Journal of Eye Diseases and Disorders

Retinal Neurodegeneration in Early Diabetes: Unmasking the Silent Phase of Diabetic Retinopathy

Sandra Okoro^* Department of Ophthalmic Neuroscience, University of Lagos, Lagos, Nigeria
^*Correspondence: Sandra Okoro, Department of Ophthalmic Neuroscience, University of Lagos, Lagos, Nigeria, Email:

Received: 03-Mar-2025 Editor assigned: 05-Mar-2025 Reviewed: 19-Mar-2025 Revised: 26-Mar-2025 Published: 02-Apr-2025, DOI: 10.35248/2704-1622.25.10.270

Description

Diabetic retinopathy has long been considered a microvascular complication of diabetes mellitus, characterized primarily by alterations in retinal blood vessels leading to hemorrhages, exudates, and neovascularization. However, emerging evidence over the past decade has challenged this view, suggesting that retinal neurodegeneration is an early and possibly independent event in the pathogenesis of diabetic retinopathy. This paradigm shift has significant implications for early diagnosis, monitoring, and intervention, particularly in the subclinical stages of the disease.

Studies utilizing Spectral-Domain Optical Coherence Tomography (SD-OCT), electrophysiological recordings, and fundus autofluorescence imaging have revealed that diabetes-induced retinal changes occur well before the appearance of visible vascular lesions. These changes include thinning of the inner retinal layers, particularly the ganglion cell layer and inner plexiform layer, as well as dysfunction of retinal neurons and glial cells. Functional deficits, such as delayed Electroretinogram (ERG) responses, diminished contrast sensitivity, and color vision disturbances, can be detected in patients with diabetes who show no signs of clinical retinopathy upon fundus examination.

The underlying mechanisms of retinal neurodegeneration in diabetes are multifactorial. Hyperglycemia induces oxidative stress, mitochondrial dysfunction, and glutamate excitotoxicity, leading to apoptosis of retinal ganglion cells and amacrine cells. Additionally, chronic inflammation driven by cytokines such as TNF-α and IL-6 contributes to neuronal loss and microglial activation. Müller glia, the principal macroglia of the retina, undergo reactive gliosis and lose their neuroprotective functions, further exacerbating retinal injury. Insulin resistance, dyslipidemia, and Advanced Glycation End Products (AGEs) also play roles in disrupting retinal homeostasis.

One of the most intriguing findings is that retinal neurodegeneration may actually precede and promote microvascular damage. Loss of neurovascular coupling, a process by which neuronal activity regulates local blood flow, results in impaired perfusion and vascular leakage. Degeneration of pericytes and endothelial cells follows, setting the stage for the classical features of diabetic retinopathy. Thus, neurodegeneration may not only be an early indicator but also a driving force in disease progression.

Early identification of retinal neurodegeneration opens new avenues for intervention before irreversible structural damage and vision loss occur. Current anti-VEGF therapies, although effective for proliferative stages, are of limited use in early diabetic retinopathy. Therefore, attention is turning to neuroprotective strategies that can preserve retinal neurons and maintain visual function. Agents such as brimonidine, somatostatin analogs, and corticosteroids have shown promise in preclinical models and small clinical trials. Nutritional supplements containing omega-3 fatty acids, lutein, zeaxanthin, and antioxidants are also being evaluated for their neuroprotective potential.

Furthermore, non-invasive diagnostic tools are being developed to detect neurodegenerative changes in the diabetic retina. SD-OCT enables precise measurement of retinal layer thickness, while multifocal ERG provides spatially resolved assessments of retinal function. These tools can be used to stratify patients based on their neurodegenerative profile and guide personalized treatment plans. Artificial Intelligence (AI) and machine learning algorithms are also being trained to analyze retinal images and predict the risk of progression, allowing for proactive disease management.

Lifestyle interventions, including glycemic control, blood pressure regulation, and physical activity, remain foundational in preventing and slowing the progression of diabetic complications. However, it is becoming clear that glucose control alone may not be sufficient to prevent retinal neurodegeneration, emphasizing the need for adjunctive therapies that specifically target neuronal health. The potential of repurposing existing neuroprotective drugs from neurology and psychiatry for use in diabetic retinopathy is an area of active research.

Animal models have been instrumental in elucidating the pathophysiological pathways of retinal neurodegeneration. Rodent models of type 1 and type 2 diabetes replicate many features of human diabetic retinopathy and are used to test new pharmacological agents. Transgenic models allow the study of specific molecular targets and gene-environment interactions. However, translating these findings into effective human therapies requires well-designed clinical trials with robust endpoints and long-term follow-up.