Vitamin D Deficiency as a Potential Biomarker of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus

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Al-Obeidi, Yahya A. Alghassaly, Reem A. Al-Raimi, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6199008/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: Diabetic retinopathy (DR) is a leading cause of vision loss globally, and vitamin D deficiency has been implicated in its pathogenesis. This study aimed to investigate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and DR in patients with type 2 diabetes mellitus (T2DM). Patients and methods: This comparative cross-sectional study included 120 Yemeni male participants aged 40–60 years. Participants were divided into four groups: 30 healthy controls, 30 T2DM patients without retinopathy (DWR), 30 T2DM patients with non-proliferative diabetic retinopathy (NPDR), and 30 T2DM patients with proliferative diabetic retinopathy (PDR). Serum 25(OH)D, HbA1c, fasting blood glucose (FBS), lipid profile, and intraocular pressure (IOP) were measured. Data were analyzed using SPSS version 22, with p < 0.05 considered statistically significant. Results: Serum 25(OH)D levels were significantly lower in the PDR group (10.6 ± 2.1 ng/mL) than in the NPDR group (20.5 ± 2.8 ng/mL), DWR group (26.4 ± 1.9 ng/mL), and control group (34.2 ± 3.9 ng/mL) (p < 0.0001). Approximately 66.6% (n=60) of DR patients had 25(OH)D deficiency (<20 ng/mL). HbA1c, FBS, total cholesterol, LDL-c, and triglycerides were significantly higher in DR patients, whereas HDL-c levels were significantly lower (p < 0.05). IOP was also significantly higher in DR patients compared with DWR and controls (p < 0.0001). A significant negative correlation was observed between serum 25(OH)D levels and HbA1c, FBS, total cholesterol, LDL-c, triglycerides, BMI, and IOP, whereas a positive correlation was observed with HDL-c (p < 0.0001). Conclusion: Serum 25(OH)D levels were significantly lower in patients with diabetic retinopathy than in healthy controls and patients with diabetes without retinopathy. Vitamin D deficiency is associated with poor glycemic control, dyslipidemia, and increased intraocular pressure, suggesting a potential role for vitamin D as a biomarker of DR. Further research is needed to evaluate the therapeutic potential of vitamin D supplementation in the prevention or management of DR. Ophthalmology Diabetic Retinopathy Vitamin D Type 2 Diabetes Mellitus Vision Loss Retinal Damage Biomarkers Introduction Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to abnormalities in insulin production, action, or both. 1 Globally, DM affects 10.5% of the population and is a leading cause of disability-adjusted life years lost. 2 The condition contributes significantly to morbidity and mortality, especially among young and middle-aged individuals, imposing a substantial economic burden on society. 3 In Yemen, a 2019 study reported the prevalence of DM among men to be 9.8%. 4 Uncontrolled hyperglycemia over time leads to organ damage and dysfunction, resulting in both microvascular and macrovascular complications, with diabetic retinopathy (DR) being a prominent microvascular consequence. 5 , 6 DR affects nearly 40% of individuals with diabetes and is one of the leading causes of blindness in people under the age of 50, with a prevalence of about 4.8%. 7 According to the World Health Organization (WHO), 422 million people globally are affected by DR, and this number is expected to rise significantly, reaching 642 million by 2040. 8 Proliferative diabetic retinopathy (PDR), a more advanced stage, is observed in 2% of T2DM patients within 5 years of diagnosis and in 16% of those with over 15 years of diabetes duration. 9 Non-proliferative diabetic retinopathy (NPDR) is more prevalent, affecting 25% of T2DM patients 5 years after diagnosis, 60% after ten years, and 80% after 15 years. 10 Vitamin D [25(OH)D] is a bioregulatory molecule that was initially recognized for its role in bone health. 11 However, increasing evidence highlights its broader significance in human health, particularly in terms of its endocrine, autocrine, and paracrine functions. 11 , 12 The presence of Vitamin D receptors (VDRs) in various tissues, including the kidney, pancreas, immune system, and eye, suggests a critical role for 25(OH)D beyond bone metabolism. 13 Recent studies have demonstrated that vitamin D is not only systemically synthesized in the kidney but is also locally produced in ocular tissues such as the sclera, corneal endothelium, and retinal pigment epithelium. 13 Several studies have proposed an inverse correlation between serum 25(OH)D levels and the severity of DR, although the causative relationship remains unclear. 14 Vitamin D exhibits protective effects against DR through its anti-proliferative, anti-inflammatory, anti-oxidant, and antiangiogenic properties. 15 The active vitamin D metabolite, calcitriol, is a potent inhibitor of retinal neovascularization in oxygen-induced ischemic retinopathy models. 18 These mechanisms highlight the potential role of Vitamin D in mitigating retinal vascular damage and DR progression. Given these associations, this study aimed to evaluate the relationship between serum 25(OH)D levels and the severity of DR in Yemeni patients with Type 2 Diabetes Mellitus (T2DM). We hypothesized that lower 25(OH)D levels are associated with increased DR severity and that analysis of these levels may offer clinical benefits for identifying and managing at-risk patients. Materials and methods This comparative cross-sectional study was conducted in the Retina Departments of multiple eye centers in Sana’a, Yemen, between January 2023 and January 2024. The study was approved by the Committee of Postgraduate Studies and Scientific Research at the Faculty of Medicine and Health Sciences, Sana’a University(Approval number: 2023-53). Written informed consent was obtained from all participants prior to their inclusion in the study. The research adhered to the ethical principles outlined in the Declaration of Helsinki, as revised in 2000. The sample size was calculated using the OpenEpi program (Version 2.3.1) based on the methodology described by Nadri et al. 16 With a 95% confidence level, 80% power, and the reported mean ± standard deviation (SD) of 25(OH)D levels in cases (18.1 ± 1.9 ng/mL) and controls (25.9 ± 1.6 ng/mL), a total of 120 participants were included. The participants were divided into four equal groups: healthy controls (n = 30), diabetic patients without retinopathy (DWR, n = 30), diabetic patients with non-proliferative diabetic retinopathy (NPDR, n = 30), and diabetic patients with proliferative diabetic retinopathy (PDR, n = 30). Eligible participants were male, aged 40–60 years, and recruited from the study centers. The exclusion criteria were systemic or ocular conditions affecting retinal vasculature, such as cardiovascular disease, renal failure, diabetic neuropathy, and other macrovascular complications of diabetes. Additionally, individuals with type 1 diabetes mellitus, tuberculosis, chronic liver disease, cancer, or conditions affecting 25(OH)D and calcium metabolism were excluded. Participants using vitamin supplements, antioxidants, or medications affecting vitamin D metabolism (e.g., Rifampin, Phenobarbital, Phenytoin) were also excluded. For data collection, 2 mL of whole blood was collected from each participant to measure glycated hemoglobin (HbA1c) levels using the Standard F Analyzer (SD Biosensor, Korea). An additional 5 mL of venous blood was drawn into plain tubes for biochemical assessments. Random blood glucose levels were measured using a KINZ MAX Biochemistry Analyzer (Biolabo, France) to confirm the diagnosis of diabetes mellitus. Serum 25(OH)D levels were analyzed using a chemiluminescence one-step delayed assay on an Abbott Architect i-1000SR analyzer (Abbott Diagnostics, Wiesbaden, Germany). Lipid profile parameters, including total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c), as well as urea, creatinine, calcium, and phosphate levels, were measured using a KINZ MAX Biochemistry Analyzer (Biolabo, France). Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software, version 22 (LEAD Technologies, Inc., USA). Descriptive statistics (frequency, percentage, means, and standard deviations) were calculated for all variables. A p-value 0.05 was considered statistically significant. Results The demographic and clinical characteristics of the study groups (Table 1) highlight significant differences across the control and diabetic groups with varying degrees of retinopathy. Age was significantly higher in the diabetic groups compared to controls, with a statistically significant p-value of <0.0001. The body mass index (BMI) was notably elevated in the diabetic groups, especially in those with proliferative diabetic retinopathy (PDR), indicating a progressive increase in BMI correlated with the severity of the condition (p=0.001). Systolic and diastolic blood pressures (SBP and DBP) were significantly higher in the diabetic groups, particularly in PDR, with p-values <0.0001, suggesting a strong association with the progression of diabetic retinopathy. The duration of diabetes mellitus and presence of metabolic syndrome also increased significantly across the groups with retinopathy, with p-values <0.0001. As detailed in Table 2, serum 25-hydroxyvitamin D [25(OH)D] levels were substantially lower in the diabetic groups, decreasing progressively from diabetic without retinopathy (DWR) to PDR (p<0.0001). Fasting blood sugar (FBS) and glycated hemoglobin (HbA1c) levels were significantly higher among the diabetic groups, with the highest value observed in those with PDR (FBS: p<0.0001, HbA1c: p=0.007). Additionally, creatinine, total cholesterol, and triglycerides exhibited significant elevations in the diabetic cohorts, indicating metabolic disturbances associated with retinopathy progression (creatinine: p=0.003, total cholesterol: p=0.004, triglycerides: p<0.05). High-density lipoprotein cholesterol (HDL-c) levels were inversely correlated with the severity of retinopathy, showing a significant decline (p=0.021). The correlation analysis presented in Tables 3 and 4 revealed strong inverse relationships between serum 25(OH)D levels and several biochemical and clinical variables. Notably, HbA1c, FBS, total cholesterol, and low-density lipoprotein cholesterol (LDL-c) demonstrated strong negative correlations (r=-0.831, -0.798, -0.742, -0.779 respectively, p<0.0001), whereas HDL-c showed a positive correlation (r=0.822, p<0.0001). Among the descriptive variables, the duration of diabetes mellitus and blood pressure also showed significant negative correlations with 25(OH)D levels (r=-0.664, -0.727 respectively, p<0.0001). However, the influence of lifestyle factors such as chewing khat and smoking was not significant. Table 5 shows the intraocular pressure measurements, which were significantly elevated in the diabetic groups, especially in those with PDR. Both left and right intraocular pressures increased markedly in correlation with the progression of diabetic retinopathy (p<0.0001), highlighting potential risk factors for ocular complications in these patients. Discussion Diabetic retinopathy (DR) is a progressive neuro-microvascular complication associated with both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) and is the leading cause of vision loss globally, particularly among middle-aged adults. 17 , 18 Nutritional status is believed to influence the biochemical mechanisms underlying DR, and vitamin D (25(OH)D) has emerged as a micronutrient that plays a critical role in the pathogenesis of DR. 19 Our study demonstrated significantly lower serum 25(OH)D levels in patients with proliferative diabetic retinopathy (PDR) (10.6 ± 2.1 ng/mL) and non-proliferative diabetic retinopathy (NPDR) (20.5 ± 2.8 ng/mL) compared with diabetic patients without retinopathy (DWR) (26.4 ± 1.9 ng/mL) and controls (34.2 ± 3.9 ng/mL) (p < 0.0001). Additionally, 66.6% of patients with DRR had 25(OH)D deficiency. These findings are consistent with the study by Nadri et al., which demonstrated significantly lower 25(OH)D levels in patients with DR compared to controls and identified serum levels below 20 ng/mL as a potential biomarker for PDR. 16 Similarly, Motahari et al. reported a significant decrease in 25(OH)D levels in PDR patients compared to NPDR patients (p = 0.038). 20 Castillo et al. also supported the association, showing that 25(OH)D deficiency increased the odds of developing DR by 5.2 times. 21 However, Bonakdaran et al. found no significant difference in 25(OH)D levels between the DR and DWR groups (p = 0.7). 22 Discrepancies between our findings and those of other studies may be attributed to variations in nutritional status, environmental factors like sunlight exposure, population genetics, and the inclusion of patients with T1DM in some studies. 22 , 23 Vitamin D plays a well-established role in modulating the pathways involved in DR. Its active metabolite, calcitriol, inhibits retinal neovascularization by regulating vascular endothelial growth factor (VEGF) through vitamin D receptor (VDR)-mediated mechanisms. 24 , 25 Additionally, 25(OH)D exerts anti-inflammatory effects by suppressing proinflammatory cytokines, natural killer cells, and metalloproteinases like MMP-9. 26 , 27 Our findings corroborate these mechanisms, highlighting the inverse correlation between 25(OH)D levels and HbA1c, LDL, triglycerides, and proinflammatory markers. Our study revealed significant differences in lipid profiles between the DR and DWR groups, with higher total cholesterol, triglycerides, LDL levels and lower HDL levels observed in the DR group. These findings are consistent with those of Nadri et al.. and Neelam et al, who reported significant lipid dysregulation in DR patients. 16 , 28 Furthermore, the TYG index and TYG-BMI index, both indicators of insulin resistance, were significantly elevated in patients with DR in our study. These indices are emerging as reliable markers of insulin resistance, as demonstrated by Lin et al.. 29 We observed a significant increase in intraocular pressure (IOP) in patients with DR compared with DWR and controls. This finding is supported by a prospective study in India, which reported significantly higher IOP in patients with diabetes compared with controls without diabetes (p < 0.001). 30 Mechanistically, vitamin D deficiency may contribute to increased IOP by modulating aqueous humor production and optic nerve function. 