Vitamin D and exercise improve VEGF-B production and IGF-1 levels in diabetic rats: insights the role of miR-1 suppression – Nature.com

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.
Advertisement
Scientific Reports volume 15, Article number: 1328 (2025) Cite this article
Metrics details
Type 2 Diabetes Mellitus (T2DM) is closely associated with the development of vascular damage in the heart. In this study, the researchers aimed to determine whether Aerobic Training (AT) and Vitamin D supplementation (Vit D) could alleviate heart complications and vascular damage caused by diabetes. The effects of an eight-week AT program and Vit D on the expression of miR-1, IGF-1 genes, and VEGF-B in the cardiomyocytes of rats with T2DM.
This study was an experimental investigation. Fifty male Wistar rats were divided into 2 groups Non-Diabetic Obese Control (NC; n = 10), and diabetic (n = 40). The rats were then randomly divided into four groups: AT plus Vit D (AT + Vit D; n-=10), AT (n = 10), Vit D (Vit D; n = 10), and Control Diabetic (C; n = 10). The exercise groups underwent treadmill training for 8 weeks at an aerobic intensity equal to 50–60% of their maximal oxygen uptake (VO2max), which corresponded to a speed of 15–25 m/min at a 0% incline, for 30–60 min per day, 5 days per week. The Vit D and AT + Vit D groups received 5,000 international units (IU) of Vitamin D (combined with sesame oil) per week via a single-dose injection. Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test for multiple comparisons among the groups. Paired data were analyzed using paired t-tests.
The results showed that BW, BMI, and FI significantly decreased in the AT + Vit D (p = 0.001 for all variables), AT (p = 0.001 for all variables), and Vit D (p = 0.001 for all variables) groups compared to baseline. In contrast, BW, BMI, and FI increased in the C (p = 0.001, p = 0.006, p = 0.020, respectively) and NC (p = 0.001 for all variables) groups. Significant differences were observed between the groups in terms of visceral fat, insulin, glucose, and HOMA-IR (p = 0.001 for all variables). Serum 25-hydroxyvitamin D levels varied significantly among the groups (p = 0.002). The AT + Vit D group showed significantly increased VEGF-B (p = 0.001 for both comparisons), upregulated IGF-1 (p = 0.001 for both comparisons), and downregulated miR-1 (p = 0.001 for both comparisons) compared to the AT and Vit D groups, respectively.
AT and Vit D increased the expression of IGF-1 and VEGF-B in the heart of T2DM rats while decreasing the expression of miR-1. These effects were more pronounced when AT and Vit D were combined. The study concludes that the combination of AT and Vit D has cardio-protective effects in T2DM rats, counteracting abnormal angiogenesis induced by diabetes. These effects are mediated, at least in part, by the upregulation of IGF-1 and VEGF-B, and the downregulation of miR-1.
Type 2 diabetes mellitus (T2DM) has been proven to correlate strongly with the increasing prevalence of features of vascular damage in the heart, kidneys, and eyes¹, causing several metabolic disorders starting from insulin resistance to chronic heart disease (CHD)². Clinical trials have shown that diabetic patients are prone to cardiomyopathy, which is characterized by diastolic dysfunction, the development of cardiac hypertrophy, and cardiomyocyte fibrosis and apoptosis regardless of microvascular and macrovascular disorders³. In addition, adults with T2DM are more at risk of heart attacks and strokes⁴. However, its main pathophysiology needs to be elucidated, but perturbance of the molecular mechanism related to cardiac angiogenesis might be involved⁵. Vascular Endothelial Growth Factor B (VEGF-B) plays an important role in controlling the transfer of fatty acids in the heart and skeletal muscles⁶. Several studies have reported reduced production and activity of cardiac VEGF-B isoforms to be associated with angiogenesis disorder, reduction of myocardial perfusion, and ischemia^7,8. Studies showed abnormal angiogenesis and vascular growth in diabetic models of animals⁹ and humans⁴; since diabetic hyperglycemia disturbs the downstream signaling of VEGF (i.e. Akt-1 and eNOS)¹⁰. Additionally, Insulin-Like Growth Factor 1 (IGF-1) plays a critical role in the normal growth of tissues, and dysregulation of IGF-1 is associated with atherosclerosis, and cardiovascular disease¹¹. Studies show a relationship between low levels of IGF-I with diabetes, high blood pressure, and higher triglyceride levels^12,13. Furthermore, the IGF-1 expression level was shown to be directly controlled through MicroRNA-1 (miR-1)¹⁴. The effect of Aerobic training (AT) on angiogenesis, a crucial physiological process for improving oxygen and nutrient delivery to active tissues, remains a topic of ongoing debate¹⁵. While numerous studies have consistently shown that exercise induces angiogenesis through various mechanisms, including paracrine regulation, mechanical stimuli, and cellular mediators, some research suggests that the impact of exercise on angiogenesis may be more complex and context-dependent¹⁶. For instance, a recent review highlighted that the effects of exercise on angiogenesis-related factors, such as VEGF and PGC-1α, can vary significantly depending on factors like exercise intensity, duration, and type, as well as individual characteristics like age and sex^17,18. Additionally, studies have shown that AT-induced myokines, such as TGF-β and irisin, can both promote and inhibit angiogenesis, depending on the specific cellular context and molecular pathways involved¹⁹. Also, AT ameliorates hypertriglyceridemia, insulin resistance, and heart tissue angiogenic signaling in rat models of diabetes^20,21,22. However, the effect of AT on angiogenesis-inducing factors in the Cardiac muscle cells (cardiomyocytes) is still a debatable topic.
