has a high prevalence affecting 30%–80% of the global population (6). Epidemiological studies have indicated an association between vitamin D deficiency and an increased risk of metabolic syndrome by reducing insulin secretion, increasing insulin resistance, hypertension, and dyslipidemia (7). The beneficial effects of regular exercise on glycemic parameters are consistently demonstrated by improving insulin sensitivity, promoting weight reduction, and decreasing systemic inflammation (8). Moreover, exercise may act synergistically with vitamin D by modulating metabolic pathways involved in glucose metabolism (9). Therefore, it is hypothesized that the combination of vitamin D supplementation and regular exercise plays a critical role in optimizing glycemic outcomes among individuals with metabolic disorders. Previous investigations have focused on the independent effect of vitamin D supplementation or exercise on glycemic parameters in adults with type 2 diabetes and metabolic syndrome. For instance, a meta-analysis of 46 randomized controlled trials reported that vitamin D supplementation significantly reduces fasting plasma glucose, glycated hemoglobin (HbA1c), and insulin resistance in patients with type 2 diabetes who were vitamin D deficient (10). Another systematic review involving 13 studies demonstrated that vitamin D supplementation reduced insulin resistance and blood pressure in adults with metabolic syndrome; however, it did not show a significant effect on HbA1c (11). The current evidence highlights the positive effect of exercise on glycemic status. For instance, a review with 13 studies with 731 participants found that the stretching interventions significantly reduced fasting blood glucose or HbA1c levels, particularly in T2DM patients (12). However, studies have demonstrated the beneficial effect of vitamin D or exercise on glycemia in individuals with T2DM and metabolic syndrome; no study has specifically analyzed the effect of vitamin D supplementation in people with metabolic disorders. Furthermore, despite evidence of the positive effect of exercise on glycemic control and vitamin D efficacy, no study has evaluated their combined effect. Current evidence remains inconclusive regarding whether vitamin D supplementation combined with exercise has a more favorable impact on vitamin D levels and glycemia in adults with metabolic disorders than either intervention alone. Therefore, this study aims to systematically evaluate the effects of vitamin D supplementation and exercise on glycemic control and circulating 25(OH)D concentration in adults with metabolic disorders. Methods Study Design and Registration We conducted this systematic review and meta-analysis in accordance with the updated PRISMA guidelines for reporting systematic reviews (13). The study's protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD420251131187). Search Strategy The databases SCOPUS, PubMed, ISI Web of Science, and Google Scholar were searched until August 2025. The search strategy included Medical Subject Headings (MeSH) and free-text terms related to “Vitamin D”, “Exercise”, “Glycemic control”, “Metabolic disorders,” and “Randomized controlled trials.” Details of our search strategy are shown in Supplementary Table 1 (see additional file 1). All related meta-analyses, review articles, and reference lists of included studies were screened to identify additional eligible studies. M.P. and G.M. independently screened titles, abstracts, and full texts for potentially eligible studies according to the selection criteria. Discrepancies were resolved by discussion. Eligibility Criteria We included randomized controlled trials (RCTs) that met the following criteria based on PICOS: Population: Adults (≥ 18 years) with metabolic disorders such as type 2 diabetes, NAFLD, metabolic syndrome, PCOS, obesity, or overweight (BMI ≥ 25) Intervention: Combined intervention of vitamin D supplementation and physical activity (main intervention of interest). Comparison: Each component alone (vitamin D or exercise alone), placebo, or no intervention — included only as comparator arms for secondary analyses. Outcomes: Fasting blood glucose (FBG), fasting insulin, HOMA-IR, HbA1c, and serum vitamin D In addition, the following criteria were applied: Only randomized controlled trials (parallel or crossover design) were included Studies were required to provide sufficient data to extract the net effect of the combined vitamin D and exercise intervention. No language restriction was applied; studies published in all languages were eligible. Animal studies, reviews, conference abstracts, protocols, and studies with incomplete or duplicate data were excluded. Studies with a duration of less than 2 weeks were excluded. Data Extraction and Quality Assessment Data were extracted by three reviewers using a standardized form. Extracted data included: first author, publication year, country, sample size, participant characteristics (age, sex, BMI, and health status), intervention details (type of physical activity, vitamin D form, dose, and duration), control group characteristics, and reported outcomes (baseline and post-intervention means and SDs). For studies that did not report means and standard deviations (SDs), these were estimated from available data (e.g., standard errors, confidence intervals, or medians and interquartile ranges) using standard formulas. Risk of bias was assessed using the revised Cochrane Risk of Bias tool for randomized trials (RoB 2.0) across five domains: randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of the reported results (14). Each study was rated as “low”, “some concerns”, or “high” risk of bias. The results of the risk of bias assessment were visualized using the online Robvis tool ( https://mcguinlu.shinyapps.io/robvis/ ) to generate both summary plots and traffic light plots. The certainty of evidence for each outcome was evaluated by using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework across five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias (15). Outcomes are classified as high, moderate, low, or very low certainty. Statistical Analysis All statistical analyses were conducted using Comprehensive Meta-Analysis software (CMA, version 3). For each outcome, effect sizes were expressed as mean difference (MD) with corresponding 95% confidence intervals (CIs). A random-effects model was applied as the primary analytical approach to account for between-study variability. When heterogeneity was negligible (I² <25%), a fixed-effects model was considered. Heterogeneity across studies was assessed using the chi-square test (Cochran’s Q) and quantified with the I² statistic. To test the robustness of the findings, sensitivity analyses were performed by sequentially removing individual studies. The primary analysis compared the combined vitamin D and exercise intervention with control/placebo groups. Secondary analyses examined vitamin D alone vs. control, exercise alone vs. control, and combined intervention vs. each single-component arm (vitamin D alone or exercise alone). For multi-arm trials sharing a common control group, the control group data were appropriately divided or adjusted to prevent double-counting. If data permitted, additional subgroup analyses were conducted based on exercise type (aerobic vs. anaerobic), and intervention duration. Furthermore, meta-regression analyses were performed for outcomes with a sufficient number of studies (≥ 9) to explore potential sources of heterogeneity and the influence of vitamin D dosage. For outcomes with fewer than nine studies, formal statistical tests for publication bias were not performed and potential bias was assessed qualitatively. For outcomes with at least nine included trials, publication bias was evaluated by visual inspection of funnel plots and formally tested with Egger’s (16) and Begg’s (17) tests. When evidence of publication bias was observed, the trim-and-fill method was applied to estimate adjusted effect sizes. Fail-safe N analyses were also conducted to determine the number of additional studies required to nullify the observed effects. Forest plots were generated to visually present the pooled estimates. A p-value < 0.05 was considered statistically significant. Language editing and clarity improvements were assisted by ChatGPT (OpenAI). All scientific content, data interpretation, and final decisions were made and verified by the authors. Results Literature search Figure 1 illustrates the study selection process used in the meta-analysis. Through the literature search, a total of 3526 studies were identified. After two rounds of screening, 3,490 studies were excluded. Of these, 1477 were removed as duplicates, and 2013 were excluded because they were reviews, non-human studies, or had irrelevant titles or abstracts. A total of 36 potentially eligible studies were retained for full-text review. Among them, 20 were excluded due to the absence of a control group (n = 12), not examining the target outcomes (n = 5), or having an intervention lasting less than four weeks (n = 2). Finally, 15 studies with 71 treatment arms were included in this systematic review and meta-analysis. Characteristics of the included studies and quality assessment Table 1 provides a summary of the general characteristics of the included studies. Among the 15 eligible studies published from 2014 to 2025, the majority originated from Iran (n = 10), while Iraq (n = 2), China (n = 2), and Korea (n = 1) contributed the remainder. All of these studies employed randomized controlled trial (RCT) designs. The combined analysis included 836 participants from all studies. Intervention groups included vitamin D combined with exercise (VDE), vitamin D alone (VD), and exercise alone. Participants included women and adults with various conditions such as vitamin D deficiency, non-alcoholic fatty liver (NAFLD), metabolic syndrome, type 2 diabetes, obesity, overweight, multiple