Circadian disruption can be experienced when one lives in a misalignment of their internal clocks with the environmental light cycles. In this study, we investigated whether a form of circadian disruption experienced by extreme chronotypes impacts the progression of diabetic retinopathy.

Ins2 Akita, hyperglycemic, male mice and healthy controls, at two months of age, were housed for 4 months in a forced desynchrony conditions within the limits of entrainment with light cycles (T22.5 and T27 cycles) that resemble circadian disruption of late and early extreme chronotypes correspondingly. Eye disease endpoints were assessed with in vivo retinal imaging (fundus imaging, OCT), ex-vivo immunohistological approaches for acellular capillaries and vascular morphology, and retina tissue was used for mRNA sequencing. Two Way ANOVA (diabetes, chronotype) was used to identify statistically significance (p<0.05)

Retinal thickness was significantly reduced in diabetes by 7% compared to controls and was further reduced by another 7% in both forced desynchrony conditions. The number of acellular capillaries in diabetes was increased by 48% in the diabetic mice undergoing forced desynchrony with effects on the intermediate and deeper vascular layers, where significantly reduced vessel area, vessel length and increased E-lacunarity. The mRNA sequence of the retina confirmed that forced misalignment in diabetes impacted the retina vasculature more than in control. Genes related to one carbon metabolism were among the top genes mostly affected by forced misalignment in diabetes, while a more inflammatory pathway activation was also observed. We further validated a particular target with immunofluorescence, its regulation by the clock and its effect on ednothelial cell physiology in vitro.

Overall, a misaligned light schedule to the internal clock that simulates the social jet lag experienced by extreme chronotypes leads to an acceleration of the retinal structure and microvascular dysfunction observed in diabetes. The effects are manifested due to circadian clock disruption and particularly affect the stress responses to the misalinged light. Circadian disruption could therefore be a modifiable risk factor for prevention of diabetic retinopathy.