31 The prevalence of metabolic syndrome (MetS) was significantly higher in patients with DR (66.6%) than in those with DWR (27%, p < 0.0001). This is consistent with findings from an American study, which reported higher DR rates among individuals with MetS. 32 However, discrepancies exist, such as the study by Sun et al., which found no significant association between MetS and DR. 33 These variations may stem from differences in the study design and the inclusion of confounding factors. Our study showed strong negative correlations between serum 25(OH)D levels and HbA1c, LDL, TG, lipid indices, BMI, blood pressure, and IOP. Conversely, a positive correlation with HDL was observed. These correlations align with prior studies, which highlighted the role of 25(OH)D in modulating glucose metabolism, lipid profiles, and vascular integrity. 28 , 34 – 39 Mechanistically, vitamin D enhances insulin secretion, reduces inflammation, and modulates the renin-angiotensin system, thereby influencing glucose and lipid metabolism. 40 , 41 This study has several strengths. Participants were recruited from specialized retina centers to reduce selection bias, and different stages of DR were analyzed, allowing for a detailed investigation of 25(OH)D’s role. Additionally, new indicators like the TYG index were used to comprehensively evaluate insulin resistance. However, limitations include a small sample size and the lack of detailed data on sunlight exposure, a major determinant of vitamin D status. Conclusion Our findings indicate that serum 25(OH)D levels are significantly lower in patients with DR than in DWR patients and controls, and 25(OH)D deficiency is strongly associated with DR development. These results suggest that 25(OH)D could serve as a biomarker of DR and emphasize the need for further research to explore its potential in preventing or managing DR. Declarations Ethics Approval and Informed Consent This study was approved by the Ethics Committee of the Faculty of Medicine and Health Sciences, Sana’a University (approval number: 2023-53). Written informed consent was obtained from all participants prior to their inclusion in the study. The research adhered to the principles of the Declaration of Helsinki. All participants were informed of the study’s objectives and procedures and provided explicit consent for data collection and analysis. Consent for Publication Consent to publish data, images, or recordings was obtained from all participants. Participants reviewed the content related to their data before giving consent for publication. Copies of signed consent forms are available at the journal editorial office upon request. Data Availability The datasets generated and analyzed during the current study are not publicly available due to ethical and privacy considerations. However, they are available from the corresponding author upon reasonable request for academic purposes. Funding This study did not receive any specific grants or financial support from public, commercial, or not-for-profit organizations. The research was conducted independently using resources provided by the authors’ affiliated institutions. Competing Interests The authors declare that they have no competing interests relevant to this work. The research, analysis, and manuscript preparation were conducted objectively, without any financial or personal relationships that could influence the outcomes presented. Authors’ Contributions Abdelkarim M. Al-Obeidi : Conceptualization, data acquisition, manuscript preparation, clinical investigations, manuscript review, and critical revision Yahya A. Alghassaly : Conceptualization, data acquisition, manuscript preparation, clinical investigations, manuscript review, and critical revision Reem A. Al-Raimi : Statistical analysis, manuscript editing, and data interpretation. Haitham M. Jowah : Supervision, manuscript drafting, and correspondence. All authors have read and approved the final manuscript and agree to take responsibility for its content. Acknowledgments The authors would like to express their gratitude to the staff of the Retina Departments at the Eye Centers in Sana’a City, Yemen, for their invaluable assistance during data collection and clinical evaluations. We wish to thank the Faculty of Medicine and Health Sciences, Sana’a University, for providing the facilities required for conducting this research. Disclosure The authors declare no conflicts of interest. References Punthakee Z, Goldenberg R, Katz P (2018) Definition, classification, and diagnosis of diabetes, prediabetes, and metabolic syndrome. Can J Diabetes 42:S10–S15. 10.1016/j.jcjd.2017.10.003 Huang HM, Wu PC, Kuo HK, Chen YJ, Poon LYC (2020) Natural history and visual outcome of nonarteritic anterior ischemic optic neuropathy in Southern Taiwan: a pilot study. Int Ophthalmol 40(10):2667–2676. 10.1007/s10792-020-01448-8 Shaw JE, Sicree RA, Zimmet PZ (2010) Global estimates of the prevalence of diabetes for 2010 and 2030. 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Food Funct 12(15):6682–6690. 10.1039/D0FO03230A Tables Table 1: Demographic and Clinical Characteristics of the Study Groups Characteristic Control (n=30) DWR (n=30) NPDR (n=30) PDR (n=30) P-value Age (years) 47.1 ± 5.9 55.9 ± 4.9 56.4 ± 4.7 57.8 ± 4.3 <0.0001 BMI (Kg/m²) 23.6 ± 1.0 27.0 ± 1.0 27.6 ± 1.2 28.4 ± 1.4 0.001 SBP (mmHg) 118.2 ± 9.4 129.9 ± 12.2 141.1 ± 14.4 146.0 ± 15.5 <0.0001 DBP (mmHg) 71.8 ± 8.6 88.5 ± 9.3 90.0 ± 9.7 92.9 ± 11.6 <0.0001 Duration of diabetes mellitus (years) - 6.2 ± 1.0 7.4 ± 1.3 9.0 ± 1.4 <0.0001 Metabolic syndrome - 3.3 ± 0.5 4.7 ± 0.4 4.9 ± 0.2 <0.0001 Note: Data are presented as mean ± standard deviation. P-values for continuous variables were obtained using one-way ANOVA. P-value ≤ 0.05 is considered significant. Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; DWR, diabetic without retinopathy; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. Table 2: Biochemical Parameters Across Study Groups Characteristic Control (n=30) DWR (n=30) NPDR (n=30) PDR (n=30) P-value 25(OH)D (ng/mL) 34.2 ± 3.9 26.4 ± 1.9 20.5 ± 2.8 10.6 ± 2.1 <0.0001 FBS (mg/dL) 90.8 ± 11.7 149.7 ± 27.4 186.8 ± 27.7 192.8 ± 24.8 <0.0001 HbA1c (%) 5.6 ± 0.3 8.8 ± 0.9 9.5 ± 1.2 10.8 ± 1.5 0.007 Creatinine (mg/dL) 0.8 ± 0.2 0.9 ± 0.2 0.9 ± 0.2 1.1 ± 0.2 0.003 Total cholesterol (mg/dL) 141.9 ± 16.3 200.2 ± 28.6 221.7 ± 22.2 228.5 ± 15.1 0.004 Triglycerides (mg/dL) 167.8 ± 13.8 250.7 ± 32.6 266.4 ± 24.4 276.2 ± 27.0 <0.05 HDL-c (mg/dL) 59.8 ± 7.3 38.2 ± 8.1 33.0 ± 7.4 25.9 ± 6.5 0.021 Note: Data are presented as mean ± standard deviation. P-values for continuous variables were obtained using one-way ANOVA. P-value ≤ 0.05 is considered significant. Abbreviations: 25(OH)D, 25-hydroxyvitamin D; FBS, fasting blood sugar; HbA1c, glycated hemoglobin; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; DWR, diabetic without retinopathy; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. Table 3: Correlation of Serum 25(OH)D Levels with Biochemical Variables Variable r-Coefficient Correlation P-value HbA1c -0.831 <0.0001 FBS -0.798 <0.0001 Total cholesterol -0.742 <0.0001 LDL-c -0.779 <0.0001 HDL-c 0.822 <0.0001 Age -0.581 <0.0001 BMI -0.727 0.003 Notes: Data are presented as correlation coefficients (r). 