Metabolic Dysregulation and Oxidative Stress in Diabetic Retinopathy: Glycogen Metabolism, Mitochondrial Dysfunction, and Antioxidant Defences

Vinuka De Silva; Lochlan J. Fennell; Mitchell A. Sullivan

doi:10.3390/antiox15091093

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Metabolic Dysregulation and Oxidative Stress in Diabetic Retinopathy: Glycogen Metabolism, Mitochondrial Dysfunction, and Antioxidant Defences

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Metabolic Dysregulation and Oxidative Stress in Diabetic Retinopathy: Glycogen Metabolism, Mitochondrial Dysfunction, and Antioxidant Defences

Vinuka De Silva, Lochlan J. Fennell and Mitchell A. Sullivan

Antioxidants, Vol.15(9), pp.1-21

2026

DOI: https://doi.org/10.3390/antiox15091093

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Abstract

diabetic retinopathy

glycogen metabolism

oxidative stress

mitochondrial dysfunction

hyperglycaemia

Diabetic retinopathy (DR) is a major cause of preventable visual impairment and develops through intertwined metabolic, oxidative, inflammatory, and neurovascular disturbances. This review examines how chronic hyperglycaemia disrupts retinal glucose handling and redox homeostasis, with particular emphasis on glycogen metabolism as an underappreciated contributor to disease progression. Pathological glycogen accumulation in retinal amacrine cells and the retinal pigment epithelium may arise through altered glycogen synthase localisation and glucose-6-phosphate-dependent activation, potentially disturbing intracellular trafficking and cellular energy balance. These metabolic changes converge with mitochondrial electron transport chain dysfunction, NADPH oxidase activation, polyol pathway flux, and light-driven lipid peroxidation to increase reactive oxygen species generation. At the same time, transient suppression of Nrf2-dependent antioxidant defences, TXNIP-NLRP3 inflammasome signalling, ferroptotic injury, and VEGF-associated oxidative feedback promote blood–retinal barrier breakdown and persistent neuroinflammation. We propose that dysregulated glycogen metabolism and impaired antioxidant capacity form an integrated metabolic–redox network that helps explain cell-specific vulnerability and metabolic memory in DR. Targeting multiple nodes within this network may support earlier, disease-modifying strategies beyond treatment of advanced vascular complications.

Details

Title: Metabolic Dysregulation and Oxidative Stress in Diabetic Retinopathy: Glycogen Metabolism, Mitochondrial Dysfunction, and Antioxidant Defences
Authors: Vinuka De Silva - University of the Sunshine Coast
Lochlan J. Fennell (Corresponding Author) - University of the Sunshine Coast
Mitchell A. Sullivan (Corresponding Author) - University of the Sunshine Coast
Publication details: Antioxidants, Vol.15(9), pp.1-21
Publisher: MDPI AG
Date published: 2026
DOI: 10.3390/antiox15091093
ISSN: 2076-3921
Copyright note: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
Data Availability: No new data were created or analysed in this study. Data sharing is not applicable to this article.
Grants: Glycogen Structural Dysregulation as a Novel Driver of Liver Injury in Diabetes-Associated MASLD, DAP-Y2600026, Diabetes Australia (Australia, Canberra)
Grant note: SERTF-Wishlist
Organisation Unit: School of Health - Biomedicine; School of Health; Cancer Research Cluster; Centre for Bioinnovation
Language: English
Record Identifier: 991255536802621
Output Type: Journal article

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