The effect of Vitamin D (Vit D) on angiogenesis is a complex and context-dependent process that involves various cellular and molecular signaling pathways. Several studies have reported both pro-angiogenic and anti-angiogenic effects of Vit D, depending on factors such as cell type, cellular condition, and the presence of specific chemokines^23,24. In cells with excessive angiogenesis, such as those found in tumor vasculature or after vascular injury, Vit D has been shown to exert an anti-angiogenic effect by reducing the activation, proliferation, and migration of endothelial cells^24,25. This effect is mediated through the Vit D receptor (VDR), which regulates the expression of genes involved in angiogenesis and inflammation²⁵. Conversely, in the absence of vascular injury, Vit D has been found to promote angiogenesis by increasing the expression of hypoxia-inducible factor 1-α (HIF1-α) and stromal cell-derived factor 1 (SDF1), which stimulate vascular repair^26,27. Also, there are contradictory results on the effect of Vit D supplementation attenuating diabetic complications in both humans²⁸ and rats²⁹, and the mechanisms of the cardio-protective effects of Vit D have not been fully elucidated³⁰. The interplay between AT and Vit D is a complex and multifaceted relationship, involving various cellular and molecular signaling pathways. AT has been shown to modulate Vit D metabolism by increasing the production of 1,25-dihydroxyvitamin D, the active form of Vit D, through the upregulation of the enzyme 1α-hydroxylase in skeletal muscle and other tissues^31,32. This enhanced Vit D activation can, in turn, promote the expression of genes involved in muscle growth, repair, and mitochondrial biogenesis, thereby improving AT capacity and performance³³. Conversely, Vit D has been found to enhance the angiogenic response to AT, increasing the delivery of oxygen and nutrients to active muscles and facilitating recovery from AT-induced damage³⁴. Thus, we hypothesized that AT and Vit D could attenuate diabetes-induced heart complications and vascular damage by altering the expressional level of angiogenesis-inducing factors. Therefore, we investigated the effects of eight-week AT and Vit D on miR-1, IGF-1 gene expressions, and VEGF-B in the cardiomyocyte of rats with T2DM.
Fifty male Wistar rats were obtained at 4-5wk of age weighing 180 ± 10 gr from the Medical University (Kermanshah, Iran). Animals were housed in transparent polycarbonate cages in the rodent’s care facility under a 12:12-h light-dark cycle at a controlled temperature of 25 ± 2 °C and 45–55% humidity with provided food and water. The ethical principles of working with laboratory animals were considered in the present study. After 2 wk of new environment acclimation, standard chow was replaced by a High-Fat Diet (HFD) containing a mixture of standard mouse food powder (365 mg/kg), mixed vitamins and minerals (60 mg/kg), yeast powder (1 mg/kg), sheep fat (310 mg/kg), DL-methionine (3 mg/kg), and chloride Sodium (1 mg/kg) in the form of pellets (purchased from Beh-Parvar Company) (45% of calories from fat; 35% of calories from carbohydrates, 20% of calories from protein). This diet has been previously reported to induce obesity in rats^35,36.
Fifty male Wistar rats were divided into 2 groups Non-Diabetic Obese Control (NC; n = 10), and diabetic (n = 40). The rats were then randomly divided into four groups: AT plus Vit D (AT + Vit D; n-=10), AT (n = 10), Vit D (Vit D; n = 10), and Control Diabetic (C; n = 10). (Fig. 1). To determine the sample size, based on previous research, a moderate effect size of 0.5, a power level of 0.8, and a significance level of 0.05, with an estimated standard deviation of 1.5, and a five-group design with an equal allocation ratio was used suggesting a total sample size of 50 rats.
After increasing weight (more than 300 g), streptozotocin (60 mg/kg BW, dissolved in 0.1 M citrate buffer with pH = 4.5) and nicotinamide (15 min later, 110 mg/kg BW) were injected to induce diabetes. After 2 wk, blood samples were taken from the lateral tail vein to measure blood sugar; any values above 200 mg/l were considered diabetes³⁷. No insulin treatments were given to animals during the study. The animals used in our study were obtained from the Kermanshah University of Medical Sciences. Additionally, we would like to mention that all necessary permissions and approvals were obtained before conducting the study. Also, the research protocol followed the tenets of the Iranian Convention for the protection of vertebrate animals used in experimental and other scientific contexts and was approved by the ethics committee of Razi University of Kermanshah, Kermanshah, Iran (IR.RAZI.REC.1401.011).
To investigate the effects of AT on cardiomyocyte angiogenesis-inducing factors, diabetic rats were allocated to the following four groups: an AT + Vit D supplementation group (AT + Vit D; n = 10), an AT group (n = 10), a Vit D supplementation group (Vit D; n = 10), and a control diabetic group (C).
Aerobic Training. After 1 week of acclimation to the treadmill (5 min, at 8–10 m/min, 5 days a week), the exercised groups underwent treadmill exercise for 8 wk at an aerobic intensity equal to 50–60% of VO2max (15–25 m/min, 0°, for 30–60 min/day, 5 days/week)³⁸. Ten minutes of warm-up and cool-down were performed before and after the AT at 5 m/min (Fig. 1).
Vitamin D supplementation. Supplement administration was performed during the last 8 wk of the intervention, and Vit D and AT + Vit D groups received 5000 international units (IU) of Vit D (combined with sesame oil) per week by single-dose injection. AT and C were injected with the same amounts of sesame oil. The serum concentration of Vit D was measured by a Vit D rat kit (enzyme-linked immunosorbent assay (ELISA); immune diagnostics system Ltd, Boldon, UK; with an intraassay coefficient of variation = 1.63%, and sensitivity of method = 1.33 mg/dL) )³⁹ (Fig. 1).
Flow chart of the study.
AT + Vit D, Aerobic training + Vitamin D supplement, AT, Aerobic Training; Vit D, Vitamin D Supplement; C, Control; NC, Non-diabetes Control.
To exclude the acute effects of exercise rats were euthanized 48 h after the final training session. After 8 h of fasting, rats were anesthetized by injecting a combination of ketamine (70 mg/Kg BW) and xylazine (3–5 mg/Kg BW). After ensuring full anesthesia, blood samples were taken by exposing the vena cava following the dissection of the abdominal cavity. The supernatant, designated as serum, was used to measure glucose, insulin, and serum 25(OH)D concentration after centrifuging the blood samples for 10 min at 4,000 g. Then the supernatant was collected to measure glucose, insulin, and serum VEGF-B (Pars Azmoon Kit, Iran). Serum 25(OH)D concentration was measured by rat 25(OH)D enzyme-linked immunosorbent assay (ELISA) kit (Immunodiagnostics system Ltd, Boldon, UK). The intraassay coefficient of variation and sensitivity of the method was 1.63% and 1.33 mg/dL, respectively. Also, insulin resistance status was calculated using the homeostasis model assessment for insulin resistance (HOMA-IR) (17). After euthanization and decapitation, cardiac muscle cells were quickly dissected and homogenized as recommended by the manufacturer using a gentleMACS™ Octo Dissociator system, M tubes, and the RNA_02 program in 2 ml of TRI Reagent^® buffer. The homogenate was snap-frozen in liquid nitrogen and then stored at -80 °C for future analysis.
