Diabetic Retinopathy: Functional Biomarkers and Visual Outcomes

A central question in preclinical diabetic retinopathy research is when visual function deteriorates relative to retinal structural and vascular changes. Histology, retinal flat mounts, and pericyte quantification require terminal tissue collection, while electroretinography can be repeated but typically requires anesthesia and is less practical for frequent, dense longitudinal sampling. These constraints can make it difficult to define the time course of visual decline or follow disease progression and treatment response within the same animals.

Diabetic retinopathy is increasingly understood as a neurovascular disease. Retinal neural dysfunction, including altered contrast sensitivity and rod-pathway function, can emerge early in diabetes and may precede or occur alongside clinically detectable microvascular pathology. Because the timing and magnitude of these changes vary by model and endpoint, repeated noninvasive functional measurements are needed to establish disease trajectories and determine whether candidate interventions preserve visual function (Sohn et al, 2016, Proc. Natl. Acad. Sci. U.S.A.; Aung et al, 2014, J. Neurosci.).

Also see: Vascular and Metabolic Disease, and Neuroinflammation.

The inner blood-retinal barrier (iBRB) is formed by tight junctions between retinal vascular endothelial cells and supported by the surrounding neurovascular unit, including pericytes, Müller glia, astrocytes, microglia, neurons, and the vascular basement membrane. By controlling exchange between the circulation and neural retina, it protects retinal homeostasis; iBRB dysfunction is an early and important feature of diabetic retinopathy (Moccia and Dragoni, 2025, Cells).

Chronic hyperglycemia can disrupt this neurovascular system through oxidative stress, endothelial dysfunction, pericyte loss, glial activation, and inflammatory signaling. These changes can increase vascular permeability and contribute to retinal edema, neurovascular injury, and vision-threatening disease, but their timing and relative contribution to functional visual loss vary across models (Duh et al, 2017, JCI Insight).

Researchers can assess iBRB dysfunction through permeability assays, retinal imaging, tight-junction markers, cytokine profiling, and histology. These approaches characterize barrier integrity and inflammatory activity, but they do not directly establish how a measured change in permeability, microglial state, or endothelial injury relates to the animal’s visual performance. Emerging preclinical work indicates that cGAMP transport into microglia through P2RX7 can promote STING-associated iBRB breakdown and retinal degeneration, illustrating one potential pathway through which innate immune activation may contribute to neural and functional consequences (Ge et al, 2025, J. Neuroinflammation).

Repeated behavioral vision testing can complement barrier, imaging, and molecular measures by following visual function within the same animals over time. This makes it possible to relate inflammatory and vascular changes to functional outcomes, and to determine whether interventions that modify these mechanisms are also associated with preserved vision.

Also see: Neuroinflammation, Retinal Degeneration and Retinal Ganglion Cell Pathology.

Current standard-of-care treatments for diabetic retinopathy (DR) include anti-VEGF agents such as ranibizumab, aflibercept, and faricimab; pan-retinal photocoagulation (PRP) for proliferative diabetic retinopathy (PDR); and intravitreal corticosteroids for selected cases of diabetic macular edema (DME) (Lim et al., 2025, Ophthalmology). These interventions can preserve vision by treating established edema or proliferative vascular disease, but they do not specifically target the early neuroretinal and neuroinflammatory changes that may accompany, or in some cases precede, clinically visible microvascular lesions (Simó et al., 2018, Diabetologia; Sohn et al., 2016, PNAS).

This creates an important preclinical research opportunity: to determine whether anti-inflammatory or immunomodulatory candidates can influence retinal pathology and preserve visual function. Molecular assays, vascular-leakage measurements, OCT, and histology can identify mechanistic and structural effects, while repeated behavioral testing adds a functional endpoint that can be measured before, during, and after treatment in the same animals.

Adding a repeatable measure of visual behavior helps connect retinal pathology with a vision-relevant outcome. Optomotor testing can track spatial visual acuity longitudinally in the same animals, providing a practical functional endpoint alongside molecular, vascular, imaging, histological, and electrophysiological assessments.

Diabetic retinopathy is traditionally staged by visible vascular lesions, yet diabetes can also affect retinal neurons and glial cells. Clinical ERG studies provide evidence of neural retinal dysfunction in patients with diabetes, including some without clinically apparent retinal vascular abnormalities (McAnany et al., 2022, Surv. Ophthalmol.). This shows that functional deficits may emerge alongside, and in some settings before, clinically apparent microvascular disease; however, the timing and relationship between functional and structural changes vary by patient population and experimental model.

Preclinical studies therefore need more than a single endpoint. OCT, fundus imaging, fluorescein angiography, histology, and molecular assays can characterize retinal structure, vascular injury, and disease-associated pathways, while ERG captures retinal electrical responses. These measures do not directly establish how well an animal responds to visual stimuli in a behavioral task.

For example, longitudinal comparisons of db/db, Ins2^Akita, and STZ-induced diabetic mice found that optomotor visual-acuity loss and OCT-detected retinal thinning followed different time courses across models. In some models, retinal thinning preceded acuity loss, whereas acuity could also decline without further thinning, demonstrating that structural measures alone cannot fully explain functional visual outcomes (Sheskey et al., 2021, Invest. Ophthalmol. Vis. Sci.).

Adding repeatable behavioral visual testing helps connect structural, vascular, and molecular findings with a vision-relevant outcome. Optomotor testing can measure spatial visual acuity and contrast sensitivity longitudinally in the same animals, providing a practical functional endpoint alongside imaging, ERG, and tissue-based assessments.