𝑝-value significant at ≤ 0.05. Abbreviations: r, correlation coefficient; 25(OH)D, 25-hydroxyvitamin D; HbA1c, glycated hemoglobin; FBS, fasting blood sugar; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol; BMI, body mass index. Table 4: Correlations of Serum 25(OH)D Levels with Descriptive Variables Variable r-Coefficient Correlation P-value Chewing khat -0.108 0.24 Smoking -0.117 0.202 Duration of diabetes mellitus -0.664 <0.0001 Blood pressure -0.727 <0.0001 Hypertensive drugs -0.190 0.038 Notes: Data are presented as correlation coefficients (r). 𝑝-value significant at ≤ 0.05. Abbreviations: r, correlation coefficient; 25(OH)D, 25-hydroxyvitamin D. Table 5: Ocular Pressure Measurements Across Study Groups Characteristic Control (n=30) DWR (n=30) NPDR (n=30) PDR (n=30) P-value Intraocular pressure L (mmHg) 15.1 ± 2.0 15.5 ± 2.8 24.4 ± 6.0 26.6 ± 5.1 <0.0001 Intraocular pressure R (mmHg) 12.9 ± 2.0 15.4 ± 2.9 25.5 ± 5.1 29.2 ± 8.6 <0.0001 Note: Data are presented as mean ± standard deviation. P-values for continuous variables were obtained using one-way ANOVA. 𝑝-value significant at ≤ 0.05. Abbreviations: DWR, diabetics without retinopathy; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; L, left; R, right; mmHg, millimeters of mercury Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6199008","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":426957595,"identity":"0bb0dea7-8674-45a7-b2a5-fa2d2129b60e","order_by":0,"name":"Abdelkarim M. Al-Obeidi","email":"","orcid":"","institution":"Department of Biochemistry and Molecular Biology, Faculty of Medicine and Health Sciences, Sana’a University, Sana'a, Yemen","correspondingAuthor":false,"prefix":"","firstName":"Abdelkarim","middleName":"M.","lastName":"Al-Obeidi","suffix":""},{"id":426957596,"identity":"d25367bc-0ae6-4bbb-997b-2ffb5af5a9a0","order_by":1,"name":"Yahya A. Alghassaly","email":"","orcid":"","institution":"Department of Ophthalmology, Faculty of Medicine and Health Sciences, Sana’a University, Sana'a, Yemen","correspondingAuthor":false,"prefix":"","firstName":"Yahya","middleName":"A.","lastName":"Alghassaly","suffix":""},{"id":426957597,"identity":"188fbd6c-3467-4f78-8345-739ced600887","order_by":2,"name":"Reem A. Al-Raimi","email":"","orcid":"","institution":"Department of Biochemistry and Molecular Biology, Faculty of Medicine and Health Sciences, Sana’a University, Sana'a, Yemen","correspondingAuthor":false,"prefix":"","firstName":"Reem","middleName":"A.","lastName":"Al-Raimi","suffix":""},{"id":426957598,"identity":"4fda8d04-6610-4b7d-bf2c-168e0724fea6","order_by":3,"name":"Haitham Mohammed Jowah","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIiWNgGAWjYBACAwaGBCB1QA7M4yFFizFJWkDgQGID0VrMGRgePuapuZM+f0YC44O3bQyJ/YS0WDYwJBvzHHuWu+FGArPhXKCWmQ2EHHaAIU06h+1w7gaJBDZpXqCWDQeI0vLvcLr8jAT23yAt+4nSktt2OIHhRgIbM9gWQn4xOAz0y9++w4YbzjxslpxzTsJ4BkFbjvckPpzx7bC8fHvywQ9vymxk+xsIWcPMkwBlMYLUSjgS1MHAwI7qEHvCOkbBKBgFo2CkAQCEAUMIrb03fgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0008-3815-3017","institution":"Department of Surgery, Faculty of Medicine and Health Sciences, Sana’a University, Sana’a, Yemen","correspondingAuthor":true,"prefix":"","firstName":"Haitham","middleName":"Mohammed","lastName":"Jowah","suffix":""}],"badges":[],"createdAt":"2025-03-11 00:35:46","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6199008/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6199008/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78330160,"identity":"aa3a5763-caa0-488c-926f-be7d2c29d528","added_by":"auto","created_at":"2025-03-12 07:07:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":845612,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6199008/v1/48618766-f79e-42bf-8436-0b92fa14af5b.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eVitamin D Deficiency as a Potential Biomarker of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDiabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to abnormalities in insulin production, action, or both.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Globally, DM affects 10.5% of the population and is a leading cause of disability-adjusted life years lost.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e The condition contributes significantly to morbidity and mortality, especially among young and middle-aged individuals, imposing a substantial economic burden on society.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e In Yemen, a 2019 study reported the prevalence of DM among men to be 9.8%.\u003csup\u003e4\u003c/sup\u003e Uncontrolled hyperglycemia over time leads to organ damage and dysfunction, resulting in both microvascular and macrovascular complications, with diabetic retinopathy (DR) being a prominent microvascular consequence.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDR affects nearly 40% of individuals with diabetes and is one of the leading causes of blindness in people under the age of 50, with a prevalence of about 4.8%.\u003csup\u003e7\u003c/sup\u003e According to the World Health Organization (WHO), 422\u0026nbsp;million people globally are affected by DR, and this number is expected to rise significantly, reaching 642\u0026nbsp;million by 2040.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Proliferative diabetic retinopathy (PDR), a more advanced stage, is observed in 2% of T2DM patients within 5 years of diagnosis and in 16% of those with over 15 years of diabetes duration.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Non-proliferative diabetic retinopathy (NPDR) is more prevalent, affecting 25% of T2DM patients 5 years after diagnosis, 60% after ten years, and 80% after 15 years.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eVitamin D [25(OH)D] is a bioregulatory molecule that was initially recognized for its role in bone health.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e However, increasing evidence highlights its broader significance in human health, particularly in terms of its endocrine, autocrine, and paracrine functions.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e The presence of Vitamin D receptors (VDRs) in various tissues, including the kidney, pancreas, immune system, and eye, suggests a critical role for 25(OH)D beyond bone metabolism.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Recent studies have demonstrated that vitamin D is not only systemically synthesized in the kidney but is also locally produced in ocular tissues such as the sclera, corneal endothelium, and retinal pigment epithelium.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSeveral studies have proposed an inverse correlation between serum 25(OH)D levels and the severity of DR, although the causative relationship remains unclear.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Vitamin D exhibits protective effects against DR through its anti-proliferative, anti-inflammatory, anti-oxidant, and antiangiogenic properties.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e The active vitamin D metabolite, calcitriol, is a potent inhibitor of retinal neovascularization in oxygen-induced ischemic retinopathy models.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e These mechanisms highlight the potential role of Vitamin D in mitigating retinal vascular damage and DR progression.\u003c/p\u003e \u003cp\u003eGiven these associations, this study aimed to evaluate the relationship between serum 25(OH)D levels and the severity of DR in Yemeni patients with Type 2 Diabetes Mellitus (T2DM). We hypothesized that lower 25(OH)D levels are associated with increased DR severity and that analysis of these levels may offer clinical benefits for identifying and managing at-risk patients.