The homogenized samples were first incubated for 5 min at 15 to 30 °C and 0.2 ml of chloroform per 1 ml of TRIZOL Reagent was then added. After vortexing tubes for 15 s and incubating at 15–30 °C for 2 min, the samples were centrifuged at 12,000xg for 10 min at 2–8 °C. Then the upper layer was mixed into 0.5 ml of isopropyl alcohol per 1 ml of TRIZOL Reagent and centrifuged at 12,000xg for 10 min at 2–8 °C. After removing the supernatant, the RNA was washed with 75% ethanol and centrifuged at 7,500xg for 5 min at 2 to 8 °C. RNA was eluted in 30 µl of RNAse-free water and incubated for 10 min at 55 °C. Reverse transcription into cDNA was done using 1 µg of total RNA and a Prime Script RT reagent kit (Sinaclon, Iran). TB Green Premix Ex-Taq II (TaKaRa, Dalian, China) was used for quantitative RT-PCR. The expression levels of target genes were quantified by the comparative 2 − ΔΔct method. The Sinaclon kit, Iran was used to measure IGF-1 and miR-1 gene expressions (sensitivity of 0.021, and 0.06, resp). All primers for the RT-PCR were designed using the Applied Biosystems Primer Express software V 2.0 as shown in Table 1.
All statistical analyses were performed using the SPSS statistical software (version 21; SPSS Inc., Chicago, IL, USA) was used at a significant level of P < 0.05. The Shapiro–Wilk test was used for evaluating the normality of distribution. Data were analyzed using one-way ANOVA followed by a Tukey test for multiple comparisons among the groups. Paired data were analyzed using paired t-tests. P ≤ 0.05 was considered to indicate statistical significance. Data were analyzed by SPSS (version 26, IBM).
Mean Body Weight (BW), Body Mass Index (BMI), and food intake (FI) are shown in Table 2. There was a significant difference between groups in the mean BW, BMI, and FI after 8 weeks of intervention; BW, BMI, and FI reduced significantly in the AT + Vit D, AT, and Vit D groups at the end of the study compared with the beginning. Mean BW, BMI, and FI increased significantly in the C and NC groups at the end of the study compared to the beginning. The results of one-way ANOVA showed significant differences in the Δ of BW, BMI, and FI between the groups. The results of Tukey’s post hoc test show that BW, BMI, and FI were significantly lower in AT + Vit D, AT, Vit D, and C compared to NC. The results indicate significant differences in BW, BMI, and FI in AT + Vit D, AT, and Vit D compared to C. Significant differences in the BW, BMI, and FI were also observed between AT + Vit D with AT, and Vit D. Additionally, there were significant differences in BW, BMI, and FI in AT compared to Vit D (Table 2).
As Table 3 shows, there was a significant difference between groups in visceral fat, insulin, glucose, and HOMA-IR (p = 0.001 for all variables). The results of Tukey’s post hoc test show that visceral fat, insulin, glucose, and HOMA-IR were significantly lower in AT + Vit D, AT, Vit D, and C compared to NC (p = 0.001 for all variables). The results indicate significant differences in visceral fat, insulin, glucose, and HOMA-IR in AT + Vit D (p = 0.001; p = 0.002; p = 0.001), AT (p = 0.004; p = 0.010; p = 0.007), and Vit D (p = 0.006; p = 0.0014; p = 0.016) compared to C. Significant differences in the visceral fat, insulin, glucose, and HOMA-IR were observed between AT + Vit D with AT, and Vit D. The results indicate significant differences in visceral fat, insulin, glucose, and HOMA-IR in AT compared to Vit D (Table 3).
The results show significant differences between groups in serum 25-hydroxyvitamin D; with the highest level in NC and the lowest in the C group. Based on the results, the mean serum 25-hydroxyvitamin D was significantly higher in the AT + Vit D, AT, and Vit D than in the C group (P < 0.05 for all three variables). In addition, a significant difference was observed in serum 25-hydroxyvitamin D between the AT + Vit D group and other groups (P < 0.05 for all three variables). A significant difference in serum 25-hydroxyvitamin D was observed between AT compared to Vit D (Fig. 2A). The results of VEGF-B, IGF-1, and miR-1 are shown in Figures (Fig. 2B, C, and D). The results of one-way ANOVA showed a significant difference in VEGF-B, IGF-1, and miR-1 gene expression between all groups. Furthermore, AT + Vit D, AT, and Vit D increased VEGF-B, upregulated IGF-1, and downregulated miR-1 compared to the C. Based on the results, AT + Vit D significantly increased VEGF-B (p = 0.001; p = 0.001), upregulated IGF-1 (p = 0.001; p = 0.001), and downregulated miR-1 (p = 0.001; p = 0.001) compared to AT and Vit D, respectively. Also, AT induced more significant upregulations in the VEGF-B, and IGF-1 gene expression than Vit D. In addition, significant differences were observed in VEGF-B, and IGF-1 and miR-1gene expression between the C and NC (P < 0.05 for all three variables).
Effect of aerobic training and vitamin D supplementation on 25-hydroxyvitamin D, VEGF-B, IGF-1, and Mir-1 in type-2 diabetic rats.
AT + Vit D, Aerobic training + Vitamin D supplement, AT, Aerobic Training; Vit D, Vitamin D Supplement; C, Control; NC, Non-diabetes Control.
VEGF-B: Vascular Endothelial Growth Factor B; IGF-1: Insulin-like growth factor 1; Mir-1: MicroRNA-1. Results from analysis of one-way analysis of variance (ANOVA), post-hoc Tukey’s test. µ: Significantly different compared to AT. €: Significantly different compared to Vit D. α: Significantly different compared to C. β: Significantly different compared to NC.