sclerosis, and depression. Across all studies, the duration of the interventions ranged from 8 weeks to 12 months. The Cochrane risk of bias evaluation, performed using the RoB2 tool, for the included controlled trials is presented in Figure 2. Among the included studies, two were rated as having a low risk, seven as raising some concerns, and six as having a high risk of bias. Certainty of Evidence (GRADE) Table 2 shows the overall quality of evidence on the effects of combined exercise and vitamin D supplementation on glycemic control and vitamin D levels. All parameters were rated as “moderate” after downgrading for inconsistency. Fasting Blood Glucose (FBG) This meta-analysis included 9 RCTs to assess FBG levels across five pairwise comparisons. According to Figure 3, the primary comparison, evaluating vitamin D supplementation plus exercise (VDE) against control, demonstrated a significant reduction in FBG levels (WMD: −16.59 mg/dL, 95% CI: −20.69 to −12.48, P < 0.001, I² = 93.07%). Further analyses were conducted to examine both the separate and combined effects of each intervention. Significant reductions in FBG levels were observed in the exercise and VD groups compared with the control group, with WMDs of -10.90 mg/dL (95% CI: -14.64 to -7.15, P < 0.001, I² = 87.79%) and -8.43 mg/dL (95% CI: -10.76 to -6.10, P < 0.001, I² = 70.83%), respectively. FBG levels decreased significantly in the VDE group compared with the exercise group (WMD: -5.84 mg/dL, 95% CI: -8.37 to -3.31, P < 0.001, I² = 77.89%). Compared to the VD group, the VDE groups showed a significant reduction in FBG levels (WMD: -8.88 mg/dL, 95% CI: -12.63 to -5.13, P < 0.001, I² = 91.44%). The subgroup analyses were conducted based on exercise type (aerobic vs. anaerobic) and intervention duration (Table 4). In the VDE versus control comparison, stratification by exercise type revealed that both aerobic and anaerobic exercises significantly reduced fasting blood glucose (FBG) levels with WMDs of −20.49 mg/dL (95% CI: −23.37 to −17.61, P < 0.001) and −15.77 mg/dL (95% CI: −34.54 to −2.98, P < 0.001), respectively. When studies were categorized by intervention length, significant reductions in FBG were observed for both 8-week (WMD = −14.07 mg/dL, 95% CI: −25.47 to −2.67, P = 0.016) and 12-week interventions (WMD = −17.48 mg/dL, 95% CI: −21.95 to −13.02, P < 0.001). Additional details of these comparisons are presented in Table 4. Sensitivity analysis showed stable effect sizes in the VDE vs. control comparison, indicating that omitting any study did not alter the pooled results. Outcomes for other comparisons are presented in Table 3. Meta-regression analysis examined the relationship between vitamin D dose and changes in FBG levels. No significant association was found in the VDE vs. control comparison (Figure 4). Funnel plots showed no significant asymmetry in vitamin D level analyses for the VDE vs. control comparison. Similarly, Egger’s regression (Intercept: 2.01, 95% CI: -1.76 to 5.78, P = 0.247) and Begg’s test (P = 0.754) revealed no publication bias in any comparison. Fasting insulin Six RCTs assessed fasting insulin across five pairwise comparisons. In the primary analysis, VDE versus control resulted in a significant reduction in fasting insulin (WMD: −1.54 μU/mL, 95% CI: −2.34 to −0.73, P < 0.001, I² = 93.60%) (Figure 5). Supplementary analyses indicated significant decreases in the exercise (WMD: −1.13 μU/mL, 95% CI: −1.81 to −0.44, P = 0.001, I² = 88.78%) and VD groups (WMD: −0.76 μU/mL, 95% CI: −1.30 to −0.23, P = 0.005, I² = 83.27%) compared with control. Furthermore, VDE significantly lowered fasting insulin relative to exercise (WMD: −0.35 μU/mL, 95% CI: −0.62 to −0.08, P = 0.009, I² = 41.99%), whereas no significant difference was observed between VDE and VD (WMD: −0.69 μU/mL, 95% CI: −1.80 to 0.41, P = 0.22, I² = 91.44%). Subgroup analyses by exercise type and intervention length showed that in VDE vs. control, fasting insulin significantly decreased in both aerobic (WMD: −1.40 μU/mL, 95% CI: −2.74 to −0.05, P = 0.041) and anaerobic subgroups (WMD: −1.55 μU/mL, 95% CI: −2.40 to −0.70, P < 0.001). By duration, 8-week interventions showed a significant reduction (WMD: −1.67 μU/mL, 95% CI: −2.68 to −0.67, P < 0.001), while 12-week interventions were not significant (WMD: −1.37 μU/mL, 95% CI: −2.76 to −0.02, P = 0.053). Further details are in Table 4. Leave-one-out sensitivity analysis confirmed the robustness of the VDE vs. control effect sizes, as removing any study did not alter the overall results. Findings for other comparisons are shown in Table 3. HbA1c This meta-analysis included three RCTs assessing HbA1c across five pairwise comparisons. As presented in Figure 6, the primary analysis (VDE vs. control) showed a significant HbA1c reduction (WMD: −0.97%, 95% CI: −1.46 to −0.48, P < 0.001, I² = 58.33%). Additional analyses examining individual and combined effects found no significant changes in the exercise (WMD: −0.59%, 95% CI: −1.40 to 0.20, P = 0.147, I² = 88.99%) or VD groups (WMD: −0.65%, 95% CI: −2.27 to 0.95, P = 0.424, I² = 91.50%) versus control. HbA1c decreased significantly in VDE compared with exercise (WMD: −0.42%, 95% CI: −0.63 to −0.21, P < 0.001, I² = 0%), but not versus VD (WMD: −0.07%, 95% CI: −0.53 to 0.38, P = 0.750, I² = 0%). Sensitivity analysis showed that the VDE vs. control effect sizes were influenced by the study of Ruipeng et al. (21); removing it rendered the results non-significant (see figure 1 on additional file 2). HOMA-IR Five RCTs evaluated HOMA-IR across five pairwise comparisons. As shown in Figure 7, the primary analysis showed a significant reduction in HOMA-IR for VDE versus control (WMD: −0.98, 95% CI: −1.54 to −0.42, P = 0.001, I² = 93.23%). Supplementary analyses indicated significant decreases for exercise (WMD: −0.58, 95% CI: −1.08 to −0.08, P = 0.022, I² = 90.85%) and VD (WMD: −0.38, 95% CI: −0.57 to −0.19, P < 0.001, I² = 40.41%) compared with control. Moreover, VDE further reduced HOMA-IR relative to exercise (WMD: −0.33, 95% CI: −0.43 to −0.23, P < 0.001, I² = 0%) and VD (WMD: −0.55, 95% CI: −0.94 to −0.16, P = 0.005, I² = 86.51%). Subgroup analyses classified interventions as aerobic or anaerobic. VDE vs. control revealed significant HOMA-IR reductions in both aerobic (WMD: −1.02, 95% CI: −1.77 to −0.27, P = 0.008) and anaerobic subgroups (WMD: −0.94, 95% CI: −1.55 to −0.32, P = 0.003). Stratification by duration also showed significant reductions for both 8-week (WMD: −1.01, 95% CI: −1.81 to −0.20, P = 0.014) and 12-week interventions (WMD: −0.96, 95% CI: −1.46 to −0.46, P < 0.001). Further details are in Table 4. The sensitivity analysis showed that the effect sizes for VDE vs. control comparison remained stable in the leave-one-out analysis (Table 3). Vitamin D Twelve RCTs were included in this meta-analysis to investigate Vitamin D levels across five pairwise comparisons. Comparing VDE with the control group in the primary analysis revealed a notable increase in vitamin D levels (WMD: 14.39 ng/mL, 95% CI: 10.39 to 18.38, P < 0.001, I² = 98.58%) (Figure 8). Further analyses were undertaken to determine the separate and additive contributions of each intervention. Significant elevations in Vitamin D levels were observed in the exercise and VD groups compared to the control group, with WMDs of 3.34 ng/ml (95% CI: 1.40 to 5.27, P = 0.001, I² = 95.50%), and 12.05 ng/ml (95% CI: 8.01 to 16.10, P < 0.001, I² = 98.43%), respectively. Comparing VDE to exercise groups, a significant elevation in Vitamin D levels was observed in the VDE group (WMD: 10.49 ng/ml, 95% CI: 7.93 to 13.95, P < 0.001, I² = 98.71%). Vitamin D levels were significantly higher in the VDE groups compared with the VD group (WMD: 2.45 ng/ml, 95% CI: 0.81 to 4.09, P = 0.003, I² = 94.66%). Subgroup analyses of VDE vs. control, stratified by exercise type and intervention duration, showed a significant vitamin D increase in the aerobic subgroup (WMD: 16.86 ng/mL, 95% CI: 13.97 to 19.75, P < 0.001), but not in the anaerobic subgroup (WMD: 8.40 ng/mL, 95% CI: −0.56 to 17.37, P = 0.066). Stratification by duration revealed significant increases for both 8-week (WMD: 13.57 ng/mL, 95% CI: 7.96 to 19.18, P < 0.001) and 12-week interventions (WMD: 15.36 ng/mL, 95% CI: 10.02 to 20.70, P < 0.001). Further details are provided in Table 4. Leave-one-out sensitivity analysis showed consistently robust effect sizes in the VDE vs. control comparison, as excluding any study did not affect the overall results (Table 3). Figure 8 shows that meta-regression found no significant association between vitamin D dose and changes in vitamin D levels in the VDE vs. control comparison. Funnel plots showed no notable asymmetry in the VDE vs. control meta-analyses for vitamin D levels. Likewise, Egger’s regression (Intercept: 4.10, 95% CI: -5.77 to 13.98, P = 0.379) and Begg’s test (P > 0.999) indicated no publication bias across comparisons. Discussion The present study, for the first time, aimed to examine the combined effects of vitamin D supplementation and exercise on glycemic parameters in adults with metabolic disorders. The results of 15 clinical trials show that vitamin D supplementation, together with regular exercise, had a more significant effect on reducing FBS, fasting insulin, HbA1c, and HOMA-IR compared with either intervention alone or the control group. Subgroup analysis illustrated that, alongside vitamin D supplementation, both aerobic and anaerobic exercise performed for 8 to 12 weeks improved FBS and HOMA-IR. However, fasting insulin levels reduced significantly when the intervention was carried out for 8 weeks. Furthermore, a substantial increase was observed in circulating 25(OH)D levels was observed when vitamin D supplementation was combined with exercise, particularly aerobic exercise, compared with the control group, the vitamin D only group, or the exercise only group. It is worth noting that the clinical trials mentioned