Retinal neurodegeneration may begin at A1c levels below the threshold currently used to define prediabetes, according to an analysis of more than 32,000 participants from the UK Biobank.
Investigators identified a turning point at approximately an A1c of 5.4 in the relationship between A1c and ganglion cell-inner plexiform layer (GCL-IPL) thickness, below both the 5.7 threshold used to define prediabetes and the 6.5 diagnostic threshold for diabetes. For total macular thickness, the estimated turning point was even lower, at approximately 5.3.
"This means that neuronal loss — and this is important — is taking place before current diagnostic criteria of diabetes," study lead Rafael Simó, MD, PhD, of the Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Barcelona, Spain, said in presenting the findings at the European Association for the Study of Diabetes (EASD) 2026 Annual Meeting.
To put the magnitude of the study findings into context, participants with diabetes had an approximately 1-µm reduction in GCL-IPL thickness compared with those with normal glucose levels, equivalent to about 6.5 years of physiological age-related retinal thinning. Among participants with prediabetes, total macular thickness was reduced by approximately 1.5 µm, comparable to at least 4 years of age-related retinal thinning.
Searching for an A1c Retinal Turning Point
The diagnosis of prediabetes and diabetes is based on glycemic thresholds associated with the development of microvascular disease. However, diabetic retinopathy is increasingly understood as a complex neurovascular disease, with neurodegeneration occurring early in its development, explained Simó.
There is "robust evidence," he said, that "the thinning of specific neuronal retinal layers can occur before overt microvascular abnormalities are detectable by ophthalmoscopic examination." If this is the case, "why do we have to wait until microvascular damage exists?" he asked.
Simó and colleagues therefore investigated whether retinal neurodegeneration might begin at A1c levels below current diagnostic cut offs, and if so, if they could identify an A1c threshold associated with the thinning of neuroretinal layers.
The analysis included 32,581 UK Biobank participants without a previous diagnosis of diabetes. Individuals with ocular diseases that could affect retinal thickness and neurodegenerative diseases were excluded. Retinal thickness was assessed using spectral-domain optical coherence tomography (OCT).
The researchers used restricted cubic spline analysis to examine nonlinear relationships between A1c and retinal thickness, with changes in slope evaluated using the Davies test. Analyses were adjusted for age, sex, mean arterial blood pressure, waist circumference, ethnicity, smoking status, and alcohol consumption. A sensitivity analysis was conducted in 20,380 participants with retinal data segmented according to the Early Treatment Diabetic Retinopathy Study system.
Retinal Thinning Before Prediabetes
The relationship between A1c and retinal thickness was nonlinear. In the GCL-IPL, retinal thickness initially increased slightly before reaching a turning point at an A1c of approximately 5.4, after which progressive thinning was observed as A1c increased. A similar pattern was observed across the neuronal retinal layers, whereas the retinal pigment epithelium behaved differently.
When total macular thickness was used as an integrated measure of all neuronal retinal layers, significant differences were seen not only between people with prediabetes and diabetes, but also between those with prediabetes and normal glucose levels. The estimated turning point for total macular thickness was at an A1c of approximately 5.3.
The findings support the concept that neural retinal changes can precede the vascular abnormalities traditionally associated with diabetic retinopathy.
"Our data extend and reinforce the concept that neurodegeneration is an early event in diabetic retinopathy," said Simó, adding that, overall, these findings "suggest that current diagnosis of diabetes based on A1c levels might need to be revisited."
What Might Drive the Changes?
The observational analysis could not establish that A1c levels around the identified turning points caused retinal neurodegeneration, nor do the turning points represent clinical thresholds at which an individual patient develops retinopathy, the researchers pointed out.
Further longitudinal research will be needed to determine whether retinal thinning at these lower A1c levels predicts subsequent diabetic retinopathy or diabetes and whether OCT-derived retinal measures could ultimately have a role in identifying individuals at increased metabolic or ocular risk.
Simó also emphasized that the study was not designed to establish the mechanism underlying the association. However, he highlighted insulin resistance as one potential contributor.
Previous experimental evidence suggests that intraocular insulin resistance could contribute to retinal neurodegeneration, he explained. Retinal neurons express insulin receptors, and impaired insulin signaling could affect neuronal survival. Simó also mentioned evidence linking systemic insulin resistance with thinning of neuronal retinal layers.
All this points "to insulin resistance as the most important element accounting for these findings," he said.
Could Earlier Intervention Help?
Commenting on the findings, session moderator Lena Thorn, MD, PhD, noted that the early appearance of neuroretinal thinning raised the question of whether earlier intervention could alter its course.
"You show that neuroretinal thinning occurs quite early in the disease process but is there any evidence that interventions at an earlier phase can slow down the thinning of the retina?" she asked.
Simó said there was evidence from experimental studies, but when Thorn asked specifically whether this had been demonstrated in humans, he replied with a no.
Simó disclosed relationships with Novo Nordisk, Abbott, Dexcom, Bayer, AstraZeneca, Menarini, and D-Sight. Thorn has declared no relevant disclosures.
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