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThis comparative cross-sectional study was conducted in the Retina Departments of multiple eye centers in Sana\u0026rsquo;a, Yemen, between January 2023 and January 2024. The study was approved by the Committee of Postgraduate Studies and Scientific Research at the Faculty of Medicine and Health Sciences, Sana\u0026rsquo;a University(Approval number: 2023-53). Written informed consent was obtained from all participants prior to their inclusion in the study. The research adhered to the ethical principles outlined in the Declaration of Helsinki, as revised in 2000.\u003c/p\u003e \u003cp\u003eThe sample size was calculated using the OpenEpi program (Version 2.3.1) based on the methodology described by Nadri et al.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e With a 95% confidence level, 80% power, and the reported mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) of 25(OH)D levels in cases (18.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 ng/mL) and controls (25.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 ng/mL), a total of 120 participants were included. The participants were divided into four equal groups: healthy controls (n\u0026thinsp;=\u0026thinsp;30), diabetic patients without retinopathy (DWR, n\u0026thinsp;=\u0026thinsp;30), diabetic patients with non-proliferative diabetic retinopathy (NPDR, n\u0026thinsp;=\u0026thinsp;30), and diabetic patients with proliferative diabetic retinopathy (PDR, n\u0026thinsp;=\u0026thinsp;30).\u003c/p\u003e \u003cp\u003eEligible participants were male, aged 40\u0026ndash;60 years, and recruited from the study centers. The exclusion criteria were systemic or ocular conditions affecting retinal vasculature, such as cardiovascular disease, renal failure, diabetic neuropathy, and other macrovascular complications of diabetes. Additionally, individuals with type 1 diabetes mellitus, tuberculosis, chronic liver disease, cancer, or conditions affecting 25(OH)D and calcium metabolism were excluded. Participants using vitamin supplements, antioxidants, or medications affecting vitamin D metabolism (e.g., Rifampin, Phenobarbital, Phenytoin) were also excluded.\u003c/p\u003e \u003cp\u003eFor data collection, 2 mL of whole blood was collected from each participant to measure glycated hemoglobin (HbA1c) levels using the Standard F Analyzer (SD Biosensor, Korea). An additional 5 mL of venous blood was drawn into plain tubes for biochemical assessments. Random blood glucose levels were measured using a KINZ MAX Biochemistry Analyzer (Biolabo, France) to confirm the diagnosis of diabetes mellitus. Serum 25(OH)D levels were analyzed using a chemiluminescence one-step delayed assay on an Abbott Architect i-1000SR analyzer (Abbott Diagnostics, Wiesbaden, Germany). Lipid profile parameters, including total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c), as well as urea, creatinine, calcium, and phosphate levels, were measured using a KINZ MAX Biochemistry Analyzer (Biolabo, France).\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software, version 22 (LEAD Technologies, Inc., USA). Descriptive statistics (frequency, percentage, means, and standard deviations) were calculated for all variables. A p-value 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe demographic and clinical characteristics of the study groups (Table 1) highlight significant differences across the control and diabetic groups with varying degrees of retinopathy. Age was significantly higher in the diabetic groups compared to controls, with a statistically significant p-value of \u0026lt;0.0001. The body mass index (BMI) was notably elevated in the diabetic groups, especially in those with proliferative diabetic retinopathy (PDR), indicating a progressive increase in BMI correlated with the severity of the condition (p=0.001). Systolic and diastolic blood pressures (SBP and DBP) were significantly higher in the diabetic groups, particularly in PDR, with p-values \u0026lt;0.0001, suggesting a strong association with the progression of diabetic retinopathy. The duration of diabetes mellitus and presence of metabolic syndrome also increased significantly across the groups with retinopathy, with p-values \u0026lt;0.0001.\u003c/p\u003e\n\u003cp\u003eAs detailed in Table 2, serum 25-hydroxyvitamin D [25(OH)D] levels were substantially lower in the diabetic groups, decreasing progressively from diabetic without retinopathy (DWR) to PDR (p\u0026lt;0.0001). Fasting blood sugar (FBS) and glycated hemoglobin (HbA1c) levels were significantly higher among the diabetic groups, with the highest value observed in those with PDR (FBS: p\u0026lt;0.0001, HbA1c: p=0.007). Additionally, creatinine, total cholesterol, and triglycerides exhibited significant elevations in the diabetic cohorts, indicating metabolic disturbances associated with retinopathy progression (creatinine: p=0.003, total cholesterol: p=0.004, triglycerides: p\u0026lt;0.05). High-density lipoprotein cholesterol (HDL-c) levels were inversely correlated with the severity of retinopathy, showing a significant decline (p=0.021).\u003c/p\u003e\n\u003cp\u003eThe correlation analysis presented in Tables 3 and 4 revealed strong inverse relationships between serum 25(OH)D levels and several biochemical and clinical variables. Notably, HbA1c, FBS, total cholesterol, and low-density lipoprotein cholesterol (LDL-c) demonstrated strong negative correlations (r=-0.831, -0.798, -0.742, -0.779 respectively, p\u0026lt;0.0001), whereas HDL-c showed a positive correlation (r=0.822, p\u0026lt;0.0001). Among the descriptive variables, the duration of diabetes mellitus and blood pressure also showed significant negative correlations with 25(OH)D levels (r=-0.664, -0.727 respectively, p\u0026lt;0.0001). However, the influence of lifestyle factors such as chewing khat and smoking was not significant.\u003c/p\u003e\n\u003cp\u003eTable 5 shows the intraocular pressure measurements, which were significantly elevated in the diabetic groups, especially in those with PDR. Both left and right intraocular pressures increased markedly in correlation with the progression of diabetic retinopathy (p\u0026lt;0.0001), highlighting potential risk factors for ocular complications in these patients.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDiabetic retinopathy (DR) is a progressive neuro-microvascular complication associated with both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) and is the leading cause of vision loss globally, particularly among middle-aged adults.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Nutritional status is believed to influence the biochemical mechanisms underlying DR, and vitamin D (25(OH)D) has emerged as a micronutrient that plays a critical role in the pathogenesis of DR.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur study demonstrated significantly lower serum 25(OH)D levels in patients with proliferative diabetic retinopathy (PDR) (10.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 ng/mL) and non-proliferative diabetic retinopathy (NPDR) (20.