that to decrease the bias of the studies, the sun exposure of all participants did not differ significantly during the study. Additionally, the exercises mainly were preferred indoors at the gym. The high prevalence of metabolic disorders and their association with the increased risk of other chronic diseases, for instance, cardiometabolic diseases, T2DM, and NAFLD, is considered one of the major global health burdens today (33). According to the evidence, roughly one-quarter of the global population suffers from metabolic syndrome, which highlights the urgent need to address these interconnected health issues (34). Metabolic disorders are strongly associated with central obesity and disturbances in glycemic control, mainly due to insulin resistance, which leads to hyperinsulinemia, increased FBS, chronic inflammation, oxidative stress, and lipid accumulation (35). Over time, it also results in impaired β-cell function in the pancreas and reduces insulin secretion capacity (35). This dual impairment of insulin action and insulin production progressively worsens glycemic control, resulting in elevated fasting glucose, increased postprandial glucose, and higher HbA1c levels (36). There is a bidirectional relationship between inflammatory cytokines and insulin resistance. Inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-α), promote insulin resistance in skeletal muscle, liver, and adipose tissue by impairing insulin receptor signaling (37). In turn, insulin resistance further stimulates the production of inflammatory cytokines and contributes to thrombogenesis by increasing fibrinogen levels, consequently leading to microvascular damage (38). Lifestyle modification, including adherence to a healthy diet and regular physical activity, is considered the main treatment for metabolic disorders (39). The American Heart Association and the American College of Cardiology recommend at least 150 minutes of moderate-intensity exercise or 75 minutes of high-intensity exercise each week (40). On the other hand, diets rich in vegetables, fruits, legumes, fish, whole grains, and nuts do not provide enough vitamin D (41). The primary source of endogenous vitamin D is sun exposure, which is often insufficient due to air pollution, the risk of skin cancer, and reduced outdoor activity. Considering the critical role of vitamin D in glycemic control and metabolic function, supplementation is necessary for individuals at risk of deficiency (42). Recent studies have reported controversial effects of vitamin D supplementation on glycemic markers in different populations. For instance, a systematic review of 25 studies found no significant effect of vitamin D supplementation on glycemic markers such as FBS, insulin, HOMA-IR, and HbA1c, in adults with obesity or related metabolic disorders (43). Another review of 18 studies declares that the combination of vitamin D supplementation and exercise has been demonstrated to improve glucolipid metabolism more effectively than either intervention alone in adults (44). A study showed that vitamin D supplementation improved FBS, HbA1c, and HOMA-IR in T2DM patients with vitamin D deficiency (45). Importantly, one study revealed that the risk of metabolic syndrome is higher in adults more than 60 years old who have insufficient or low levels of total serum vitamin D and vitamin D3. Hence, providing enough vitamin D is a crucial issue to prevent metabolic syndrome among this population (46). However, the findings about the beneficial effect of exercise on glycemic indices were almost conclusive. An investigation included 20 studies and 1,192 participants reported that the combined aerobic and resistance training significantly reduced HbA1c in overweight and obese T2DM patients (47). Another meta-analysis of 24 clinical trials concluded that engaging in any form of exercise is more effective than no exercise for improving glycemic control in individuals with prediabetes. However, it illustrated that different exercise modalities have distinct benefits: the combination of moderate-intensity aerobic exercise with low-to moderate-load resistance training resulted in the substantial reduction in HbA1c; low-to moderate-load resistance training alone indicated the most significant improvement in FBG; and vigorous-intensity aerobic exercise led to the considerable reductions in 2-hour postprandial glucose (2hPG) levels (48). Furthermore, analysis from 775 prediabetics indicated that resistance and interval training have a positive impact on glycemic indices, especially on FBS (49). Both vitamin D supplementation and exercise exert beneficial effects on glycemic regulation through three main mechanisms that result in a synergistic improvement in insulin sensitivity and glucose homeostasis. Exercise increases insulin sensitivity by stimulating GLUT4 translocation to the skeletal muscle cell membrane, thereby increasing glucose uptake (50). Vitamin D, however, enhances insulin signaling by activating the vitamin D receptor (VDR) in muscle and adipose tissue, leading to upregulation of insulin receptor expression and improved downstream signaling pathways involved in glucose metabolism (51). The overall processes result in greater translocation of GLUT4 and improved insulin receptor responsiveness. The combined intervention may also affect β-cell function. Vitamin D regulates calcium homeostasis and protects pancreatic β-cells against oxidative and inflammatory injury, while exercise reduces glucotoxicity and lipotoxicity, helping to mitigate β-cell stress and insulin secretory capacity (52). Finally, both vitamin D and exercise possess anti-inflammatory properties. Exercise, including aerobic and resistance training, reduces systemic inflammation partly by increasing muscle-derived IL-6, which subsequently suppresses TNF-α and other pro-inflammatory markers (53). However, vitamin D inhibits the activation of the NF-κB pathway (54). Thus, the combined effect may have an effect on lowering systemic inflammation, improving insulin signaling pathways, and reducing insulin resistance. The analysis of the present study illustrates that both vitamin D supplementation and exercise positively improve glycemic parameters in adults with metabolic disorders, while the combination appears to have a synergistic effect. Moreover, the combination intervention showed a clinically significant reduction in FBS (>14 mg/dl) and HbA1c (> 0.5%) in these patients (55). Hence, incorporating exercise alongside vitamin D supplementation may be considered as a valuable adjunctive treatment for glycemic control in individuals with metabolic disorders. Strengths, Limitations, Future Suggestions The present GRADE-assessed meta-analysis offers several notable strengths. The most important one is the large-scale inclusion of RCTs across diverse metabolic disorders, including overweight and obesity, premenopausal women, T2DM, NAFLD, and PCOS, which enhances the reliability and generalizability of the findings. Additionally, it provides a comprehensive assessment of glycemic parameters such as FBS, fasting insulin, HbA1c, and HOMA-IR by detailing the combined effects of vitamin D supplementation and exercise on metabolic health. This study conducted detailed subgroup analyses to explore sources of heterogeneity of study duration and types of exercises. Moreover, in order to ensure the robustness and reliability of the findings, rigorous sensitivity analyses and publication bias assessments were performed. However, a number of limitations should be acknowledged. Considerable heterogeneity exists among the included studies in terms of study settings, participant characteristics (such as gender, age, and BMI), study locations, and intervention durations. Hence, the findings should be interpreted with caution, as definitive conclusions cannot be made. Furthermore, the relatively small sample size of many included studies may have limited the generalizability and the statistical power of the findings. To overcome these limitations, future research is suggested to focus on conducting large-scale, multicenter RCTs with longer follow-up durations. Conclusion The result of this study sheds light on the beneficial effect of the combination of vitamin D supplementation and exercise on glycemic profile, including reducing FBS, fasting insulin, HbA1c, and HOMA-IR more than either intervention alone or the control group. Furthermore, subgroup analysis illustrated that, alongside vitamin D supplementation, 8 to 12 weeks of both aerobic and anaerobic exercise significantly reduced the level of FBS and HOMA-IR, while fasting insulin levels reduced when the intervention was carried out for 8 weeks. Vitamin D supplementation combined with exercise, specifically aerobic, can increase circulating 25(OH)D levels more than the other comparison groups. However, further well-designed studies with large-scale RCTs with longer duration are needed to strengthen and confirm these findings. Abbreviations non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), serum 25-hydroxy vitamin D (25OHD), glycated hemoglobin (HbA1c), Medical Subject Headings (MeSH), Fasting blood glucose (FBG), standard deviations (SDs), Grading of Recommendations, Assessment, Development, and Evaluation (GRADE), confidence intervals (CIs), tumor necrosis factor-alpha (TNF-α), homeostatic model assessment of insulin resistance (HOMA-IR), vitamin D + exercise group (VDE), vitamin D group (VD), exercise group (E), control group (C), indoor physical activity (IPA), outdoor physical activity (OPA) Declarations Ethics approval and consent to participate: Not applicable. This study is a systematic review and meta-analysis of previously published human studies. The study protocol was registered in PROSPERO (registration number CRD420251131187, retrospectively registered on 24 August 2025). Consent for publication: Not applicable. This article does not contain any individual person’s data. Availability of data and materials: All data generated or analysed during this study are included in this published article and its additional information files. Competing interests: The authors declare that they have no competing interests. Funding: Not applicable. This research did not receive any specific funding. Authors' contributions: MJP: conceptualized the study, designed the title, conducted the literature search and screening, drafted the methods section, prepared most of the tables, and performed the statistical analyses. MS: wrote the Introduction and Discussion sections. SS: performed data extraction and wrote the Results section. GM: performed data extraction, designed the table of included studies, and double-checked screening and extracted information. FE: performed data extraction, designed the Abstract figure, and assisted with figure preparation. All authors read and approved the final manuscript. 