Circadian disruption produces lasting retinal dysfunction in a type II diabetic rat model

Abstract

Purpose : Circadian disruption, encountered during shift work and jet lag, is associated with the development of metabolic diseases such as Type II diabetes (T2D). However, it is unclear whether circadian disruption promotes the progression of retinal disease. We evaluated whether chronic circadian disruption affected retinal function and glucose tolerance in Goto-Kakizaki (GK) rats, a non-obese T2D model.

Methods : Male and female GK rats were housed in 12:12 LD control (n=13) or disrupted lighting (n=12) from conception to 3 months of age. Retinal function was measured with dark-adapted electroretinograms (ERGs) at 4 and 8 weeks of age. To evaluate whether ERG differences between groups were due to altered circadian time or to alterations in retinal function, the disrupted lighting groups were housed in control lighting conditions for a 2-week “wash-out” period and ERGs repeated at 10 weeks of age. Additionally, cognitive function was assessed using Y-maze at 2 months of age and hyperglycemia using glucose tolerance tests (GTT) at 3 months of age. Statistical significance was assessed with 2-way repeated measures ANOVA and 2-sided t-tests.

Results : By 8 weeks of age, GK rats in the circadian disruption group displayed significant decreases in ERG amplitudes of dark-adapted b-waves in response to bright flash stimuli and flicker compared to GK rats in the control group (p < 0.05). These differences did not reverse at 10 weeks after being housed in control lighting conditions (Figure). However, GK rats in the circadian disruption group did not show any differences in ERG oscillatory potential amplitudes, implicit times, Y-maze, or GTT compared to GK rats in the control lighting group.

Conclusions : GK rats in disrupted lighting conditions had reduced b-wave and flicker ERG amplitudes, which persisted after housing in control lighting conditions, suggesting lasting retinal dysfunction. Greater differences found with brighter ERG flash stimuli and flicker may indicate an influence on cone pathways. We have previously found that GK rats have high levels of dopamine in the retina, and others have reported that GK rats produce high levels of corticosterone; therefore, we plan to evaluate whether corticosterone and dopamine may play a role in these results.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

Figure. Dark-adapted ERG b-wave amplitudes (mean±SEM) of GK rats housed from conception in control or disrupted lighting conditions, indicated with shaded grey area.