The effects of early diabetes on inner retinal neurons

Abstract

Diabetic retinopathy is now well understood as a neurovascular disease. Significant deficits early in diabetes are found in the inner retina that consists of bipolar cells that receive inputs from rod and cone photoreceptors, ganglion cells that receive inputs from bipolar cells, and amacrine cells that modulate these connections. These functional deficits can be measured in vivo in diabetic humans and animal models using the electroretinogram (ERG) and behavioral visual testing. Early effects of diabetes on both the human and animal model ERGs are changes to the oscillatory potentials that suggest dysfunctional communication between amacrine cells and bipolar cells as well as ERG measures that suggest ganglion cell dysfunction. These are coupled with changes in contrast sensitivity that suggest inner retinal changes. Mechanistic in vitro neuronal studies have suggested that these inner retinal changes are due to decreased inhibition in the retina, potentially due to decreased gamma aminobutyric acid (GABA) release, increased glutamate release, and increased excitation of retinal ganglion cells. Inner retinal deficits in dopamine levels have also been observed that can be reversed to limit inner retinal damage. Inner retinal targets present a promising new avenue for therapies for early-stage diabetic eye disease.

Spontaneous electroretinogram signals to screen people with early risk factors for diabetic retinopathy

“…The presence of these intrinsic oscillators in the inner retina 21–25,61,62 , the fact that retinal neurons can be electrically coupled 63 , and the large-scale network interactions happening in the retina 20 are likely to result in spontaneous fluctuations of the field potential 64 in this tissue. Consistent with the existence of bipolar/amacrine cell oscillators and our findings showing that spontaneous activity is altered in the high-fat diet-induced obesity, spontaneous obesity, and streptozotocin-induced type 1 diabetes models, inner retinal deficits have been detected at the onset of diabetes 31,65,66 . Overall, we found reduced peak frequencies of the low range activities (0.2-2.5 Hz), which is agreement with decreased inhibition in the early diabetic retina 31,67–71 .…”

“…Consistent with the existence of bipolar/amacrine cell oscillators and our findings showing that spontaneous activity is altered in the high-fat diet-induced obesity, spontaneous obesity, and streptozotocin-induced type 1 diabetes models, inner retinal deficits have been detected at the onset of diabetes 31,65,66 . Overall, we found reduced peak frequencies of the low range activities (0.2-2.5 Hz), which is agreement with decreased inhibition in the early diabetic retina 31,67–71 . Also in favor of part of the spontaneous oscillations detected by the non-evoked ERG being produced in the retina is the recent finding that DR can be detected by machine learning processing of electrooculogram (EOG) signal —corresponding to the potential difference between cornea and retina— 72 .…”

“…Spontaneous brain activity changes with diabetes 9 , but also with obesity 10–14 . Notably, retinal neurons can produce spontaneous activities 15–27 and neurodegenerative retinas showed altered patterns of spontaneous activity 28–30 , including in diabetes conditions 31 . Here we propose a diagnostic prediction method for early risk factors of DR based on the non-invasive recording of spontaneous retinal oscillations using a simple, yet meaningful non-evoked electroretinogram (ERG) protocol.…”

Single-cell transcriptomic analysis revealing changes in retinal cell subpopulation levels and the pathways involved in diabetic retinopathy

“…In the present study, the abundance of microglia were increased, which might drive DR progression, and we found that microglia subpopulations in DR participate in inflammation-related pathways. In the retina, bipolar cells receive input from rod and cone photoreceptors, ganglion cells receive input from bipolar cells, and amacrine cells regulate these interactions (42). Bipolar cells are a fundamental component of vision, as they serve as a link between the 2 synaptic layers of the retina (43,44).…”

Early Neural Changes as Underlying Pathophysiological Mechanism in Diabetic Retinopathy

“…The results of these studies have shown little effect on vascular changes in the retina, but have shown a beneficial impact on retinal function, suggesting that they can be adequate adjuvant therapies in the early phases of DR [113]. Flavonoids and carotenoids are antioxidants that have been shown to inhibit DR neuronal damage [114]. An antioxidant that has demonstrated positive effects on retinal neurodegeneration in animal models of diabetes is sulforaphane.…”