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Alignment between outcomes and minimal clinically important differences in the Dutch type 2 diabetes mellitus guideline and healthcare professionals' preferences. Pharmacology research & perspectives. 2021;9(3):e00750. Tables Tables 1 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files additionalfile1supplementarytables.docx additionalfile2supplementaryfigures.pdf Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 12 Dec, 2025 Reviewers invited by journal 12 Dec, 2025 Editor invited by journal 21 Nov, 2025 Editor assigned by journal 20 Nov, 2025 Submission checks completed at journal 20 Nov, 2025 First submitted to journal 15 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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supplementation on fasting blood glucose (FBG). (B) Meta-regression plot illustrating the association between vitamin D dose and effect size on FBG.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8122833/v1/3bc1cb81926379986da23c60.jpg"},{"id":98623065,"identity":"cd43db8d-c718-446b-89ee-ae7f178e2292","added_by":"auto","created_at":"2025-12-19 17:04:22","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":512743,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing the pooled effect of combined exercise and vitamin D supplementation on fasting insulin.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8122833/v1/619a078d14c183c7cd31e797.jpg"},{"id":98450301,"identity":"148cfe0d-e57a-4da6-a694-b3c1b33046de","added_by":"auto","created_at":"2025-12-17 17:30:17","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":489508,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing the pooled effect of combined exercise and vitamin D supplementation on Hb1c.\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8122833/v1/450af97128bd1913119fe787.jpg"},{"id":98450110,"identity":"fd97f224-c58f-44f4-b22d-5517d57e7725","added_by":"auto","created_at":"2025-12-17 17:30:11","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":377482,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing the pooled effect of combined exercise and vitamin D supplementation on HOMA-IR.\u003c/p\u003e","description":"","filename":"Figure7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8122833/v1/4c803ed21d623c2cea65397d.jpg"},{"id":98450315,"identity":"c28dcf31-6d37-4b75-bae9-9dd865ee8bce","added_by":"auto","created_at":"2025-12-17 17:30:19","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":631312,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Forest plot showing the pooled effect of combined exercise and vitamin D supplementation on serum vitamin D.\u003c/p\u003e\n\u003cp\u003e(B) Meta-regression plot illustrating the association between vitamin D dose and effect size on serum vitamin D.\u003c/p\u003e","description":"","filename":"Figure8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8122833/v1/05285dead9d74a44feacde40.jpg"},{"id":98631289,"identity":"477b8c46-9d61-42a6-a5f6-d2d3293ae272","added_by":"auto","created_at":"2025-12-19 17:19:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5473981,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8122833/v1/6765da65-bf27-4c40-a3a8-9bc3876cddb7.pdf"},{"id":98449894,"identity":"522a2f25-19d9-4e9d-9954-bd15a5c669a3","added_by":"auto","created_at":"2025-12-17 17:30:04","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32257,"visible":true,"origin":"","legend":"","description":"","filename":"additionalfile1supplementarytables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8122833/v1/7b11299c1f052283a2985d16.docx"},{"id":98450250,"identity":"04046249-d10d-41dd-8250-67634cec8906","added_by":"auto","created_at":"2025-12-17 17:30:15","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":413705,"visible":true,"origin":"","legend":"","description":"","filename":"additionalfile2supplementaryfigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8122833/v1/81b53c04e6bb7f1eeacba6fb.pdf"},{"id":98449879,"identity":"80706da0-a089-4078-9f7f-d65c56f8e877","added_by":"auto","created_at":"2025-12-17 17:30:03","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":83231,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8122833/v1/0bee74cd1a4aed517251c48c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eEffects of vitamin D and exercise on glycemic control and circulating 25(OH)D in adults with metabolic disorders: A systematic review and meta-analysis with GRADE assessment\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMetabolic disorders are mainly considered as metabolic syndrome and type 2 diabetes mellitus, affecting approximately 25% worldwide population (1). They are defined by central obesity, hyperglycemia, insulin resistance, hypertension, and dyslipidemia (2). The pathophysiology of metabolic disorders is complex and involves interactions between genetic predisposition and environmental factors, including sedentary lifestyle, high-calorie dietary patterns, excess adiposity, and, in some cases, vitamin D deficiency. Furthermore, chronic inflammation and atherogenic lipid profiles resulting from excess adiposity and insulin resistance exacerbate the condition (3). Metabolic disorders encompass a wide range of chronic diseases, such as overweight and obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, and polycystic ovary syndrome (PCOS), which have substantially increased the global health burden. This indicated the necessity for developing effective approaches to prevent or manage these disorders (4).\u003c/p\u003e\u003cp\u003eVitamin D is a fat-soluble vitamin that is primarily synthesized in the epidermis of the skin and can be obtained through dietary intake. It plays several critical roles in the body, such as calcium homeostasis regulation, anti-inflammatory effects, and insulin-sensitizing effects (5). Vitamin D status is determined by serum 25-hydroxy vitamin D (25OHD) concentration, and levels below 50 nmol/L are defined as deficiency based on Endocrine Society guidelines, and it has a high prevalence affecting 30%\u0026ndash;80% of the global population (6). Epidemiological studies have indicated an association between vitamin D deficiency and an increased risk of metabolic syndrome by reducing insulin secretion, increasing insulin resistance, hypertension, and dyslipidemia (7).\u003c/p\u003e\u003cp\u003eThe beneficial effects of regular exercise on glycemic parameters are consistently demonstrated by improving insulin sensitivity, promoting weight reduction, and decreasing systemic inflammation (8). Moreover, exercise may act synergistically with vitamin D by modulating metabolic pathways involved in glucose metabolism (9). Therefore, it is hypothesized that the combination of vitamin D supplementation and regular exercise plays a critical role in optimizing glycemic outcomes among individuals with metabolic disorders.\u003c/p\u003e\u003cp\u003ePrevious investigations have focused on the independent effect of vitamin D supplementation or exercise on glycemic parameters in adults with type 2 diabetes and metabolic syndrome. For instance, a meta-analysis of 46 randomized controlled trials reported that vitamin D supplementation significantly reduces fasting plasma glucose, glycated hemoglobin (HbA1c), and insulin resistance in patients with type 2 diabetes who were vitamin D deficient (10). Another systematic review involving 13 studies demonstrated that vitamin D supplementation reduced insulin resistance and blood pressure in adults with metabolic syndrome; however, it did not show a significant effect on HbA1c (11). The current evidence highlights the positive effect of exercise on glycemic status. For instance, a review with 13 studies with 731 participants found that the stretching interventions significantly reduced fasting blood glucose or HbA1c levels, particularly in T2DM patients (12).\u003c/p\u003e\u003cp\u003eHowever, studies have demonstrated the beneficial effect of vitamin D or exercise on glycemia in individuals with T2DM and metabolic syndrome; no study has specifically analyzed the effect of vitamin D supplementation in people with metabolic disorders. Furthermore, despite evidence of the positive effect of exercise on glycemic control and vitamin D efficacy, no study has evaluated their combined effect. Current evidence remains inconclusive regarding whether vitamin D supplementation combined with exercise has a more favorable impact on vitamin D levels and glycemia in adults with metabolic disorders than either intervention alone. Therefore, this study aims to systematically evaluate the effects of vitamin D supplementation and exercise on glycemic control and circulating 25(OH)D concentration in adults with metabolic disorders.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design and Registration\u003c/h2\u003e\u003cp\u003eWe conducted this systematic review and meta-analysis in accordance with the updated PRISMA guidelines for reporting systematic reviews (13). The study's protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD420251131187).