{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:18:22Z","timestamp":1788153502150,"version":"build-2803163510"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Diabetic retinopathy (DR) is usually interpreted as a complication of chronic hyperglycemia and vascular injury. This model remains fundamental, but it does not fully explain early, rapid, or treatment-resistant disease in some patients. Puberty, pregnancy, menopause, obstructive sleep apnea, thyroid dysfunction, chronic stress, and rapid improvement in glycemic control are clinical settings in which retinal disease may change despite standard risk assessment. We propose the Hormonal Metabolic Burden (HMB) hypothesis, which views the diabetic retina as an endocrine-responsive neural and vascular tissue. In this model, growth hormone\/insulin-like growth factor-1 (GH\/IGF-1), hypothalamic\u2013pituitary\u2013adrenal (HPA)\u2013glucocorticoid signaling and related glucocorticoid receptor\/mineralocorticoid receptor (GR\/MR) balance, thyroid hormone, and sex steroid signaling act on retinal neurons, M\u00fcller glia, endothelial cells, pericytes, and retinal pigment epithelial cells through receptor- and enzyme-mediated pathways. These axes may converge with hyperglycemia on oxidative stress, nuclear factor kappa B (NF-\u03baB)-mediated inflammation, vascular endothelial growth factor (VEGF) signaling, blood-retinal barrier (BRB) dysfunction, neurodegeneration, and metabolic memory. HMB is proposed as an additional research layer rather than a replacement for established DR risk assessment, and it should not be used to justify broad hormone testing or off-label endocrine treatment. This hypothesis generates testable predictions: multi-axis endocrine profiling should improve risk prediction beyond standard variables; prespecified endocrine-retinal profiles characterized by greater magnitude, persistence, or co-occurrence of selected axis-specific disturbances should be associated with distinct optical coherence tomography (OCT) or optical coherence tomography angiography (OCTA) trajectories; persistent or suboptimally responsive diabetic macular edema (DME) despite an adequate course of anti-VEGF therapy should be enriched for selected endocrine signals; and later-stage biomarker-selected studies should test whether matched endocrine correction has greater retinal effects than unselected intervention. It is a research-oriented model for selected phenotypes, including rapid nonproliferative diabetic retinopathy, persistent or suboptimally responsive DME, pubertal proliferative disease, postmenopausal acceleration, thyroid-linked disease, and diabetic retinopathy with sleep apnea. If validated, this framework may support more focused endocrine-retinal research and improve the design of precision prevention studies in selected DR phenotypes.<\/jats:p>","DOI":"10.3389\/fendo.2026.1899237","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T04:28:14Z","timestamp":1788150494000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hormonal metabolic burden in diabetic retinopathy: the diabetic retina as an endocrine-responsive target organ"],"prefix":"10.3389","volume":"17","author":[{"given":"Jing","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, People\u2019s Hospital of Leshan","place":["Leshan, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, People\u2019s Hospital of Leshan","place":["Leshan, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","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":"B2","doi-asserted-by":"publisher","DOI":"10.3949\/ccjm.91a.24028","article-title":"Diabetic retinopathy: screening, prevention, and treatment","volume":"91","author":"Chong","year":"2024","journal-title":"Cleve Clin J Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/s41574-020-00451-4","article-title":"Current understanding of the molecular and cellular pathology of diabetic retinopathy","volume":"17","author":"Antonetti","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1077669","article-title":"Diabetic retinopathy: looking forward to 2030","volume":"13","author":"Tan","year":"2023","journal-title":"Front Endocrinol"},{"key":"B5","unstructured":"Diabetic retinopathy: management and monitoring. 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