{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:54:09Z","timestamp":1789430049837,"version":"build-2803163510"},"reference-count":29,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Oscillating hyperglycemia (glycemic variability) and vitamin D deficiency each damage the retinal microvasculature, yet their combined effect on sight-threatening proliferative diabetic retinopathy (PDR) is uncertain. Objective: To determine whether high GV and severe vitamin D deficiency independently, and additively, associate with retinal neovascularization in adults with diabetes. Materials and Methods: We conducted a cross-sectional study between January 2025 and June 2025 in 58 adults with diabetes at Constan\u021ba County Emergency Hospital, Romania. GV was classified as high (coefficient of variation &gt; 36% or SMBG-SD &gt; 50 mg\/dL) or low. Serum 25-hydroxy-vitamin D [25(OH)D] was measured; severe deficiency &lt; 10 ng\/mL. Dilated funduscopy graded retinopathy as non-proliferative (NPDR) or proliferative (PDR). Multivariable logistic regression adjusted for HbA1c, diabetes duration, BMI, smoking, triglycerides and therapy. Results: From 58 adults (mean \u00b1 SD 59 \u00b1 11 years), high GV characterized 29\/58 participants (50%). Severe vitamin D deficiency was more frequent in the GV-high group (45% vs. 31%). PDR prevalence was 48% in GV-high and 31% in GV-low patients. After adjustment, high GV (adjusted OR 2.31, 95% CI 1.05\u20135.09) and severe vitamin D deficiency (OR 2.04, 95% CI 0.98\u20134.25) each predicted PDR. Concomitant exposure to both stressors conferred 3.9-fold higher odds of PDR (OR 3.88, 95% CI 1.35\u201311.1). No interaction term reached significance (p = 0.21), indicating additive effects. Conclusions: High GV and severe vitamin D deficiency independently and additively associate with PDR. Screening for both parameters may enhance risk stratification of PDR. Within adults with diabetes, high glycemic variability and severe vitamin D deficiency were each associated with higher odds of PDR after adjustment for HbA1c, diabetes duration, BMI, smoking, triglycerides, and treatment pattern; their effects appeared additive rather than multiplicative. These findings reflect associations within diabetes and do not imply that vitamin D deficiency produces retinopathy in euglycemic individuals.<\/jats:p>","DOI":"10.3390\/nu17203210","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T07:51:28Z","timestamp":1760428288000},"page":"3210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Synergistic Association of Glycemic Variability and Severe Vitamin D Deficiency with Proliferative Diabetic Retinopathy"],"prefix":"10.3390","volume":"17","author":[{"given":"Nejla","family":"Dervis","sequence":"first","affiliation":[{"name":"Diabetes Department, Ovidius University, 900527 Constan\u021ba, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Carniciu","sequence":"additional","affiliation":[{"name":"Hygiene Department, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Spinean","sequence":"additional","affiliation":[{"name":"Diabetes Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanda","family":"Jurja","sequence":"additional","affiliation":[{"name":"Ophthalmology Department, Ovidius University, 900527 Constan\u021ba, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1016\/j.ophtha.2021.04.027","article-title":"Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Meta-analysis","volume":"128","author":"Teo","year":"2021","journal-title":"Ophthalmology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1167\/iovs.64.15.47","article-title":"The Diabetic Retinopathy \u201cPandemic\u201d and Evolving Global Strategies: The 2023 Friedenwald Lecture","volume":"64","author":"Wong","year":"2023","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_3","unstructured":"Vision Loss Expert Group of the Global Burden of Disease Study, and GBD 2019 Blindness and Vision Impairment Collaborators (2024). Global estimates on the number of people blind or visually impaired by diabetic retinopathy: A meta-analysis from 2000 to 2020. Eye, 38, 2047\u20132057."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/dom.16098","article-title":"The clinical importance of measuring glycaemic variability: Utilising new metrics to optimise glycaemic control","volume":"26","author":"Ajjan","year":"2024","journal-title":"Diabetes Obes. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1111\/jdi.14303","article-title":"Clinical significance of coefficient of variation in continuous glucose monitoring for glycemic management in children and adolescents with type\u20091 diabetes","volume":"15","author":"Urakami","year":"2024","journal-title":"J. Diabetes Investig."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Firouzabadi, F.D., Poopak, A., Samimi, S., Deravi, N., Nakhaei, P., Sheikhy, A., Moosaie, F., Rabizadeh, S., Meysamie, A., and Nakhjavani, M. (2024). Glycemic profile variability as an independent predictor of diabetic retinopathy in patients with type 2 diabetes: A prospective cohort study. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1383345"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Cui, A., Zhang, T., Xiao, P., Fan, Z., Wang, H., and Zhuang, Y. (2023). Global and regional prevalence of vitamin D deficiency in population-based studies from 2000 to 2022: A pooled analysis of 7.9 million participants. Front. Nutr., 10.","DOI":"10.3389\/fnut.2023.1070808"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e000950","DOI":"10.1136\/bmjnph-2024-000950","article-title":"Fahmina Anwar\u2014Burden of micronutrient deficiency among patients with type 2 diabetes: Systematic review and meta-analysis","volume":"8","author":"Mangal","year":"2025","journal-title":"BMJ Nutr. Prev. Health"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Petrea, C.E., Ghenciu, L.A., Iacob, R., Stoicescu, E.R., and S\u0103ndesc, D. (2024). Vitamin D Deficiency as a Risk Factor for Diabetic Retinopathy: A Systematic Review and Meta-Analysis. Biomedicines, 13.","DOI":"10.3390\/biomedicines13010068"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lazzara, F., Longo, A.M., Giurdanella, G., Lupo, G., Platania, C.B.M., Rossi, S., Drago, F., Anfuso, C.D., and Bucolo, C. (2022). Vitamin D3 preserves blood retinal barrier integrity in an in vitro model of diabetic retinopathy. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.971164"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.2337\/dci19-0028","article-title":"Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations from the International Consensus on Time in Range","volume":"42","author":"Battelino","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"832","DOI":"10.2337\/dc16-1769","article-title":"Toward Defining the Threshold Between Low and High Glucose Variability in Diabetes","volume":"40","author":"Monnier","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"777","DOI":"10.2337\/dc16-2426","article-title":"Association of Glycemic Variability in Type 1 Diabetes with Progression of Microvascular Outcomes in the Diabetes Control and Complications Trial","volume":"40","author":"Lachin","year":"2017","journal-title":"Diabetes Care"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1210\/jc.2011-0385","article-title":"Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline","volume":"96","author":"Holick","year":"2011","journal-title":"Med. J. Clin. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"752","DOI":"10.4065\/mcp.2010.0138","article-title":"Vitamin D deficiency in adults: When to test and how to treat","volume":"85","author":"Kennel","year":"2010","journal-title":"Mayo Clin. Proc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.2337\/dc10-0953","article-title":"2010 consensus statement on the worldwide standardization of the hemoglobin A1C measurement","volume":"33","author":"Hanas","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1016\/j.jacc.2018.11.002","article-title":"2018 AHA\/ACC\/AACVPR\/AAPA\/ABC\/ACPM\/ADA\/AGS\/APhA\/ASPC\/NLA\/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines","volume":"73","author":"Grundy","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1016\/S0161-6420(03)00475-5","article-title":"Global Diabetic Retinopathy Project Group. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales","volume":"110","author":"Wilkinson","year":"2003","journal-title":"Ophthalmology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"P75","DOI":"10.1016\/j.ophtha.2024.12.020","article-title":"American Academy of Ophthalmology Preferred Practice Pattern Retina\/Vitreous Committee. Diabetic Retinopathy Preferred Practice Pattern\u00ae","volume":"132","author":"Lim","year":"2025","journal-title":"Ophthalmology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e001923","DOI":"10.1136\/bmjdrc-2020-001923","article-title":"Associations between continuous glucose monitoring-derived metrics and diabetic retinopathy and albuminuria in patients with type 2 diabetes","volume":"9","author":"Wakasugi","year":"2021","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_21","first-page":"214","article-title":"The role of vitamin D in the onset and progression of diabetic retinopathy","volume":"66","author":"Totolici","year":"2022","journal-title":"Rom. J. Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.clnesp.2023.11.011","article-title":"Is vitamin D deficiency associated with retinopathy in type 2 diabetes mellitus? A case-control study","volume":"59","author":"Zahedi","year":"2023","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Jee, D., Han, K.D., and Kim, E.C. (2014). Inverse association between high blood 25-hydroxy-vitamin D levels and diabetic retinopathy in a representative Korean population. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115199"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jiang, W., Li, L., Wang, W., Liang, Y., Bai, X., Xu, Y., Guo, Q., Ge, L., Liang, J., and Lu, B. (2025). Association of circulating 25-hydroxy-vitamin D with time in range and insulin secretion in type 2 diabetes. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1573963"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8193523","DOI":"10.1155\/2018\/8193523","article-title":"Vitamin D3 Protects against Diabetic Retinopathy by Inhibiting High-Glucose-Induced Activation of the ROS\/TXNIP\/NLRP3 Inflammasome Pathway","volume":"2018","author":"Lu","year":"2018","journal-title":"J. Diabetes Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Song, Y.-S., Jamali, N., Sorenson, C.M., and Sheibani, N. (2023). Vitamin D Receptor Expression Limits the Angiogenic and Inflammatory Properties of Retinal Endothelial Cells. Cells, 12.","DOI":"10.3390\/cells12020335"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kim, D.-H., Meza, C.A., Clarke, H., Kim, J.-S., and Hickner, R.C. (2020). Vitamin D and Endothelial Function. Nutrients, 12.","DOI":"10.3390\/nu12020575"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.1007\/s10792-022-02333-2","article-title":"The effect of vitamin D supplementation on the outcome of treatment with bevacizumab in diabetic macular edema: A randomized clinical trial","volume":"42","author":"Fekri","year":"2022","journal-title":"Int. Ophthalmol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Antunica, A.G., Znaor, L., Ivankovi\u0107, M., Puzovi\u0107, V., Markovi\u0107, I., and Ka\u0161telan, S. (2023). Vitamin D and Diabetic Retinopathy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241512014"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/20\/3210\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T04:10:33Z","timestamp":1761106233000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/20\/3210"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":29,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["nu17203210"],"URL":"https:\/\/doi.org\/10.3390\/nu17203210","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,13]]}}}