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSearch Strategy\u003c/h3\u003e\n\u003cp\u003eThe databases SCOPUS, PubMed, ISI Web of Science, and Google Scholar were searched until August 2025. The search strategy included Medical Subject Headings (MeSH) and free-text terms related to \u0026ldquo;Vitamin D\u0026rdquo;, \u0026ldquo;Exercise\u0026rdquo;, \u0026ldquo;Glycemic control\u0026rdquo;, \u0026ldquo;Metabolic disorders,\u0026rdquo; and \u0026ldquo;Randomized controlled trials.\u0026rdquo; Details of our search strategy are shown in Supplementary Table\u0026nbsp;1 (see additional file 1). All related meta-analyses, review articles, and reference lists of included studies were screened to identify additional eligible studies. M.P. and G.M. independently screened titles, abstracts, and full texts for potentially eligible studies according to the selection criteria. Discrepancies were resolved by discussion.\u003c/p\u003e\n\u003ch3\u003eEligibility Criteria\u003c/h3\u003e\n\u003cp\u003eWe included randomized controlled trials (RCTs) that met the following criteria based on PICOS:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003ePopulation: Adults (\u0026ge;\u0026thinsp;18 years) with metabolic disorders such as type 2 diabetes, NAFLD, metabolic syndrome, PCOS, obesity, or overweight (BMI\u0026thinsp;\u0026ge;\u0026thinsp;25)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eIntervention: Combined intervention of vitamin D supplementation and physical activity (main intervention of interest).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eComparison: Each component alone (vitamin D or exercise alone), placebo, or no intervention \u0026mdash; included only as comparator arms for secondary analyses.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eOutcomes: Fasting blood glucose (FBG), fasting insulin, HOMA-IR, HbA1c, and serum vitamin D\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eIn addition, the following criteria were applied:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eOnly randomized controlled trials (parallel or crossover design) were included\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStudies were required to provide sufficient data to extract the net effect of the combined vitamin D and exercise intervention.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eNo language restriction was applied; studies published in all languages were eligible.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAnimal studies, reviews, conference abstracts, protocols, and studies with incomplete or duplicate data were excluded.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStudies with a duration of less than 2 weeks were excluded.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\n\u003ch3\u003eData Extraction and Quality Assessment\u003c/h3\u003e\n\u003cp\u003eData were extracted by three reviewers using a standardized form. Extracted data included: first author, publication year, country, sample size, participant characteristics (age, sex, BMI, and health status), intervention details (type of physical activity, vitamin D form, dose, and duration), control group characteristics, and reported outcomes (baseline and post-intervention means and SDs). For studies that did not report means and standard deviations (SDs), these were estimated from available data (e.g., standard errors, confidence intervals, or medians and interquartile ranges) using standard formulas.\u003c/p\u003e\u003cp\u003eRisk of bias was assessed using the revised Cochrane Risk of Bias tool for randomized trials (RoB 2.0) across five domains: randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, and selection of the reported results (14). Each study was rated as \u0026ldquo;low\u0026rdquo;, \u0026ldquo;some concerns\u0026rdquo;, or \u0026ldquo;high\u0026rdquo; risk of bias.\u003c/p\u003e\u003cp\u003eThe results of the risk of bias assessment were visualized using the online Robvis tool (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://mcguinlu.shinyapps.io/robvis/\u003c/span\u003e\u003cspan address=\"https://mcguinlu.shinyapps.io/robvis/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to generate both summary plots and traffic light plots.\u003c/p\u003e\u003cp\u003eThe certainty of evidence for each outcome was evaluated by using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework across five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias (15). Outcomes are classified as high, moderate, low, or very low certainty.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eAll statistical analyses were conducted using Comprehensive Meta-Analysis software (CMA, version 3). For each outcome, effect sizes were expressed as mean difference (MD) with corresponding 95% confidence intervals (CIs). A random-effects model was applied as the primary analytical approach to account for between-study variability. When heterogeneity was negligible (I\u0026sup2; \u0026lt;25%), a fixed-effects model was considered. Heterogeneity across studies was assessed using the chi-square test (Cochran\u0026rsquo;s Q) and quantified with the I\u0026sup2; statistic.\u003c/p\u003e\u003cp\u003eTo test the robustness of the findings, sensitivity analyses were performed by sequentially removing individual studies. The primary analysis compared the combined vitamin D and exercise intervention with control/placebo groups. Secondary analyses examined vitamin D alone vs. control, exercise alone vs. control, and combined intervention vs. each single-component arm (vitamin D alone or exercise alone).\u003c/p\u003e\u003cp\u003eFor multi-arm trials sharing a common control group, the control group data were appropriately divided or adjusted to prevent double-counting.\u003c/p\u003e\u003cp\u003eIf data permitted, additional subgroup analyses were conducted based on exercise type (aerobic vs. anaerobic), and intervention duration.\u003c/p\u003e\u003cp\u003eFurthermore, meta-regression analyses were performed for outcomes with a sufficient number of studies (\u0026ge;\u0026thinsp;9) to explore potential sources of heterogeneity and the influence of vitamin D dosage. For outcomes with fewer than nine studies, formal statistical tests for publication bias were not performed and potential bias was assessed qualitatively. For outcomes with at least nine included trials, publication bias was evaluated by visual inspection of funnel plots and formally tested with Egger\u0026rsquo;s (16) and Begg\u0026rsquo;s (17) tests. When evidence of publication bias was observed, the trim-and-fill method was applied to estimate adjusted effect sizes. Fail-safe N analyses were also conducted to determine the number of additional studies required to nullify the observed effects. Forest plots were generated to visually present the pooled estimates. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003cp\u003eLanguage editing and clarity improvements were assisted by ChatGPT (OpenAI). All scientific content, data interpretation, and final decisions were made and verified by the authors.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eLiterature search\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 illustrates the study selection process used in the meta-analysis. Through the literature search, a total of 3526 studies were identified. After two rounds of screening, 3,490 studies were excluded. Of these, 1477 were removed as duplicates, and 2013 were excluded because they were reviews, non-human studies, or had irrelevant titles or abstracts. A total of 36 potentially eligible studies were retained for full-text review. Among them, 20 were excluded due to the absence of a control group (n = 12), not examining the target outcomes (n = 5), or having an intervention lasting less than four weeks (n = 2). Finally, 15 studies with 71 treatment arms were included in this systematic review and meta-analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCharacteristics of the included studies and quality assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 provides a summary of the general characteristics of the included studies. Among the 15 eligible studies published from 2014 to 2025, the majority originated from Iran (n = 10), while Iraq (n = 2), China (n = 2), and Korea (n = 1) contributed the remainder. All of these studies employed randomized controlled trial (RCT) designs. The combined analysis included 836 participants from all studies. Intervention groups included vitamin D combined with exercise (VDE), vitamin D alone (VD), and exercise alone. Participants included women and adults with various conditions such as vitamin D deficiency, non-alcoholic fatty liver (NAFLD), metabolic syndrome, type 2 diabetes, obesity, overweight, multiple sclerosis, and depression. Across all studies, the duration of the interventions ranged from 8 weeks to 12 months. The Cochrane risk of bias evaluation, performed using the RoB2 tool, for the included controlled trials is presented in Figure 2. Among the included studies, two were rated as having a low risk, seven as raising some concerns, and six as having a high risk of bias.\u003c/p\u003e\n\u003cp\u003eCertainty of Evidence (GRADE)\u003c/p\u003e\n\u003cp\u003eTable 2 shows the overall quality of evidence on the effects of combined exercise and vitamin D supplementation on glycemic control and vitamin D levels. All parameters were rated as \u0026ldquo;moderate\u0026rdquo; after downgrading for inconsistency.