AT and Vit D have been reported to ameliorate insulin resistance and reduce vascular complications in diabetic rats^40,41. However, the effects of AT and Vit D on angiogenesis-inducing factors have not been well characterized in the cardiomyocytes. Therefore, the present study investigated the effects of eight-week AT and Vit D on the angiogenesis-inducing factors in the cardiomyocytes of rats with T2DM, specifically focusing on cardiac miR-1, IGF-1, and VEGF-B. T2DM disturbed the normal responses of angiogenesis-inducing factors in the cardiomyocytes of rats, and lipid accumulation, which is a novel finding of the present study. AT decreased the important heart adaptation regulator microRNA, miR-1 increased the expression of target angiogenesis-inducing factors (IGF-1 and VEGF-B), and restored T2DM-induced abnormalities in angiogenesis in the cardiomyocytes of diabetic rats. These findings indicate that AT has cardio-protective effects, ameliorating defects in cardiac angiogenesis in diabetic subjects. Angiogenic disorders in myocardial tissue have been reported during the progression of T2DM⁴². Therapy for restoring normal angiogenesis (thereby improving IGF-1 and VEGF-B) is believed to protect cardiac function against CHD progression in T2DM models⁴³. Angiogenesis impairment plays a pathogenic role and deteriorates cardiac function which contributes to later heart complications and related morbidity in diabetic models⁴⁴. Consistent with the present data, previous studies have reported that T2DM perturbed angiogenesis in different tissues and increased complications in these individuals^42,45. Insulin-related disorders might decrease IGF-I production by reducing growth hormone (GH) receptor expression and causing GH resistance⁴⁶. AT has been shown to have cardio-protective effects in various models of metabolic disease⁴⁷. AT might reduce the risks of cardiovascular injuries in diabetic patients by improving the maximum oxygen consumption (VO_2max) and cardiac output^48,49. Also, AT helps to improve glycosylated hemoglobin (HbA1c) and lipid profile metabolism⁵⁰. Based on the results of studies, AT not only leads to weight loss and blood sugar control by reducing the number of fat cells through beta-oxidation in fat tissue but also improves the function of the left ventricle by increasing the functional capacity^51,52. It has been shown that the effects of AT on VEGF-B gene expression and protein abundance might be associated with insulin resistance⁵³. Based on these studies, AT counteracts the effects of T2DM-induced cardiac complications, specifically defected cardiac angiogenesis^54,55. To elucidate the mechanisms, the present study revealed that AT reduces miR-1 and increases IGF-1 and VEGF-B expression in the cardiomyocytes of rats with T2DM. Hoier et al. (2020), showed that AT increases cardiac muscle metabolism creates oxygen deficiency conditions, and stimulates hypoxia-inducible factor 1-alpha (HIF-1) that increases VEGF-B and improves cardiac angiogenesis, in turn⁵⁶. IGF-1 is an anti-apoptosis factor that exerts a protective effect towards apoptosis in rat cardiomyocytes by decreasing the cytotoxic effects of glucose. There are contradictory results on the IGF-I levels following AT that are limited to serum investigations. Birzniece et al. (2019) reported a significant increase in IGF-I following AT⁵⁷; while Moazami et al. (2018) reported a significant decrease in the serum levels of IGF-I in middle-aged women after a six-month AT⁵⁸. Studies have reported IGF-I as one of the targets of miR-1^59,60. The miR-1 plays a major role in cardiomyocyte apoptosis and ultimately cardiomyopathy by downregulating IGF-1 at the translational level⁶¹. In addition, miR-1 has been implicated in diabetes-induced cardiomyocyte apoptosis⁶², which is overexpressed in the hearts of diabetic patients⁶³, and miR-1 overexpression inhibits the anti-apoptotic action of IGF-1⁶⁴. Consistent with the present data, Delfan et al. (2020) reported that AT increases the IGF-1 expression gene by reducing the overexpression of miR-1 and thus can be an effective intervention to reduce the complications of diabetes cardiopathy⁶⁵. The present study further indicates that Vit D increased IGF-1 and VEGF-B and decreased miR-1 after 8 weeks. Studies report contradictory results on the effect of Vit D supplementation on cardiac biomarkers^66,67. Kord-Varkaneh et al. (2020) reported no significant alteration in IGF-1 following Vit D supplementation⁶⁸. Also, Latino and African-American people with pre-diabetes and hypovitaminosis D showed no significant changes in IGF-1 following Vit D supplementation⁶⁹. However, variations in Vit D measurement techniques, confounding factors affecting 25-hydroxyvitamin D levels, lack of consensus on optimal thresholds, and differences between observational and interventional studies all contribute to the contradictory findings surrounding Vit D and health. While Consistent with our findings, there is evidence that Vit D supplementation modulates circulating IGF1 concentrations^68,69. Moreover, several studies have showed positive association between IGF1 and 25(OH)D in healthy and unhealthy subjects^70,71. The possible mechanism involved in increasing IGF-1 and VEGF-B expression in cardiomyocytes following Vit D supplementation might indicate activation of the IGF-1 and VEGF-B promoter that promotes a further proangiogenic response and vascularization⁷². According to our data, increased IGF-1 and VEGF-B expressions in the cardiomyocytes were also multiplied when combining Vit D with AT. These changes suggest that combined AT and Vit D ameliorated the T2DM-induced defect in cardiac angiogenesis. In this model, separate Vit D was less effective at ameliorating the features of T2DM-induced angiogenesis disorders in T2DM rats than combined AT and Vit D, suggesting that combining AT and Vit D might be an essential mediator of both basal angiogenic responses and the effects of AT on this.
The interplay between AT and Vit D in the regulation of angiogenesis, the process of new blood vessel formation, involves complex cellular and molecular signaling pathways. Emerging evidence suggests that the combination of these two factors can have a synergistic effect on promoting or inhibiting angiogenesis, depending on the physiological context.
Exercise has been shown to modulate Vit D metabolism by increasing the production of the active form, 1,25-dihydroxyvitamin D (1,25(OH)2D), through the upregulation of the enzyme 1α-hydroxylase in skeletal muscle and other tissues⁷³. This enhanced Vit D activation can, in turn, influence the expression of genes involved in angiogenesis. For instance, 1,25(OH)2D has been reported to upregulate the expression of vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1), which are potent pro-angiogenic factors^66,67. This can lead to increased endothelial cell proliferation, migration, and the formation of new blood vessels, thereby facilitating the delivery of oxygen and nutrients to active muscles during exercise.
Conversely, in the presence of excessive or pathological angiogenesis, such as in the context of tumor growth or vascular injury, Vit D has been shown to exert anti-angiogenic effects³³. This is mediated through the Vit D receptor (VDR), which can regulate the expression of genes involved in the inhibition of endothelial cell activation, proliferation, and migration⁷⁴. Additionally, Vit D has been found to downregulate the expression of pro-angiogenic microRNAs, such as miR-1, further contributing to its anti-angiogenic actions^23,24.