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8 ng/mL) compared with diabetic patients without retinopathy (DWR) (26.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 ng/mL) and controls (34.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9 ng/mL) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Additionally, 66.6% of patients with DRR had 25(OH)D deficiency. These findings are consistent with the study by Nadri et al., which demonstrated significantly lower 25(OH)D levels in patients with DR compared to controls and identified serum levels below 20 ng/mL as a potential biomarker for PDR.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Similarly, Motahari et al. reported a significant decrease in 25(OH)D levels in PDR patients compared to NPDR patients (p\u0026thinsp;=\u0026thinsp;0.038).\u003csup\u003e20\u003c/sup\u003e Castillo et al. also supported the association, showing that 25(OH)D deficiency increased the odds of developing DR by 5.2 times.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e However, Bonakdaran et al. found no significant difference in 25(OH)D levels between the DR and DWR groups (p\u0026thinsp;=\u0026thinsp;0.7).\u003csup\u003e22\u003c/sup\u003e Discrepancies between our findings and those of other studies may be attributed to variations in nutritional status, environmental factors like sunlight exposure, population genetics, and the inclusion of patients with T1DM in some studies.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eVitamin D plays a well-established role in modulating the pathways involved in DR. Its active metabolite, calcitriol, inhibits retinal neovascularization by regulating vascular endothelial growth factor (VEGF) through vitamin D receptor (VDR)-mediated mechanisms.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Additionally, 25(OH)D exerts anti-inflammatory effects by suppressing proinflammatory cytokines, natural killer cells, and metalloproteinases like MMP-9.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Our findings corroborate these mechanisms, highlighting the inverse correlation between 25(OH)D levels and HbA1c, LDL, triglycerides, and proinflammatory markers.\u003c/p\u003e \u003cp\u003eOur study revealed significant differences in lipid profiles between the DR and DWR groups, with higher total cholesterol, triglycerides, LDL levels and lower HDL levels observed in the DR group. These findings are consistent with those of Nadri et al.. and Neelam et al, who reported significant lipid dysregulation in DR patients.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e Furthermore, the TYG index and TYG-BMI index, both indicators of insulin resistance, were significantly elevated in patients with DR in our study. These indices are emerging as reliable markers of insulin resistance, as demonstrated by Lin et al..\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe observed a significant increase in intraocular pressure (IOP) in patients with DR compared with DWR and controls. This finding is supported by a prospective study in India, which reported significantly higher IOP in patients with diabetes compared with controls without diabetes (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003csup\u003e30\u003c/sup\u003e Mechanistically, vitamin D deficiency may contribute to increased IOP by modulating aqueous humor production and optic nerve function.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe prevalence of metabolic syndrome (MetS) was significantly higher in patients with DR (66.6%) than in those with DWR (27%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). This is consistent with findings from an American study, which reported higher DR rates among individuals with MetS.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e However, discrepancies exist, such as the study by Sun et al., which found no significant association between MetS and DR.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e These variations may stem from differences in the study design and the inclusion of confounding factors.\u003c/p\u003e \u003cp\u003eOur study showed strong negative correlations between serum 25(OH)D levels and HbA1c, LDL, TG, lipid indices, BMI, blood pressure, and IOP. Conversely, a positive correlation with HDL was observed. These correlations align with prior studies, which highlighted the role of 25(OH)D in modulating glucose metabolism, lipid profiles, and vascular integrity.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan additionalcitationids=\"CR35 CR36 CR37 CR38\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e Mechanistically, vitamin D enhances insulin secretion, reduces inflammation, and modulates the renin-angiotensin system, thereby influencing glucose and lipid metabolism.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis study has several strengths. Participants were recruited from specialized retina centers to reduce selection bias, and different stages of DR were analyzed, allowing for a detailed investigation of 25(OH)D\u0026rsquo;s role. Additionally, new indicators like the TYG index were used to comprehensively evaluate insulin resistance. However, limitations include a small sample size and the lack of detailed data on sunlight exposure, a major determinant of vitamin D status.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings indicate that serum 25(OH)D levels are significantly lower in patients with DR than in DWR patients and controls, and 25(OH)D deficiency is strongly associated with DR development. These results suggest that 25(OH)D could serve as a biomarker of DR and emphasize the need for further research to explore its potential in preventing or managing DR.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics Approval and Informed Consent\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of the Faculty of Medicine and Health Sciences, Sana\u0026rsquo;a University (approval number: 2023-53). Written informed consent was obtained from all participants prior to their inclusion in the study. The research adhered to the principles of the Declaration of Helsinki. All participants were informed of the study\u0026rsquo;s objectives and procedures and provided explicit consent for data collection and analysis.\u003c/p\u003e\n\u003ch2\u003eConsent for Publication\u003c/h2\u003e\n\u003cp\u003eConsent to publish data, images, or recordings was obtained from all participants. Participants reviewed the content related to their data before giving consent for publication. Copies of signed consent forms are available at the journal editorial office upon request.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are not publicly available due to ethical and privacy considerations. However, they are available from the corresponding author upon reasonable request for academic purposes.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study did not receive any specific grants or financial support from public, commercial, or not-for-profit organizations. The research was conducted independently using resources provided by the authors\u0026rsquo; affiliated institutions.\u003c/p\u003e\n\u003ch2\u003eCompeting Interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests relevant to this work. The research, analysis, and manuscript preparation were conducted objectively, without any financial or personal relationships that could influence the outcomes presented.