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFasting Blood Glucose (FBG)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis meta-analysis included 9 RCTs to assess FBG levels across five pairwise comparisons. According to Figure 3, the primary comparison, evaluating vitamin D supplementation plus exercise (VDE) against control, demonstrated a significant reduction in FBG levels (WMD: \u0026minus;16.59 mg/dL, 95% CI: \u0026minus;20.69 to \u0026minus;12.48, P \u0026lt; 0.001, I\u0026sup2; = 93.07%). Further analyses were conducted to examine both the separate and combined effects of each intervention. Significant reductions in FBG levels were observed in the exercise and VD groups compared with the control group, with WMDs of -10.90 mg/dL (95% CI: -14.64 to -7.15, P \u0026lt; 0.001, I\u0026sup2; = 87.79%) and -8.43 mg/dL (95% CI: -10.76 to -6.10, P \u0026lt; 0.001, I\u0026sup2; = 70.83%), respectively. FBG levels decreased significantly in the VDE group compared with the exercise group (WMD: -5.84 mg/dL, 95% CI: -8.37 to -3.31, P \u0026lt; 0.001, I\u0026sup2; = 77.89%). Compared to the VD group, the VDE groups showed a significant reduction in FBG levels (WMD: -8.88 mg/dL, 95% CI: -12.63 to -5.13, P \u0026lt; 0.001, I\u0026sup2; = 91.44%). The subgroup analyses were conducted based on exercise type (aerobic vs. anaerobic) and intervention duration (Table 4). In the VDE versus control comparison, stratification by exercise type revealed that both aerobic and anaerobic exercises significantly reduced fasting blood glucose (FBG) levels with WMDs of \u0026minus;20.49 mg/dL (95% CI: \u0026minus;23.37 to \u0026minus;17.61, P \u0026lt; 0.001) and \u0026minus;15.77 mg/dL (95% CI: \u0026minus;34.54 to \u0026minus;2.98, P \u0026lt; 0.001), respectively. When studies were categorized by intervention length, significant reductions in FBG were observed for both 8-week (WMD = \u0026minus;14.07 mg/dL, 95% CI: \u0026minus;25.47 to \u0026minus;2.67, P = 0.016) and 12-week interventions (WMD = \u0026minus;17.48 mg/dL, 95% CI: \u0026minus;21.95 to \u0026minus;13.02, P \u0026lt; 0.001). Additional details of these comparisons are presented in Table 4. Sensitivity analysis showed stable effect sizes in the VDE vs. control comparison, indicating that omitting any study did not alter the pooled results. Outcomes for other comparisons are presented in Table 3. Meta-regression analysis examined the relationship between vitamin D dose and changes in FBG levels. No significant association was found in the VDE vs. control comparison (Figure 4). Funnel plots showed no significant asymmetry in vitamin D level analyses for the VDE vs. control comparison. Similarly, Egger\u0026rsquo;s regression (Intercept: 2.01, 95% CI: -1.76 to 5.78, P = 0.247) and Begg\u0026rsquo;s test (P = 0.754) revealed no publication bias in any comparison.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFasting insulin\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSix RCTs assessed fasting insulin across five pairwise comparisons. In the primary analysis, VDE versus control resulted in a significant reduction in fasting insulin (WMD: \u0026minus;1.54 \u0026mu;U/mL, 95% CI: \u0026minus;2.34 to \u0026minus;0.73, P \u0026lt; 0.001, I\u0026sup2; = 93.60%) (Figure 5). Supplementary analyses indicated significant decreases in the exercise (WMD: \u0026minus;1.13 \u0026mu;U/mL, 95% CI: \u0026minus;1.81 to \u0026minus;0.44, P = 0.001, I\u0026sup2; = 88.78%) and VD groups (WMD: \u0026minus;0.76 \u0026mu;U/mL, 95% CI: \u0026minus;1.30 to \u0026minus;0.23, P = 0.005, I\u0026sup2; = 83.27%) compared with control. Furthermore, VDE significantly lowered fasting insulin relative to exercise (WMD: \u0026minus;0.35 \u0026mu;U/mL, 95% CI: \u0026minus;0.62 to \u0026minus;0.08, P = 0.009, I\u0026sup2; = 41.99%), whereas no significant difference was observed between VDE and VD (WMD: \u0026minus;0.69 \u0026mu;U/mL, 95% CI: \u0026minus;1.80 to 0.41, P = 0.22, I\u0026sup2; = 91.44%). Subgroup analyses by exercise type and intervention length showed that in VDE vs. control, fasting insulin significantly decreased in both aerobic (WMD: \u0026minus;1.40 \u0026mu;U/mL, 95% CI: \u0026minus;2.74 to \u0026minus;0.05, P = 0.041) and anaerobic subgroups (WMD: \u0026minus;1.55 \u0026mu;U/mL, 95% CI: \u0026minus;2.40 to \u0026minus;0.70, P \u0026lt; 0.001). By duration, 8-week interventions showed a significant reduction (WMD: \u0026minus;1.67 \u0026mu;U/mL, 95% CI: \u0026minus;2.68 to \u0026minus;0.67, P \u0026lt; 0.001), while 12-week interventions were not significant (WMD: \u0026minus;1.37 \u0026mu;U/mL, 95% CI: \u0026minus;2.76 to \u0026minus;0.02, P = 0.053). Further details are in Table 4. Leave-one-out sensitivity analysis confirmed the robustness of the VDE vs. control effect sizes, as removing any study did not alter the overall results. Findings for other comparisons are shown in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHbA1c\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis meta-analysis included three RCTs assessing HbA1c across five pairwise comparisons. As presented in Figure 6, the primary analysis (VDE vs. control) showed a significant HbA1c reduction (WMD: \u0026minus;0.97%, 95% CI: \u0026minus;1.46 to \u0026minus;0.48, P \u0026lt; 0.001, I\u0026sup2; = 58.33%). Additional analyses examining individual and combined effects found no significant changes in the exercise (WMD: \u0026minus;0.59%, 95% CI: \u0026minus;1.40 to 0.20, P = 0.147, I\u0026sup2; = 88.99%) or VD groups (WMD: \u0026minus;0.65%, 95% CI: \u0026minus;2.27 to 0.95, P = 0.424, I\u0026sup2; = 91.50%) versus control. HbA1c decreased significantly in VDE compared with exercise (WMD: \u0026minus;0.42%, 95% CI: \u0026minus;0.63 to \u0026minus;0.21, P \u0026lt; 0.001, I\u0026sup2; = 0%), but not versus VD (WMD: \u0026minus;0.07%, 95% CI: \u0026minus;0.53 to 0.38, P = 0.750, I\u0026sup2; = 0%). Sensitivity analysis showed that the VDE vs. control effect sizes were influenced by the study of Ruipeng et al. (21); removing it rendered the results non-significant (see figure 1 on additional file 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHOMA-IR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFive RCTs evaluated HOMA-IR across five pairwise comparisons. As shown in Figure 7, the primary analysis showed a significant reduction in HOMA-IR for VDE versus control (WMD: \u0026minus;0.98, 95% CI: \u0026minus;1.54 to \u0026minus;0.42, P = 0.001, I\u0026sup2; = 93.23%). Supplementary analyses indicated significant decreases for exercise (WMD: \u0026minus;0.58, 95% CI: \u0026minus;1.08 to \u0026minus;0.08, P = 0.022, I\u0026sup2; = 90.85%) and VD (WMD: \u0026minus;0.38, 95% CI: \u0026minus;0.57 to \u0026minus;0.19, P \u0026lt; 0.001, I\u0026sup2; = 40.41%) compared with control. Moreover, VDE further reduced HOMA-IR relative to exercise (WMD: \u0026minus;0.33, 95% CI: \u0026minus;0.43 to \u0026minus;0.23, P \u0026lt; 0.001, I\u0026sup2; = 0%) and VD (WMD: \u0026minus;0.55, 95% CI: \u0026minus;0.94 to \u0026minus;0.16, P = 0.005, I\u0026sup2; = 86.51%). Subgroup analyses classified interventions as aerobic or anaerobic. VDE vs. control revealed significant HOMA-IR reductions in both aerobic (WMD: \u0026minus;1.02, 95% CI: \u0026minus;1.77 to \u0026minus;0.27, P = 0.008) and anaerobic subgroups (WMD: \u0026minus;0.94, 95% CI: \u0026minus;1.55 to \u0026minus;0.32, P = 0.003). Stratification by duration also showed significant reductions for both 8-week (WMD: \u0026minus;1.01, 95% CI: \u0026minus;1.81 to \u0026minus;0.20, P = 0.014) and 12-week interventions (WMD: \u0026minus;0.96, 95% CI: \u0026minus;1.46 to \u0026minus;0.46, P \u0026lt; 0.001). Further details are in Table 4. The sensitivity analysis showed that the effect sizes for VDE vs. control comparison remained stable in the leave-one-out analysis (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVitamin D\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwelve RCTs were included in this meta-analysis to investigate Vitamin D levels across five pairwise comparisons. Comparing VDE with the control group in the primary analysis revealed a notable increase in vitamin D levels (WMD: 14.39 ng/mL, 95% CI: 10.39 to 18.38, P \u0026lt; 0.001, I\u0026sup2; = 98.58%) (Figure 8). Further analyses were undertaken to determine the separate and additive contributions of each intervention. Significant elevations in Vitamin D levels were observed in the exercise and VD groups compared to the control group, with WMDs of 3.34 ng/ml (95% CI: 1.40 to 5.27, P = 0.001, I\u0026sup2; = 95.50%), and 12.05 ng/ml (95% CI: 8.01 to 16.10, P \u0026lt; 0.001, I\u0026sup2; = 98.43%), respectively. Comparing VDE to exercise groups, a significant elevation in Vitamin D levels was observed in the VDE group (WMD: 10.49 ng/ml, 95% CI: 7.93 to 13.95, P \u0026lt; 0.001, I\u0026sup2; = 98.71%). Vitamin D levels were significantly higher in the VDE groups compared with the VD group (WMD: 2.45 ng/ml, 95% CI: 0.81 to 4.09, P = 0.003, I\u0026sup2; = 94.66%). Subgroup analyses of VDE vs. control, stratified by exercise type and intervention duration, showed a significant vitamin D increase in the aerobic subgroup (WMD: 16.86 ng/mL, 95% CI: 13.97 to 19.75, P \u0026lt; 0.001), but not in the anaerobic subgroup (WMD: 8.40 ng/mL, 95% CI: \u0026minus;0.56 to 17.37, P = 0.066). Stratification by duration revealed significant increases for both 8-week (WMD: 13.57 ng/mL, 95% CI: 7.96 to 19.18, P \u0026lt; 0.001) and 12-week interventions (WMD: 15.36 ng/mL, 95% CI: 10.02 to 20.70, P \u0026lt; 0.001). Further details are provided in Table 4. Leave-one-out sensitivity analysis showed consistently robust effect sizes in the VDE vs. control comparison, as excluding any study did not affect the overall results (Table 3). Figure 8 shows that meta-regression found no significant association between vitamin D dose and changes in vitamin D levels in the VDE vs. control comparison. Funnel plots showed no notable asymmetry in the VDE vs. control meta-analyses for vitamin D levels. Likewise, Egger\u0026rsquo;s regression (Intercept: 4.10, 95% CI: -5.77 to 13.98, P = 0.379) and Begg\u0026rsquo;s test (P \u0026gt; 0.999) indicated no publication bias across comparisons.