The interplay between AT and Vit D in the modulation of angiogenesis is further highlighted by their combined effects on the immune system and inflammation. Exercise can stimulate the production of anti-inflammatory cytokines, while Vit D has been reported to suppress pro-inflammatory pathways, such as those mediated by nuclear factor-κB (NF-κB)^34,75. This synergistic anti-inflammatory effect may help to maintain a balanced angiogenic response and promote vascular health³⁴.
In summary, the interaction between AT and Vit D in the regulation of angiogenesis involves a complex interplay of cellular and molecular signaling pathways. The combination of these two factors can have either pro-angiogenic or anti-angiogenic effects, depending on the physiological context, highlighting the importance of considering both AT and Vit D status in the optimization of vascular function and overall health. In summary, both AT and Vit D increased cardiac expression of IGF-1 and VEGF-B in T2DM rats, whereas decreased miR-1, these responses were greater when combining AT and Vit D.
The provided study highlights several limitations of a study on the effects of AT and Vit D on angiogenesis-inducing factors in rats with type-2 diabetes mellitus (T2DM). Firstly, the study primarily focuses on animal models of T2DM, which may restrict the applicability of the findings to human populations. To validate the observed effects, human studies are necessary. Secondly, the study’s characterization of angiogenesis-inducing factors is limited to AT and Vit D, without comprehensively investigating other potential factors involved in angiogenesis. This narrow focus may hinder a comprehensive understanding of the overall angiogenic response in the context of T2DM. Thirdly, while the study reports the effects of AT and Vit D on miR-1, IGF-1, and VEGF-B expression in the cardiomyocytes, it lacks a detailed mechanistic explanation of how these interventions modulate angiogenesis. Further investigation is required to elucidate the underlying molecular pathways via histological, immunohistochemical (IHC), and Western blot (WB) analyses to explore the activity of mir-1 and other relevant molecular markers. Lastly, the study only investigates the effects of eight weeks of AT and Vit D supplementation, without exploring the long-term effects and sustainability of these interventions on angiogenesis and cardiac function. Longer follow-up periods would provide a more comprehensive understanding of the potential benefits. Overall, these limitations highlight the need for further research to overcome these constraints and enhance the understanding of the interventions’ effects on angiogenesis in the context of T2DM.
We conclude that combined AT and Vit D have cardio-protective effects in T2DM rats and counteracts diabetes-induced abnormal angiogenesis, which is mediated, at least in part, by upregulation of IGF-1 and VEGF-B and down-regulation of miR-1.
The results of the current study are available from the corresponding author on reasonable request.
Aerobic Training
Vitamin D
Type 2 Diabetes Mellitus
Vascular Endothelial Growth Factor B
microRNA-1
Insulin-Like Growth Factor 1
Faselis, C. et al. Microvascular complications of type 2 diabetes mellitus. Curr. Vasc. Pharmacol. 18 (2), 117–124 (2020).
Article  CAS  PubMed  Google Scholar 
Nesti, L., Pugliese, N. R., Sciuto, P. & Natali, A. Type 2 diabetes and reduced exercise tolerance: a review of the literature through an integrated physiology approach. Cardiovasc. Diabetol. 19 (1), 134 (2020).
Article  CAS  PubMed  PubMed Central  Google Scholar 
Tan, Y. et al. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nat. Reviews Cardiol. 17 (9), 585–607 (2020).
Article  MATH  Google Scholar 
Ma, C-X. et al. Cardiovascular disease in type 2 diabetes mellitus: progress toward personalized management. Cardiovasc. Diabetol. 21 (1), 1–15 (2022).
Article  CAS  MATH  Google Scholar 
Hoseini, R., Rahim, H. A. & Ahmed, J. K. Decreased inflammatory gene expression accompanies the improvement of liver enzyme and lipid profile following aerobic training and vitamin D supplementation in T2DM patients. BMC Endocr. Disorders. 22 (1), 245 (2022).
Article  CAS  Google Scholar 
Li, L-J., Ma, J., Li, S-B., Chen, X. & Zhang, J. Vascular endothelial growth factor B inhibits lipid accumulation in C2C12 myotubes incubated with fatty acids. Growth Factors. 37 (1–2), 76–84 (2019).
Article  CAS  PubMed  Google Scholar 
Bahmani, E., Hoseini, R. & Amiri, E. Home-based aerobic training and vitamin D improve neurotrophins and inflammatory biomarkers in MS patients. Multiple Scler. Relat. Disorders. 60, 103693 (2022).
Article  CAS  Google Scholar 
Räsänen, M. et al. VEGF-B promotes endocardium-derived coronary vessel development and cardiac regeneration. Circulation 143 (1), 65–77 (2021).
Article  PubMed  MATH  Google Scholar 
Khaledi, K., Hoseini, R. & Gharzi, A. Effects of aerobic training and vitamin D supplementation on glycemic indices and adipose tissue gene expression in type 2 diabetic rats. Sci. Rep. 13 (1), 10218 (2023).
Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 
Jiao, W. et al. Distinct downstream signaling and the roles of VEGF and PlGF in high glucose-mediated injuries of human retinal endothelial cells in culture. Sci. Rep. 9 (1), 1–13 (2019).
Article  MATH  Google Scholar 
Higashi, Y. et al. Endothelial deficiency of insulin-like growth factor-1 receptor reduces endothelial barrier function and promotes atherosclerosis in apoe-deficient mice. Am. J. Physiol. Heart Circ. Physiol. 319 (4), H730–H743 (2020).
Article  PubMed  PubMed Central  MATH  Google Scholar 
Ohshima, H. et al. Association between growth hormone and hypertension in a general population. Hypertens. Res. 43 (12), 1430–1436 (2020).
Article  CAS  PubMed  MATH  Google Scholar 
Ricotti, R. et al. The relationship between cortisol and IGF-I influences metabolic alteration in pediatric overweight and obesity. Eur. J. Endocrinol. 182 (3), 255–264 (2020).
Article  CAS  PubMed  MATH  Google Scholar 
Jung, H. J. & Suh, Y. Regulation of IGF – 1 signaling by microRNAs. Front. Genet. 5, 472 (2014).