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; Contributions\u003c/h2\u003e\n\u003cp\u003e\u003cstrong\u003eAbdelkarim M. Al-Obeidi\u003c/strong\u003e: Conceptualization, data acquisition, manuscript preparation, clinical investigations, manuscript review, and critical revision\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYahya A. Alghassaly\u003c/strong\u003e: Conceptualization, data acquisition, manuscript preparation, clinical investigations, manuscript review, and critical revision\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReem A. Al-Raimi\u003c/strong\u003e: Statistical analysis, manuscript editing, and data interpretation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHaitham M. Jowah\u003c/strong\u003e: Supervision, manuscript drafting, and correspondence.\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the final manuscript and agree to take responsibility for its content.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eThe authors would like to express their gratitude to the staff of the Retina Departments at the Eye Centers in Sana\u0026rsquo;a City, Yemen, for their invaluable assistance during data collection and clinical evaluations. We wish to thank the Faculty of Medicine and Health Sciences, Sana\u0026rsquo;a University, for providing the facilities required for conducting this research.\u003c/p\u003e\n\u003ch2\u003eDisclosure\u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePunthakee Z, Goldenberg R, Katz P (2018) Definition, classification, and diagnosis of diabetes, prediabetes, and metabolic syndrome. 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Food Funct 12(15):6682\u0026ndash;6690. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1039/D0FO03230A\u003c/span\u003e\u003cspan address=\"10.1039/D0FO03230A\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Demographic and Clinical Characteristics of the Study Groups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDWR (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNPDR (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePDR (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e47.1 \u0026plusmn; 5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e55.9 \u0026plusmn; 4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e56.4 \u0026plusmn; 4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e57.8 \u0026plusmn; 4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBMI (Kg/m\u0026sup2;)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e23.6 \u0026plusmn; 1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e27.0 \u0026plusmn; 1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e27.6 \u0026plusmn; 1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e28.4 \u0026plusmn; 1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSBP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e118.2 \u0026plusmn; 9.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e129.9 \u0026plusmn; 12.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e141.1 \u0026plusmn; 14.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e146.0 \u0026plusmn; 15.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDBP (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e71.8 \u0026plusmn; 8.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e88.5 \u0026plusmn; 9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e90.0 \u0026plusmn; 9.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e92.9 \u0026plusmn; 11.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDuration of diabetes mellitus (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6.2 \u0026plusmn; 1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7.4 \u0026plusmn; 1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9.0 \u0026plusmn; 1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMetabolic syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3.3 \u0026plusmn; 0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.7 \u0026plusmn; 0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.9 \u0026plusmn; 0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNote:\u003c/strong\u003e Data are presented as mean \u0026plusmn; standard deviation. P-values for continuous variables were obtained using one-way ANOVA. P-value \u0026le; 0.05 is considered significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; DWR, diabetic without retinopathy; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Biochemical Parameters Across Study Groups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDWR (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNPDR (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePDR (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e25(OH)D (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e34.2 \u0026plusmn; 3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26.4 \u0026plusmn; 1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20.5 \u0026plusmn; 2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10.6 \u0026plusmn; 2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFBS (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e90.8 \u0026plusmn; 11.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e149.7 \u0026plusmn; 27.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e186.8 \u0026plusmn; 27.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e192.8 \u0026plusmn; 24.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHbA1c (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.6 \u0026plusmn; 0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8.8 \u0026plusmn; 0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9.5 \u0026plusmn; 1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10.8 \u0026plusmn; 1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCreatinine (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.8 \u0026plusmn; 0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.9 \u0026plusmn; 0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.9 \u0026plusmn; 0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.1 \u0026plusmn; 0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal cholesterol (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e141.9 \u0026plusmn; 16.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e200.2 \u0026plusmn; 28.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e221.7 \u0026plusmn; 22.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e228.5 \u0026plusmn; 15.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTriglycerides (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e167.8 \u0026plusmn; 13.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e250.7 \u0026plusmn; 32.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e266.4 \u0026plusmn; 24.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e276.2 \u0026plusmn; 27.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHDL-c (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e59.8 \u0026plusmn; 7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38.2 \u0026plusmn; 8.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33.0 \u0026plusmn; 7.