Highlights
- Neuroretinal layer thinning, specifically in the ganglion cell and inner plexiform layers, occurs in youth with type 1 diabetes even before clinical diabetic retinal disease is evident.
- Higher hemoglobin A1c levels correlate with reduced thickness of key neuroretinal layers, suggesting glycemic control influences early neurodegenerative changes.
- Optical coherence tomography (OCT) offers a noninvasive biomarker to detect early diabetic retinal neurodegeneration, potentially improving screening and prognostication in pediatric diabetes care.
Background
Type 1 diabetes (T1D) commonly affects youth and carries a significant risk of diabetic retinal disease (DRD), a leading cause of vision loss. Traditionally, DRD diagnosis relies on detection of retinal vascular changes; however, accumulating evidence shows that neural retinal degeneration precedes these vascular manifestations. Understanding early neurodegeneration is critical to improve early diagnosis, risk stratification, and intervention in youth with T1D, a population in which data remain comparatively sparse. Optical coherence tomography (OCT), a high-resolution imaging modality, enables quantitative analysis of discrete retinal layers, offering a unique window into neuroretinal health. This review synthesizes current literature, including new prospective evidence from the ACCESS2 study, correlating retinal layer thinning with glycemic control metrics and early DRD in pediatric T1D cohorts.
Key Content
Chronological Development of Evidence on Neuroretinal Changes in Diabetes
Early studies in adults with T1D demonstrated thinning of inner retinal layers such as the retinal nerve fiber layer (RNFL) and ganglion cell layers prior to overt diabetic retinopathy. Meta-analyses of OCT metrics established these structural changes as consistent biomarkers correlating with disease severity and glycemic indices. However, pediatric data were limited due to challenges in recruiting asymptomatic youth and differences in disease duration and severity.
The recent ACCESS2 prospective cohort (Ramanujam et al., 2026) marked a pivotal advance by enrolling 294 youth aged 9 to 21 years with T1D, characterizing OCT-derived retinal layer thicknesses relative to hemoglobin A1c (HbA1c) and DRD staging. This study uniquely integrated AI-supported segmentation and expert reading center validation, enhancing measurement precision and diagnostic reliability.
OCT-Based Retinal Layer Thickness Findings in Youth With T1D
In this large pediatric cohort (n=578 eyes), the study identified that despite the majority lacking clinical DRD, thinning of neuroretinal layers—particularly the ganglion cell plus inner plexiform layer (GCL+IPL)—correlated inversely with HbA1c levels. Specifically, higher HbA1c was associated with decreased GCL+IPL and outer retinal thickness, suggesting that hyperglycemia contributes to early neurodegeneration independently of measurable vascular damage. Moderate DRD eyes showed trends toward thinner RNFL and GCL+IPL, though these differences did not reach statistical significance possibly reflecting the early disease spectrum.
These findings align with smaller pediatric studies and adult datasets, reinforcing the hypothesis that inner retinal neurodegeneration predates and potentially predicts subsequent vascular retinopathy progression. The data imply that meticulous glycemic control is imperative in mitigating neuroretinal damage early in diabetes course.
Mechanistic Insights Into Diabetic Neuroretinopathy
Experimental models elucidate hyperglycemia-induced retinal neuronal apoptosis, glial dysfunction, and disrupted neurovascular coupling preceding microvascular abnormalities. Oxidative stress, inflammation, and advanced glycation end-products contribute to retinal ganglion cell loss and thinning detectable on OCT. The neurovascular unit concept underscores the intertwined fate of neurons and blood vessels, where early neurodegeneration may serve as a sentinel event signaling retinal vulnerability.
Clinical and Translational Implications
Integrating OCT assessment of neuroretinal layers into routine pediatric diabetes care could enhance early identification of patients at high risk for DRD, enabling personalized monitoring and timely interventions. Furthermore, OCT biomarkers may serve as surrogate endpoints in clinical trials testing neuroprotective or vasculoprotective therapies. Artificial intelligence approaches, as utilized in ACCESS2, promise to streamline retinal image analysis and broaden applicability in clinical practice.
Current screening programs emphasize vascular changes via fundoscopy or fundus photography; the addition of neuroretinal metrics represents a paradigm shift toward a preclinical stage biomarker.
Expert Commentary
While the accumulating evidence supports neuroretinal thinning as an early and clinically relevant manifestation of diabetic retinal disease in youth, challenges remain. The direct causal relationship between elevated HbA1c and retinal thinning needs further clarification through longitudinal studies. The clinical utility of OCT measurements must be balanced against costs, access, and standardization across diverse populations and imaging platforms.
Additionally, variability in OCT segmentation algorithms and normative databases may influence thresholds for pathological thinning. The interpretation of subtle thickness differences requires careful clinical correlation. Nonetheless, findings from the ACCESS2 study extend prior adult data to youths and underscore the importance of glycemic optimization to preserve neural retinal integrity.
Ongoing research should elucidate whether neuroretinal damage predicts subsequent vascular disease progression and the potential reversibility of these changes with improved metabolic control. The possibility of neuroprotective agents and lifestyle interventions offers an exciting horizon.
Conclusion
The prospect of OCT-detected neuroretinal layer thinning as a biomarker of early diabetic retinal neurodegeneration in youth with T1D is underscored by emerging evidence linking higher HbA1c levels with structural retinal changes prior to clinically visible diabetic retinopathy. These advances spotlight the critical need for early detection and glycemic management to prevent vision-threatening complications. Future research must validate these biomarkers longitudinally, standardize imaging protocols, and integrate neuroretinal assessment into comprehensive pediatric diabetes eye care algorithms.
References
- Ramanujam S et al. Neuroretinal Layer Thinning on OCT Imaging and Hemoglobin A1c in Youth With Type 1 Diabetes. JAMA Ophthalmol. 2026 Jun 25. PMID: 42348200.
- Shao EY et al. Retinal nerve fiber layer thinning in diabetes without retinopathy: A systematic review and meta-analysis. Diabetes Care. 2020;43(11):2872-2881. PMID: 32953319.
- van Dijk HW et al. Early neurodegeneration in the retina of patients with type 2 diabetes: The Rotterdam study. Invest Ophthalmol Vis Sci. 2012;53(6):2715-2719. PMID: 22427545.
- Antonetti DA et al. Diabetic retinopathy: Seeing beyond glucose-induced microvascular disease. Diabetes. 2021;70(4):831-845. PMID: 33766511.
- Simó R et al. Neurodegeneration in the diabetic eye: New insights and therapeutic perspectives. Trends Endocrinol Metab. 2018;29(7):439-449. PMID: 29656635.