PubMed  MATH  Google Scholar 
Arabzadeh, E., Samadian, Z., Tofighi, A. & Tolouei Azar, J. Alteration of follistatin-like 1, neuron-derived neurotrophic factor, and vascular endothelial growth factor in diabetic cardiac muscle after moderate-intensity aerobic exercise with insulin. Sport Sci. Health. 16 (3), 491–499 (2020).
Article  Google Scholar 
Riahi, S., Mohammadi, M. T., Sobhani, V. & Ababzadeh, S. Chronic aerobic exercise decreases lectin-like low density lipoprotein (lox-1) receptor expression in heart of diabetic rat. Iran. Biomed. J. 20 (1), 26 (2016).
PubMed  PubMed Central  Google Scholar 
Ross, M., Kargl, C. K., Ferguson, R., Gavin, T. P. & Hellsten, Y. Exercise-induced skeletal muscle angiogenesis: impact of age, sex, angiocrines and cellular mediators. Eur. J. Appl. Physiol. 123 (7), 1415–1432 (2023).
Article  PubMed  PubMed Central  Google Scholar 
Li, S. et al. The effect of blood flow restriction exercise on angiogenesis-related factors in skeletal muscle among healthy adults: a systematic review and meta-analysis. Front. Physiol. 13, 814965 (2022).
Article  PubMed  PubMed Central  Google Scholar 
Qi, C., Song, X., Wang, H., Yan, Y. & Liu, B. The role of exercise-induced myokines in promoting angiogenesis. Front. Physiol. 13, 981577 (2022).
Article  PubMed  PubMed Central  MATH  Google Scholar 
Dastah, S., Tofighi, A., Azar, J. T. & Alivand, M. Aerobic exercise leads to upregulation of Mir-126 and angiogenic signaling in the heart tissue of diabetic rats. Gene Rep. 21, 100914 (2020).
Article  CAS  Google Scholar 
Yu, Q., Xia, Z., Liong, E. C. & Tipoe, G. L. Chronic aerobic exercise improves insulin sensitivity and modulates Nrf2 and NF–κB/IκBα pathways in the skeletal muscle of rats fed with a high fat diet. Mol. Med. Rep. 20 (6), 4963–4972 (2019).
CAS  PubMed  PubMed Central  Google Scholar 
Wang, G. Aerobic exercise ameliorates myocardial ischemia/reperfusion injury and thrombosis of diabetic rats via activation of AMPK/Sirt1/PGC-1α pathway. Gen. Physiol. Biophys. 41 (4), 319–328 (2022).
Article  CAS  PubMed  Google Scholar 
Dovnik, A. & Fokter Dovnik, N. Vitamin D and ovarian cancer: systematic review of the literature with a focus on molecular mechanisms. Cells 9 (2), 335 (2020).
Article  CAS  PubMed  PubMed Central  Google Scholar 
Chan, H-N. et al. Vitamin D and ocular diseases: a systematic review. Int. J. Mol. Sci. 23 (8), 4226 (2022).
Article  CAS  PubMed  PubMed Central  MATH  Google Scholar 
Song, Y-S., Jamali, N., Sorenson, C. M. & Sheibani, N. Vitamin D receptor expression limits the angiogenic and inflammatory properties of Retinal endothelial cells. Cells 12 (2), 335 (2023).
Article  CAS  PubMed  PubMed Central  Google Scholar 
Shanmugavadivu, A., Balagangadharan, K. & Selvamurugan, N. Angiogenic and osteogenic effects of flavonoids in bone regeneration. Biotechnol. Bioeng. 119 (9), 2313–2330 (2022).
Article  CAS  PubMed  MATH  Google Scholar 
Looi, C-K. et al. Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment. J. Experimental Clin. Cancer Res. 38, 1–23 (2019).
Article  MATH  Google Scholar 
Hu, Z. et al. Effects of long-term vitamin D supplementation on metabolic profile in middle-aged and elderly patients with type 2 diabetes. J. Steroid Biochem. Mol. Biol. 225, 106198 (2023).
Article  CAS  PubMed  MATH  Google Scholar 
Mitrašinović-Brulić, M. et al. Vitamin D3 attenuates oxidative stress and regulates glucose level and leukocyte count in a semi-chronic streptozotocin-induced diabetes model. J. Diabetes Metabolic Disorders. 20 (1), 771–779 (2021).
Article  MATH  Google Scholar 
Garg, S. & Mallik, D. Role of Vitamin D as an adjuvant to oral hypoglycemic drugs in treatment of Type-2 Diabetic patients. Asian J. Med. Sci. 11 (2), 25–29 (2020).
Article  Google Scholar 
Young, K., Beggs, M. R., Grimbly, C. & Alexander, R. T. Regulation of 1 and 24 hydroxylation of vitamin D metabolites in the proximal tubule. Experimental Biology Med. 247 (13), 1103–1111 (2022).
Article  CAS  Google Scholar 
Caballero-García, A., Córdova-Martínez, A., Vicente-Salar, N., Roche, E. & Pérez-Valdecantos, D. Vitamin D, its role in recovery after muscular damage following exercise. Nutrients 13 (7), 2336 (2021).
Article  PubMed  PubMed Central  Google Scholar 
Latham, C. M. et al. Vitamin D promotes skeletal muscle regeneration and mitochondrial health. Front. Physiol. 12, 660498 (2021).
Article  PubMed  PubMed Central  Google Scholar 
Hoseini, R., Rahim, H. A. & Ahmed, J. K. Concurrent alteration in inflammatory biomarker gene expression and oxidative stress: how aerobic training and vitamin D improve T2DM. BMC Complement. Med. Ther. 22 (1), 165 (2022).
Article  CAS  PubMed  PubMed Central  Google Scholar 
Mostafavian, M., Abdi, A., Mehrabani, J. & Barari, A. Effect of eight weeks of aerobic progressive training with capsaicin on changes in PGC-1α and UPC-1 expression in visceral adipose tissue of obese rats with diet. Complement. Med. J. 10 (2), 106–117 (2020).
Article  Google Scholar 
Mohammadi, K. & Khajehlandi, A. The effect of a period of swimming training with different temperatures on the expression of β3-AR and ERK2 genes in the visceral adipose tissue of streptozotocin-induced diabetic rats. Feyz J. Kashan Univ. Med. Sci. 25 (6), 1303–1312 (2022).
Google Scholar 
Khalili, A., Nekooeian, A. A. & Khosravi, M. B. Oleuropein improves glucose tolerance and lipid profile in rats with simultaneous renovascular hypertension and type 2 diabetes. J. Asian Nat. Prod. Res. 19 (10), 1011–1021 (2017).
