Diabetes does not irreversibly impair photoreceptor and ON-bipolar cell function

Abstract

Purpose : Diabetic retinopathy is the most common cause of blindness in working-age adults in the developed world and associated with reduced photoreceptor (PR) and ON-bipolar cell (BC) function. Multiple systemic stressors such as hyperglycemia, oxidative stress and inflammatory factors, have been identified in diabetes, but effects on outer retinal function remain unknown. We investigated whether PR and BC are irreversibly affected in diabetic retinas and whether long-term or acute hyperglycemia modulate retinal function.

Methods : 6 month old diabetic db/db mice and age-matched non-diabetic db/+ control mice were dark adapted and in vivo ERG was recorded under isoflurane anesthesia. For ex vivo ERG mice were sacrificed by CO₂ asphyxia and retinas were isolated and superfused with Ames’ media (containing 6 mM glucose, supplemented with 0.25 mM glutamate, 0.1 mM BaCl₂ and either 30 mM mannitol (iso-osmotic control) or glucose, oxygenated with 95% O₂, 5% CO₂) and responses to light stimuli of increasing intensity were recorded. BC responses were obtained by subtracting PR responses (in the presence of 40μM DL-AP4) from combined PR and BPC responses (in the absence of DL-AP4).

Results : In vivo ERG PR and BPC amplitudes were reduced and implicit times increased in db/db compared to db/+ mice (n=5, p<0.001). Ex vivo ERG PR and BPC amplitudes were not different between db/db and db/+ mice (n=11 for PR and n=4-6 for BC, respectively), although PR implicit time was reduced in diabetes (p<0.05). Acutely elevated glucose resulted in increased PR amplitude (n=11, p<0.001) and implicit time (p<0.05) in db/+ control mice. In contrast, acute hyperglycemia did not change PR amplitudes in diabetic db/db mice (n=11), but implicit times were increased (p<0.001). No BC amplitude differences were observed in either control or diabetic mice between normal and high glucose concentration (n=4-6).

Conclusions : Our data suggest that long-term diabetes does not irreversibly damage PR light signal transduction and transmission. Differences between in vivo and ex vivo ERG indicate that circulating factors in diabetes impair PR and BC function. Since acute hyperglycemia does not reduce PR and BC function ex vivo, reduced in vivo ERG amplitudes in db/db mice are not likely to be due to hyperglycemia. Our results suggest that adaptational changes in long-term diabetes results in decreased sensitivity of PRs to increased glucose concentration.

This is a 2020 ARVO Annual Meeting abstract.