Circadian clocks in diabetes – implications for diabetic retinopathy

Approaches included behavioural monitoring, electroretinography, optical coherence tomography, histology, gene expression analysis, and endothelial assays.<br><br>Diabetic mice showed disrupted behavioural rhythms, including increased daytime activity, reduced rhythm amplitude, delayed re-entrainment after jet lag, and heightened sensitivity to dim light. Retinal recordings revealed loss of circadian modulation in photoreceptor and inner retinal responses.

Separately, chronic circadian misalignment alone induced retinal thinning, vascular pathology, and impaired rod and cone function. Transcriptomic analysis indicated that circadian misalignment particularly disrupted retinal pigment epithelium function, including extracellular matrix regulation and photoreceptor phagocytosis. In vitro, HRMECs exposed to hyperglycaemia and hypoxia exhibited altered rhythmicity of core circadian genes (Bmal1, Per2), disrupted mitochondrial rhythms, and clock-dependent changes in angiogenic potential.<br><br>Together, these findings show that diabetes disrupts both master and retinal clocks, while circadian misalignment independently drives retinal degeneration.

Their combined effects may create a pathological feedback loop that accelerates DR. Protecting circadian rhythms may therefore offer a novel strategy to slow or prevent diabetic retinal disease.<br><br><i>Thesis is embargoed until 31 December 2028.</i>