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study, for the first time, aimed to examine the combined effects of vitamin D supplementation and exercise on glycemic parameters in adults with metabolic disorders. The results of 15 clinical trials show that vitamin D supplementation, together with regular exercise, had a more significant effect on reducing FBS, fasting insulin, HbA1c, and HOMA-IR compared with either intervention alone or the control group. Subgroup analysis illustrated that, alongside vitamin D supplementation, both aerobic and anaerobic exercise performed for 8 to 12 weeks improved FBS and HOMA-IR. However, fasting insulin levels reduced significantly when the intervention was carried out for 8 weeks. Furthermore, a substantial increase was observed in circulating 25(OH)D levels was observed when vitamin D supplementation was combined with exercise, particularly aerobic exercise, compared with the control group, the vitamin D only group, or the exercise only group. It is worth noting that the clinical trials mentioned that to decrease the bias of the studies, the sun exposure of all participants did not differ significantly during the study. Additionally, the exercises mainly were preferred indoors at the gym. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe high prevalence of metabolic disorders and their association with the increased risk of other chronic diseases, for instance, cardiometabolic diseases, T2DM, and NAFLD, is considered one of the major global health burdens today (33). According to the evidence, roughly one-quarter of the global population suffers from metabolic syndrome, which highlights the urgent need to address these interconnected health issues (34). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMetabolic disorders are strongly associated with central obesity and disturbances in glycemic control, mainly due to insulin resistance, which leads to hyperinsulinemia, increased FBS, chronic inflammation, oxidative stress, and lipid accumulation (35). Over time, it also results in impaired \u0026beta;-cell function in the pancreas and reduces insulin secretion capacity (35). This dual impairment of insulin action and insulin production progressively worsens glycemic control, resulting in elevated fasting glucose, increased postprandial glucose, and higher HbA1c levels (36). There is a bidirectional relationship between inflammatory cytokines and insulin resistance. Inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-\u0026alpha;), promote insulin resistance in skeletal muscle, liver, and adipose tissue by impairing insulin receptor signaling (37). In turn, insulin resistance further stimulates the production of inflammatory cytokines and contributes to thrombogenesis by increasing fibrinogen levels, consequently leading to microvascular damage (38).\u003c/p\u003e\n\u003cp\u003eLifestyle modification, including adherence to a healthy diet and regular physical activity, is considered the main treatment for metabolic disorders (39). The American Heart Association and the American College of Cardiology recommend at least 150 minutes of moderate-intensity exercise or 75 minutes of high-intensity exercise each week (40). On the other hand, diets rich in vegetables, fruits, legumes, fish, whole grains, and nuts do not provide enough vitamin D (41). The primary source of endogenous vitamin D is sun exposure, which is often insufficient due to air pollution, the risk of skin cancer, and reduced outdoor activity. Considering the critical role of vitamin D in glycemic control and metabolic function, supplementation is necessary for individuals at risk of deficiency (42).\u003c/p\u003e\n\u003cp\u003eRecent studies have reported controversial effects of vitamin D supplementation on glycemic markers in different populations. For instance, a systematic review of 25 studies found no significant effect of vitamin D supplementation on glycemic markers such as FBS, insulin, HOMA-IR, and HbA1c, in adults with obesity or related metabolic disorders (43). Another review of 18 studies declares that the combination of vitamin D supplementation and exercise has been demonstrated to improve glucolipid metabolism more effectively than either intervention alone in adults (44). A study showed that vitamin D supplementation improved FBS, HbA1c, and HOMA-IR in T2DM patients with vitamin D deficiency (45). \u0026nbsp;Importantly, one study revealed that the risk of metabolic syndrome is higher in adults more than 60 years old who have insufficient or low levels of total serum vitamin D and vitamin D3. Hence, providing enough vitamin D is a crucial issue to prevent metabolic syndrome among this population (46). However, the findings about the beneficial effect of exercise on glycemic indices were almost conclusive. An investigation included 20 studies and 1,192 participants reported that the combined aerobic and resistance training significantly reduced HbA1c in overweight and obese T2DM patients (47). Another meta-analysis of 24 clinical trials concluded that engaging in any form of exercise is more effective than no exercise for improving glycemic control in individuals with prediabetes. However, it illustrated that different exercise modalities have distinct benefits: the combination of moderate-intensity aerobic exercise with low-to moderate-load resistance training resulted in the substantial reduction in HbA1c; low-to moderate-load resistance training alone indicated the most significant improvement in FBG; and vigorous-intensity aerobic exercise led to the considerable reductions in 2-hour postprandial glucose (2hPG) levels (48). Furthermore, analysis from 775 prediabetics indicated that resistance and interval training have a positive impact on glycemic indices, especially on FBS (49).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBoth vitamin D supplementation and exercise exert beneficial effects on glycemic regulation through three main mechanisms that result in a synergistic improvement in insulin sensitivity and glucose homeostasis. Exercise increases insulin sensitivity by stimulating GLUT4 translocation to the skeletal muscle cell membrane, thereby increasing glucose uptake (50). Vitamin D, however, enhances insulin signaling by activating the vitamin D receptor (VDR) in muscle and adipose tissue, leading to upregulation of insulin receptor expression and improved downstream signaling pathways involved in glucose metabolism\u0026nbsp;(51).\u0026nbsp;The overall processes result in greater translocation of GLUT4 and improved insulin receptor responsiveness. The combined intervention may also affect \u0026beta;-cell function. Vitamin D regulates calcium homeostasis and protects pancreatic \u0026beta;-cells against oxidative and inflammatory injury, while exercise reduces glucotoxicity and lipotoxicity, helping to mitigate \u0026beta;-cell stress and insulin secretory capacity\u0026nbsp;(52). Finally, both vitamin D and exercise possess anti-inflammatory properties. Exercise, including aerobic and resistance training, reduces systemic inflammation partly by increasing muscle-derived IL-6, which subsequently suppresses TNF-\u0026alpha; and other pro-inflammatory markers\u0026nbsp;(53). However, vitamin D inhibits the activation of the NF-\u0026kappa;B pathway\u0026nbsp;(54). Thus, the combined effect may have an effect on lowering systemic inflammation, improving insulin signaling pathways, and reducing insulin resistance.\u003c/p\u003e\n\u003cp\u003eThe analysis of the present study illustrates that both vitamin D supplementation and exercise positively improve glycemic parameters in adults with metabolic disorders, while the combination appears to have a synergistic effect. Moreover, the combination intervention showed a clinically significant reduction in FBS (\u0026gt;14 mg/dl) and HbA1c (\u0026gt; 0.5%) in these patients (55). Hence, incorporating exercise alongside vitamin D supplementation may be considered as a valuable adjunctive treatment for glycemic control in individuals with metabolic disorders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths, Limitations, Future Suggestions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present GRADE-assessed meta-analysis offers several notable strengths. The most important one is the large-scale inclusion of RCTs across diverse metabolic disorders, including overweight and obesity, premenopausal women, T2DM, NAFLD, and PCOS, which enhances the reliability and generalizability of the findings. \u0026nbsp; Additionally, it provides a comprehensive assessment of glycemic parameters such as FBS, fasting insulin, HbA1c, and HOMA-IR by detailing the combined effects of vitamin D supplementation and exercise on metabolic health. This study conducted detailed subgroup analyses to explore sources of heterogeneity of study duration and types of exercises. Moreover, in order to ensure the robustness and reliability of the findings, rigorous sensitivity analyses and publication bias assessments were performed. However, a number of limitations should be acknowledged. Considerable heterogeneity exists among the included studies in terms of study settings, participant characteristics (such as gender, age, and BMI), study locations, and intervention durations. Hence, the findings should be interpreted with caution, as definitive conclusions cannot be made. Furthermore, the relatively small sample size of many included studies may have limited the generalizability and the statistical power of the findings. To overcome these limitations, future research is suggested to focus on conducting large-scale, multicenter RCTs with longer follow-up durations.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe result of this study sheds light on the beneficial effect of the combination of vitamin D supplementation and exercise on glycemic profile, including reducing FBS, fasting insulin, HbA1c, and HOMA-IR more than either intervention alone or the control group. Furthermore, subgroup analysis illustrated that, alongside vitamin D supplementation, 8 to 12 weeks of both aerobic and anaerobic exercise significantly reduced the level of FBS and HOMA-IR, while fasting insulin levels reduced when the intervention was carried out for 8 weeks. Vitamin D supplementation combined with exercise, specifically aerobic, can increase circulating 25(OH)D levels more than the other comparison groups. However, further well-designed studies with large-scale RCTs with longer duration are needed to strengthen and confirm these findings.