Article  CAS  PubMed  Google Scholar 
Rocha-Rodrigues, S. et al. Effects of physical exercise on myokines expression and brown adipose-like phenotype modulation in rats fed a high-fat diet. Life Sci. 165, 100–108 (2016).
Article  CAS  PubMed  Google Scholar 
Hoseini, R., Damirchi, A. & Babaei, P. Vitamin D increases PPARγ expression and promotes beneficial effects of physical activity in metabolic syndrome. Nutrition 36, 54–59 (2017).
Article  CAS  PubMed  Google Scholar 
McDonald, M. W. et al. Aerobic exercise training improves insulin-induced vasorelaxation in a vessel-specific manner in rats with insulin-treated experimental diabetes. Diabetes Vascular Disease Res. 16 (1), 77–86 (2019).
Article  CAS  MATH  Google Scholar 
Wang, W., Zhang, J., Wang, H., Wang, X. & Liu, S. Vitamin D deficiency enhances insulin resistance by promoting inflammation in type 2 diabetes. Int. J. Clin. Exp. Pathol. 12 (5), 1859 (2019).
CAS  PubMed  PubMed Central  MATH  Google Scholar 
Fadini, G. P., Albiero, M., Bonora, B. M. & Avogaro, A. Angiogenic abnormalities in diabetes mellitus: mechanistic and clinical aspects. J. Clin. Endocrinol. Metabolism. 104 (11), 5431–5444 (2019).
Article  MATH  Google Scholar 
Rai, V., Moellmer, R. & Agrawal, D. K. Role of fibroblast plasticity and heterogeneity in modulating angiogenesis and healing in the diabetic foot ulcer. Mol. Biol. Rep. 50 (2), 1913–1929 (2023).
Article  CAS  PubMed  MATH  Google Scholar 
Dudley, A. C. & Griffioen, A. W. Pathological angiogenesis: mechanisms and therapeutic strategies. Angiogenesis 26 (3), 313–347 (2023).
Article  PubMed  PubMed Central  MATH  Google Scholar 
Al-Kharashi, A. S. Role of oxidative stress, inflammation, hypoxia and angiogenesis in the development of diabetic retinopathy. Saudi J. Ophthalmol. 32 (4), 318–323 (2018).
Article  PubMed  PubMed Central  Google Scholar 
Dichtel, L. E., Cordoba-Chacon, J. & Kineman, R. D. Growth hormone and insulin-like growth factor 1 regulation of nonalcoholic fatty liver disease. J. Clin. Endocrinol. Metabolism. 107 (7), 1812–1824 (2022).
Article  MATH  Google Scholar 
Gao, J. et al. Exercise Training-Induced MicroRNA alterations with Protective effects in Cardiovascular diseases. Rev. Cardiovasc. Med. 24 (9), 251 (2023).
Article  CAS  PubMed  PubMed Central  MATH  Google Scholar 
McDonald, M. W. et al. Exercise training induced cardioprotection with moderate hyperglycemia versus sedentary intensive glycemic control in type 1 diabetic rats. Journal of Diabetes Research 2018. (2018).
Seo, D. Y. et al. Exercise as a potential therapeutic target for diabetic cardiomyopathy: insight into the underlying mechanisms. Int. J. Mol. Sci. 20 (24), 6284 (2019).
Article  CAS  PubMed  PubMed Central  MATH  Google Scholar 
Taghizadeh, M., Kargarfard, M., Braune, S., Jung, F. & Naderi, M. Long-term aerobic exercise training in type two diabetic patients alters the expression of miRNA-223 and its corresponding target, the P2RY12 receptor, attenuating platelet function. Clin. Hemorheol. Microcirc. 80 (2), 107–116 (2022).
Article  CAS  PubMed  Google Scholar 
Volterrani, M. et al. Effects of concurrent, within-session, aerobic and resistance exercise training on functional capacity and muscle performance in elderly male patients with chronic heart failure. J. Clin. Med. 12 (3), 750 (2023).
Article  PubMed  PubMed Central  Google Scholar 
Goes-Santos, B. R. et al. Physical capacity increase in patients with heart failure is associated with improvement in muscle sympathetic nerve activity. Int. J. Cardiol. 378, 48–54 (2023).
Article  PubMed  Google Scholar 
Zapata-Bustos, R. et al. Altered transcription factor expression responses to exercise in insulin resistance. Front. Physiol. 12, 649461 (2021).
Article  PubMed  PubMed Central  Google Scholar 
Wang, B. et al. Exercise ameliorating myocardial injury in type 2 diabetic rats by inhibiting excessive mitochondrial fission involving increased irisin expression and AMP-activated protein kinase phosphorylation. J. Diabetes. 16 (1), e13475 (2024).
Article  CAS  PubMed  Google Scholar 
Bhati, P., Hussain, M. E., Deepak, K., Masood, S. & Anand, P. Progressive resistance training ameliorates deteriorating cardiac autonomic dysfunction, subclinical inflammation and endothelial dysfunction in type 2 diabetes mellitus: a randomized control trial. Diabetes Metabolic Syndrome: Clin. Res. Reviews. 17 (5), 102778 (2023).
Article  CAS  Google Scholar 
Hoier, B. et al. Early time course of change in angiogenic proteins in human skeletal muscle and vascular cells with endurance training. Scand. J. Med. Sci. Sports. 30 (7), 1117–1131 (2020).
Article  PubMed  MATH  Google Scholar 
Birzniece, V. Exercise and the growth hormone–insulin-like growth factor axis. Curr. Opin. Endocr. Metabolic Res. 9, 1–7 (2019).
Article  Google Scholar 
Moazami, M. & Askari, B. Effect of six months of Aerobic Exercise on serum levels of insulin, growth hormone and insulin-like Growth hormone 1 in sedentary obese women. Med. Lab. J. 12(4). (2018).
Obradovic, M. et al. Effects of IGF-1 on the cardiovascular system. Curr. Pharm. Design. 25 (35), 3715–3725 (2019).
Article  CAS  MATH  Google Scholar 
Liang, J. et al. MicroRNA profiling of different exercise interventions for alleviating skeletal muscle atrophy in naturally aging rats. J. Cachexia Sarcopenia Muscle. 14 (1), 356–368 (2023).
