Abstract
Purpose :
Circadian disruption occurs when internal circadian clocks are in misalignment with the external light cycle, most commonly experienced in night shift work and in individuals with extreme chronotypes. Circadian disruption is exacerbated in diabetes but its role in the progression of diabetic complications is not known. In this study, the impact of circadian misalignment on retinal health was examined in an experimental model of Type 1 diabetes.
Methods :
Ins2Akita mice and littermate controls were maintained in a normal 24-hour (T24) or a condensed 22.5-hour light/dark cycle (T22.5) (n=10-14/group). This protocol recapitulates the chronic circadian misalignment experienced in late human chronotype and shift work. After four months in either T24 or T22.5 light cycles, eye health was assessed using Fundus imaging, optical coherence tomography (OCT), and electroretinography (ERG) followed by histological validation.
Results :
Diabetes in the absence of circadian disruption resulted in significant retinal thinning (C-T24 204±4 vs D-T24 197±5µm, p=0.02). When compared to these disease-controls, diabetic mice maintained in the 22.5-hour cycle displayed greater numbers of white spots without any vessel abnormality in retina images and exacerbated retinal thinning (D-T22.5 186±6 vs D-T24 197±5µm, p=0.03) which was primarily due to photoreceptor layer reduction (86±4 vs 91±3µm, p=0.005). In addition, T22.5 diabetic mice exhibited ERG abnormalities in the photopic b-wave but not the a-wave, with lower amplitudes (131.6±0.9 vs 184.1±2.8µV, p=0.009 at 30cd.s/m2) and higher implicit times (40.8±0.5 vs 36.4±0.4ms, p=0.0003). Flicker ERG amplitudes were reduced in rod bipolar cell-mediated pathways (235.8±17.6 vs 310.4±20.3µV, p=0.02) and cone ON pathways (90.78±6.5 vs 120.8±6.6µV, p=0.02), but not cone OFF pathways. Interestingly, circadian misalignment also reduced retinal thickness in the 22.5-hour maintained non-diabetic group, especially closer to the optic nerve (C-T22.5 194±7 vs C-T24 201±5µm, p=0.02).
Conclusions :
Circadian misalignment drives retinal pathology in both non-diabetic and diabetic mice, with several changes in the retinas of T22.5 cohorts before their respective T24 counterparts, including retinal thinning and dampened responses to light. Our results suggest an additional risk of vision loss in diabetic patients related to misalignment with the external light cycle.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.