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003enon-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), serum 25-hydroxy vitamin D (25OHD), glycated hemoglobin (HbA1c), Medical Subject Headings (MeSH), Fasting blood glucose (FBG), standard deviations (SDs), Grading of Recommendations, Assessment, Development, and Evaluation (GRADE), confidence intervals (CIs), tumor necrosis factor-alpha (TNF-\u0026alpha;), homeostatic model assessment of insulin resistance (HOMA-IR), vitamin D + exercise group (VDE), vitamin D group (VD), exercise group (E), control group (C), indoor physical activity (IPA), outdoor physical activity (OPA)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate:\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eNot applicable. This study is a systematic review and meta-analysis of previously published human studies. The study protocol was registered in PROSPERO (registration number CRD420251131187, retrospectively registered on 24 August 2025).\u003c/p\u003e\n\u003cp\u003eConsent for publication:\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eNot applicable. This article does not contain any individual person\u0026rsquo;s data.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials:\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eAll data generated or analysed during this study are included in this published article and its additional information files.\u003c/p\u003e\n\u003cp\u003eCompeting interests:\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding:\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eNot applicable. This research did not receive any specific funding.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions:\u003c/p\u003e\n\u003cp\u003eMJP: conceptualized the study, designed the title, conducted the literature search and screening, drafted the methods section, prepared most of the tables, and performed the statistical analyses.\u003c/p\u003e\n\u003cp\u003eMS: wrote the Introduction and Discussion sections.\u003c/p\u003e\n\u003cp\u003eSS: performed data extraction and wrote the Results section.\u003c/p\u003e\n\u003cp\u003eGM: performed data extraction, designed the table of included studies, and double-checked screening and extracted information.\u003c/p\u003e\n\u003cp\u003eFE: performed data extraction, designed the Abstract figure, and assisted with figure preparation.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements:\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBoddu SK, Giannini C, Marcovecchio ML. 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Effects of combined aerobic and resistance training on glycemic control, blood pressure, inflammation, cardiorespiratory fitness and quality of life in patients with type 2 diabetes and overweight/obesity: a systematic review and meta-analysis. PeerJ. 2024;12:e17525.\u003c/li\u003e\n\u003cli\u003eZhang H, Guo Y, Hua G, Guo C, Gong S, Li M, et al. Exercise training modalities in prediabetes: a systematic review and network meta-analysis. Frontiers in endocrinology. 2024;15:1308959.\u003c/li\u003e\n\u003cli\u003eBennasar-Veny M, Malih N, Galmes-Panades AM, Hernandez-Bermudez IC, Garcia-Coll N, Ricci-Cabello I, et al. Effect of physical activity and different exercise modalities on glycemic control in people with prediabetes: a systematic review and meta-analysis of randomized controlled trials. Frontiers in endocrinology. 2023;14:1233312.\u003c/li\u003e\n\u003cli\u003eMcGee SL, Hargreaves M. Exercise performance and health: Role of GLUT4. Free Radical Biology and Medicine. 2024;224:479-83.\u003c/li\u003e\n\u003cli\u003eContreras-Bol\u0026iacute;var V, Garc\u0026iacute;a-Fontana B, Garc\u0026iacute;a-Fontana C, Mu\u0026ntilde;oz-Torres M. Mechanisms involved in the relationship between vitamin D and insulin resistance: impact on clinical practice. Nutrients. 2021;13(10):3491.\u003c/li\u003e\n\u003cli\u003eWu M, Lu L, Guo K, Lu J, Chen H. Vitamin D protects against high glucose-induced pancreatic \u0026beta;-cell dysfunction via AMPK-NLRP3 inflammasome pathway. Molecular and cellular endocrinology. 2022;547:111596.\u003c/li\u003e\n\u003cli\u003eCalcaterra V, Vandoni M, Rossi V, Berardo C, Grazi R, Cordaro E, et al. Use of physical activity and exercise to reduce inflammation in children and adolescents with obesity. International journal of environmental research and public health. 2022;19(11):6908.\u003c/li\u003e\n\u003cli\u003eZhang C, Tong T, Miao D-c, Wang L-f. Vitamin D inhibits TNF-\u0026alpha; induced apoptosis of human nucleus pulposus cells through regulation of NF-kB signaling pathway. Journal of orthopaedic surgery and research. 2021;16(1):411.\u003c/li\u003e\n\u003cli\u003eDankers M, Nelissen-Vrancken M, Hart BH, Lambooij AC, van Dijk L, Mantel-Teeuwisse AK. Alignment between outcomes and minimal clinically important differences in the Dutch type 2 diabetes mellitus guideline and healthcare professionals\u0026apos; preferences. Pharmacology research \u0026amp; perspectives. 2021;9(3):e00750.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"metabolic disorders, vitamin D, exercise, glycemic control","lastPublishedDoi":"10.21203/rs.3.rs-8122833/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8122833/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eHowever, vitamin D and exercise are both key factors in regulating glycemic control; no previous study has examined their combined effects in adults with metabolic disorders. Hence, the current systematic review and meta-analysis aimed to evaluate the impact of vitamin D supplementation and exercise, both individually and in combination, on glycemic control and circulating 25(OH)D levels in adults with metabolic disorders.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis systematic review and meta-analysis followed PRISMA guidelines. SCOPUS, PubMed, Web of Science, and Google Scholar were searched until August 2025 for randomized controlled trials examining combined vitamin D supplementation and exercise in adults with metabolic disorders. Data extraction and risk of bias assessment were performed independently using the Cochrane RoB 2.0 tool, and evidence certainty was graded via GRADE. Random-effects models were applied using Comprehensive Meta-Analysis (version 3).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFifteen randomized controlled trials were analyzed. Vitamin D supplementation plus exercise significantly improved fasting blood glucose (FBG) (WMD: \u0026minus;16.59 mg/dL, 95% CI: \u0026minus;20.69 to \u0026minus;\u0026thinsp;12.48, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), fasting insulin (WMD: \u0026minus;1.54 \u0026micro;U/mL, 95% CI: \u0026minus;2.34 to \u0026minus;\u0026thinsp;0.73, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), HbA1c (WMD: \u0026minus;0.97%, 95% CI: \u0026minus;1.46 to \u0026minus;\u0026thinsp;0.48, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), HOMA-IR (WMD: \u0026minus;0.98, 95% CI: \u0026minus;1.54 to \u0026minus;\u0026thinsp;0.42, P\u0026thinsp;=\u0026thinsp;0.001), vitamin D (WMD: 14.39 ng/mL, 95% CI: 10.39 to 18.38, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared to control. Vitamin D increased significantly in the aerobic group, while FBG, HOMA-IR, and fasting insulin declined in both aerobic and anaerobic subgroups. FBG, HOMA-IR, and vitamin D improved after 8- and 12-week interventions, whereas fasting insulin decreased only after 8 weeks.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThe results of this study indicated that vitamin D supplementation alongside exercise can reduce FBS, fasting insulin, HbA1c, and HOMA-IR more effectively than either intervention alone or the control group. Furthermore, vitamin D supplementation combined with exercise, aerobic exercise can increase circulating 25(OH)D levels more than the other comparison groups. Nevertheless, additional well-designed studies are needed to strengthen and confirm these findings.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e\u003cp\u003ePROSPERO, registration number CRD420251131187, retrospectively registered on 24 August 2025.\u003c/p\u003e","manuscriptTitle":"Effects of vitamin D and exercise on glycemic control and circulating 25(OH)D in adults with metabolic disorders: A systematic review and meta-analysis with GRADE assessment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-17 17:06:18","doi":"10.21203/rs.3.rs-8122833/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"317448830306024105002403190699390718365","date":"2025-12-12T07:43:19+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-12T06:56:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-21T07:34:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-20T13:56:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-20T13:56:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Endocrine Disorders","date":"2025-11-15T14:44:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-endocrine-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bend","sideBox":"Learn more about [BMC Endocrine Disorders](http://bmcendocrdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bend/default.aspx","title":"BMC Endocrine Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"237f0d4b-344d-49bc-9bf3-5c00e93b88d0","owner":[],"postedDate":"December 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-30T09:08:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-17 17:06:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8122833","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8122833","identity":"rs-8122833","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}