Outer Retinal Structure and Function Deficits Contribute to Circadian Disruption in Patients With Type 2 Diabetes

Abstract

PURPOSE. Light transmitted by retinal photoreceptors provides the input for circadian photoentrainment. In diabetes, there is a high prevalence of circadian and sleep disruption but the underlying causes are not well understood. Patients with diabetes can exhibit dysfunctional photoreceptors but their role in circadian health is not known. Here we quantify photoreceptor function and contributions to circadian health and sleep in patients with diabetes without diabetic retinopathy and healthy controls. METHODS. Rod, cone, and melanopsin function was derived using chromatic pupillometry in 47 participants including 23 patients with type 2 diabetes and 24 age-matched healthy controls after an ophthalmic examination including retinal thickness assessment using optical coherence tomography. Circadian health was determined using dim light melatonin onset (DLMO) and sleep questionnaires; light exposure was measured using actigraphy. RESULTS. Compared with the control group, the patients with diabetes had a significantly earlier DLMO (1 hour) (P ¼ 0.008), higher subjective sleep scores (P < 0.05), a reduction in pupil constriction amplitude for red stimuli (P ¼ 0.039) and for the early postillumination pupil response (PIPR) for blue (P ¼ 0.024) stimuli. There were no between-group differences in the light exposure pattern, activity levels, and intrinsic melanopsin-mediated PIPR amplitude (P > 0.05). A significant correlation was evident between outer retinal thickness and DLMO (r ¼ À0.65, P ¼ 0.03) and the pupil constriction amplitude (r ¼ 0.63, P ¼ 0.03); patients with thinner retina had earlier DLMO and lower pupil amplitudes. CONCLUSIONS. We infer that the observed changes in circadian function in patients with no diabetic retinopathy are due to structural and functional outer retinal rod photoreceptor deficits at early stage of diabetic eye disease.

Thinning of Macular Neuroretinal Layers Contributes to Sleep Disorder in Patients With Type 2 Diabetes Without Clinical Evidences of Neuropathy and Retinopathy

“…Recently, Dumpala et al (12) reported the outer retinal thinning and dysfunction in a small number of patients with type 2 diabetes and inferred that outer retinal structure and function deficits contribute to the sleep disruption in type 2 diabetes. However, they determined the thickness of total outer retina and did not directly associate the individual components of sleep disorder with the thickness at ETDRS grids of each outer retinal layers.…”

“…Diabetic retinopathy and neuropathy influence the thickness of the macular neuroretinal layers (8,9) and sleep disorder (10,11); however, these have not been investigated in detail. Recently, Dumpala et al (12) reported that the thinning and dysfunction of the outer retina in the small number of patients with type 2 diabetes may contribute to poor sleep behavior. However, they did not find a significant direct association between the thicknesses at the individual grids defined by the Early Treatment Diabetic Retinopathy Study (ETDRS) of outer retinal layers and the components of sleep disorder.…”

δ Opioid Receptor Agonism Preserves the Retinal Pigmented Epithelial Cell Tight Junctions and Ameliorates the Retinopathy in Experimental Diabetes

“…31 The importance of RPE to DR development depends on the photoreceptor abnormalities present early in the DR pathogenesis. [32][33][34][35] Another important feature of increasing outer retinal barrier resistance is the fluid accumulation in the subretinal space, particularly in the macular area, [36][37][38][39] which is a hallmark of diabetic macular edema and has important clinical relevance. Thus, the RPE role in DR deserves further investigation and could represent a possible site for novel therapeutic approaches.…”

The Role of Daylight for Humans: Gaps in Current Knowledge

“…Light responses depending on generalised medical and psychiatric status [ 176 , 177 , 178 , 179 ] and medication [ 180 ]…”

“…Light responses depending on generalised medical and psychiatric status [176][177][178][179] and medication [180] (ii) Genetic differences: (iv) Mixed physiological/behavioural effects:…”