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e25.9 \u0026plusmn; 6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNote:\u003c/strong\u003e Data are presented as mean \u0026plusmn; standard deviation. P-values for continuous variables were obtained using one-way ANOVA. P-value \u0026le; 0.05 is considered significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e 25(OH)D, 25-hydroxyvitamin D; FBS, fasting blood sugar; HbA1c, glycated hemoglobin; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; DWR, diabetic without retinopathy; NPDR, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3: Correlation of Serum 25(OH)D Levels with Biochemical Variables\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003er-Coefficient Correlation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHbA1c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.831\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFBS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.798\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.742\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLDL-c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.779\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHDL-c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.822\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.581\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.727\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNotes:\u003c/strong\u003e Data are presented as correlation coefficients (r).\u0026nbsp;𝑝-value significant at \u0026le; 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e r, correlation coefficient; 25(OH)D, 25-hydroxyvitamin D; HbA1c, glycated hemoglobin; FBS, fasting blood sugar; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol; BMI, body mass index.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4: Correlations of Serum 25(OH)D Levels with Descriptive Variables\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003er-Coefficient Correlation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eChewing khat\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.202\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDuration of diabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.664\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBlood pressure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.727\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHypertensive drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e-0.190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNotes:\u003c/strong\u003e Data are presented as correlation coefficients (r).\u0026nbsp;𝑝-value significant at \u0026le; 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e r, correlation coefficient; 25(OH)D, 25-hydroxyvitamin D.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5: Ocular Pressure Measurements Across Study Groups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDWR (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNPDR (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePDR (n=30)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIntraocular pressure L (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15.1 \u0026plusmn; 2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15.5 \u0026plusmn; 2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e24.4 \u0026plusmn; 6.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26.6 \u0026plusmn; 5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIntraocular pressure R (mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.9 \u0026plusmn; 2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15.4 \u0026plusmn; 2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e25.5 \u0026plusmn; 5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29.2 \u0026plusmn; 8.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNote:\u003c/strong\u003e Data are presented as mean \u0026plusmn; standard deviation. P-values for continuous variables were obtained using one-way ANOVA. 𝑝-value significant at \u0026le; 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e DWR, diabetics without retinopathy; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; L, left; R, right; mmHg, millimeters of mercury\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Sana'a University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Diabetic Retinopathy, Vitamin D, Type 2 Diabetes Mellitus, Vision Loss, Retinal Damage, Biomarkers","lastPublishedDoi":"10.21203/rs.3.rs-6199008/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6199008/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e Diabetic retinopathy (DR) is a leading cause of vision loss globally, and vitamin D deficiency has been implicated in its pathogenesis. This study aimed to investigate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and DR in patients with type 2 diabetes mellitus (T2DM).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and methods:\u003c/strong\u003e This comparative cross-sectional study included 120 Yemeni male participants aged 40–60 years. Participants were divided into four groups: 30 healthy controls, 30 T2DM patients without retinopathy (DWR), 30 T2DM patients with non-proliferative diabetic retinopathy (NPDR), and 30 T2DM patients with proliferative diabetic retinopathy (PDR). Serum 25(OH)D, HbA1c, fasting blood glucose (FBS), lipid profile, and intraocular pressure (IOP) were measured. Data were analyzed using SPSS version 22, with p \u0026lt; 0.05 considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Serum 25(OH)D levels were significantly lower in the PDR group (10.6 ± 2.1 ng/mL) than in the NPDR group (20.5 ± 2.8 ng/mL), DWR group (26.4 ± 1.9 ng/mL), and control group (34.2 ± 3.9 ng/mL) (p \u0026lt; 0.0001). Approximately 66.6% (n=60) of DR patients had 25(OH)D deficiency (\u0026lt;20 ng/mL). HbA1c, FBS, total cholesterol, LDL-c, and triglycerides were significantly higher in DR patients, whereas HDL-c levels were significantly lower (p \u0026lt; 0.05). IOP was also significantly higher in DR patients compared with DWR and controls (p \u0026lt; 0.0001). A significant negative correlation was observed between serum 25(OH)D levels and HbA1c, FBS, total cholesterol, LDL-c, triglycerides, BMI, and IOP, whereas a positive correlation was observed with HDL-c (p \u0026lt; 0.0001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Serum 25(OH)D levels were significantly lower in patients with diabetic retinopathy than in healthy controls and patients with diabetes without retinopathy. Vitamin D deficiency is associated with poor glycemic control, dyslipidemia, and increased intraocular pressure, suggesting a potential role for vitamin D as a biomarker of DR. Further research is needed to evaluate the therapeutic potential of vitamin D supplementation in the prevention or management of DR.\u003c/p\u003e","manuscriptTitle":"Vitamin D Deficiency as a Potential Biomarker of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-12 06:51:23","doi":"10.21203/rs.3.rs-6199008/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"05b1dc45-21cd-4e82-9c5d-7a0ba1efc3b1","owner":[],"postedDate":"March 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":45491972,"name":"Ophthalmology"}],"tags":[],"updatedAt":"2025-03-12T06:51:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-12 06:51:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6199008","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6199008","identity":"rs-6199008","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}