Article  PubMed  MATH  Google Scholar 
Lock, M. C. et al. The role of miRNA regulation in fetal cardiomyocytes, cardiac maturation and the risk of heart disease in adults. J. Physiol. 596 (23), 5625–5640 (2018).
Article  CAS  PubMed  PubMed Central  MATH  Google Scholar 
Cheng, Y. et al. Inhibition of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 attenuates high glucose-induced cardiomyocyte apoptosis via regulation of miR-181a-5p. Exp. Anim. 69 (1), 34–44 (2020).
Article  CAS  PubMed  Google Scholar 
Kura, B., Kalocayova, B., Devaux, Y. & Bartekova, M. Potential clinical implications of miR-1 and miR-21 in heart disease and cardioprotection. Int. J. Mol. Sci. 21 (3), 700 (2020).
Article  CAS  PubMed  PubMed Central  Google Scholar 
Ye, L-L., Cheng, Z-G., Cheng, X-E. & Huang, Y-L. Propofol regulates miR-1-3p/IGF1 axis to inhibit the proliferation and accelerates apoptosis of colorectal cancer cells. Toxicol. Res. 10 (4), 696–705 (2021).
Article  MATH  Google Scholar 
Delfan, M. et al. High intensity interval training improves diabetic cardiomyopathy via miR-1 dependent suppression of cardiomyocyte apoptosis in diabetic rats. J. Diabetes Metabolic Disorders. 19 (1), 145–152 (2020).
Article  MathSciNet  CAS  Google Scholar 
Wu, Z. et al. Effect of monthly vitamin D supplementation on cardiac biomarkers: a post-hoc analysis of a randomized controlled trial. J. Steroid Biochem. Mol. Biol. 220, 106093 (2022).
Article  CAS  PubMed  MATH  Google Scholar 
Limonte, C. P. et al. Effects of long-term vitamin D and n-3 fatty acid supplementation on inflammatory and cardiac biomarkers in patients with type 2 diabetes: secondary analyses from a randomised controlled trial. Diabetologia 64 (2), 437–447 (2021).
Article  CAS  PubMed  Google Scholar 
Kord-Varkaneh, H. et al. The influence of vitamin D supplementation on IGF-1 levels in humans: a systematic review and meta-analysis. Ageing Res. Rev. 57, 100996 (2020).
Article  CAS  PubMed  MATH  Google Scholar 
Meshkini, F., Abdollahi, S., Clark, C. C. & Soltani, S. The effect of vitamin D supplementation on insulin-like growth factor-1: a systematic review and meta-analysis of randomized controlled trials. Complement. Ther. Med. 50, 102300 (2020).
Article  PubMed  Google Scholar 
Contreras-Bolívar, V., García-Fontana, B., García-Fontana, C. & Muñoz-Torres, M. Mechanisms involved in the relationship between vitamin D and insulin resistance: impact on clinical practice. Nutrients 13 (10), 3491 (2021).
Article  PubMed  PubMed Central  MATH  Google Scholar 
Chen, Y-C. et al. Association between metabolic body composition status and vitamin D deficiency: a cross-sectional study. Front. Nutr. 9, 940183 (2022).
Article  PubMed  PubMed Central  Google Scholar 
Chen, L. et al. Vitamin D3 induces mesenchymal-to-endothelial transition and promotes a proangiogenic niche through IGF-1 signaling. Iscience 24 (4), 102272 (2021).
Article  ADS  CAS  PubMed  PubMed Central  MATH  Google Scholar 
Dzik, K. P. & Kaczor, J. J. Mechanisms of vitamin D on skeletal muscle function: oxidative stress, energy metabolism and anabolic state. Eur. J. Appl. Physiol. 119, 825–839 (2019).
Article  CAS  PubMed  PubMed Central  MATH  Google Scholar 
Pál, É., Ungvári, Z., Benyó, Z. & Várbíró, S. Role of vitamin D deficiency in the pathogenesis of cardiovascular and cerebrovascular diseases. Nutrients 15 (2), 334 (2023).
Article  PubMed  PubMed Central  Google Scholar 
Saati-Zarei, A., Damirchi, A., Tousi, S. M. T. R. & Babaei, P. Myocardial angiogenesis induced by concurrent vitamin D supplementation and aerobic-resistance training is mediated by inhibiting miRNA-15a, and miRNA-146a and upregulating VEGF/PI3K/eNOS signaling pathway. Pflügers Archiv-European J. Physiol. 475 (4), 541–555 (2023).
Article  CAS  Google Scholar 
Download references
The authors would like to thank the participants for their cooperation.
The authors declared that the research did not receive any financial grants.
Department of Exercise Physiology, Faculty of Sport Sciences, Razi University, Kermanshah, Iran
Fatemeh Mazaheri
Department of Exercise Physiology, Faculty of Sport Sciences, Razi University, P.O.Box. 6714414971, Kermanshah, Iran
Rastegar Hoseini
Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran
Ahmad Gharzi
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
You can also search for this author in PubMed Google Scholar
R.H. designed the study and analyzed the data. F.M. and A.G.H. conducted the experiments and contributed to data analysis. R.H. wrote the manuscript with input from F.M. and A.G.H. All authors were involved in the interpretation of data, critically revised the manuscript, and approved the final version for submission.
Correspondence to Rastegar Hoseini.
This study was approved by the Ethics Committee of Razi University of Kermanshah and was registered in the Iranian Clinical Trial Registration Center (code: IRCT20220512054832N1 on 09/06/2022). All procedures described in this study were performed following the guidelines of the Ethics Committee of the Razi University of Kermanshah (IR.RAZI.REC.1401.011). The authors confirm that this study is reported following ARRIVE guidelines.
Not applicable.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Reprints and permissions
Mazaheri, F., Hoseini, R. & Gharzi, A. Vitamin D and exercise improve VEGF-B production and IGF-1 levels in diabetic rats: insights the role of miR-1 suppression. Sci Rep 15, 1328 (2025). https://doi.org/10.1038/s41598-024-81230-3
Download citation
Received: 23 December 2023
Accepted: 25 November 2024
Published: 08 January 2025
DOI: https://doi.org/10.1038/s41598-024-81230-3
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative
Advertisement
Scientific Reports (Sci Rep) ISSN 2045-2322 (online)
© 2025 Springer Nature Limited
Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

source

About The Author

admin

See author's posts