scholarly journals Early retinal pigment epithelium dysfunction is concomitant with hyperglycemia in mouse models of type 1 and type 2 diabetes

2015 ◽  
Vol 113 (4) ◽  
pp. 1085-1099 ◽  
Author(s):  
Ivy S. Samuels ◽  
Brent A. Bell ◽  
Ariane Pereira ◽  
Joseph Saxon ◽  
Neal S. Peachey
Keyword(s):  
Type 2 Diabetes ◽  
Retinal Pigment Epithelium ◽  
Mouse Models ◽  
Time Course ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Fast Oscillation

In the diabetic retina, cellular changes in the retinal pigment epithelium (RPE) and neurons occur before vision loss or diabetic retinopathy can be identified clinically. The precise etiologies of retinal pathology are poorly defined, and it remains unclear if the onset and progression of cellular dysfunction differ between type 1 and type 2 diabetes. Three mouse models were used to compare the time course of RPE involvement in type 1 and type 2 diabetes. C57BL/6J mice injected with streptozotocin (STZ mice) modeled type 1 diabetes, whereas Lepr db/db mice on both BKS and B6.BKS background strains modeled type 2 diabetes. Electroretinogram (ERG)-based techniques were used to measure light-evoked responses of the RPE (direct current-coupled ERG, dc-ERG) and the neural retina (a-wave, b-wave). Following onset of hyperglycemia, a-wave and b-wave amplitudes of STZ mice declined progressively and by equivalent degrees. Components of the dc-ERG were also altered, with the largest reduction seen in the c-wave. Lepr db/db mice on the BKS strain (BKS.Lepr) displayed sustained hyperglycemia and a small increase in insulin, whereas Lepr db/db mice on the B6.BKS background (B6.BKS.Lepr) were transiently hyperglycemic and displayed severe hyperinsulinemia. BKS.Lepr mice exhibited sustained reductions in the dc-ERG c-wave, fast oscillation, and off response that were not attributable to reduced photoreceptor activity; B6.BKS.Lepr mice displayed transient reductions in the c-wave and fast oscillation that correlated with hyperglycemia and magnitude of photoreceptor activity. In summary, all mouse models displayed altered RPE function concomitant with the onset of hyperglycemia. These results suggest that RPE function is directly reduced by elevated blood glucose levels. That RPE dysfunction was reversible and mitigated in hyperinsulinemic B6.BKS.Lepr mice provides insight into the underlying mechanism.

scholarly journals The Impact of Glycemic Control on Retinal Photoreceptor Layers and Retinal Pigment Epithelium in Patients With Type 2 Diabetes Without Diabetic Retinopathy: A Follow-Up Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Fukashi Ishibashi ◽  
Aiko Kosaka ◽  
Mitra Tavakoli
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Retinal Pigment Epithelium ◽  
Glycemic Control ◽  
Pigment Epithelium ◽  
Outer Nuclear Layer ◽  
Retinal Pigment ◽  
Glycemic Variability ◽  
Hba1c Levels

AimsTo establish the sequential changes by glycemic control in the mean thickness, volume and reflectance of the macular photoreceptor layers (MPRLs) and retinal pigment epithelium in patients with type 2 diabetes without diabetic retinopathy.MethodsThirty-one poorly controlled (HbA1c > 8.0%) patients with type 2 diabetes without diabetic retinopathy undergoing glycemic control and 39 control subjects with normal HbA1c levels (< 5.9%) underwent periodical full medical, neurological and ophthalmological examinations over 2 years. Glycemic variability was evaluated by standard deviation and coefficient of variation of monthly measured HbA1c levels and casual plasma glucose. 3D swept source-optical coherence tomography (OCT) and OCT-Explorer-generated enface thickness, volume and reflectance images for 9 subfields defined by Early Treatment Diabetic Retinopathy Study of 4 MPRLs {outer nuclear layer, ellipsoid zone, photoreceptor outer segment (PROS) and interdigitation zone} and retinal pigment epithelium were acquired every 3 months.ResultsGlycemic control sequentially restored the thickness and volume at 6, 4 and 5 subfields of outer nuclear layer, ellipsoid zone and PROS, respectively. The thickness and volume of outer nuclear layer were restored related to the decrease in HbA1c and casual plasma glucose levels, but not related to glycemic variability and neurological tests. The reflectance of MPRLs and retinal pigment epithelium in patients was marginally weaker than controls, and further decreased at 6 or 15 months during glycemic control. The reduction at 6 months coincided with high HbA1c levels.ConclusionGlycemic control sequentially restored the some MPRL thickness, especially of outer nuclear layer. In contrast, high glucose during glycemic control decreased reflectance and may lead to the development of diabetic retinopathy induced by glycemic control. The repeated OCT examinations can clarify the benefit and hazard of glycemic control to the diabetic retinopathy.

scholarly journals Delayed basal hyperpolarization of cat retinal pigment epithelium and its relation to the fast oscillation of the DC electroretinogram.

1984 ◽  
Vol 83 (2) ◽  
pp. 213-232 ◽  
Author(s):  
R A Linsenmeier ◽  
R H Steinberg
Keyword(s):  
Retinal Pigment Epithelium ◽  
Time Course ◽  
Apical Membrane ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Basal Membrane ◽  
Fast Oscillation ◽  
Light Peak ◽  
Absorption Of Light ◽  
Intermediate Time

Previous work has shown that the cat retinal pigment epithelium (RPE) is the source of two potential changes that follow the absorption of light by photoreceptors: a hyperpolarization of the apical membrane, peaking in 2-4 s, which leads to the RPE component of the electroretinogram (ERG) c-wave, and a depolarization of the basal membrane, peaking in 5 min, which leads to the light peak. This paper describes a new basal membrane response of intermediate time course, called the delayed basal hyperpolarization. Isolation of this response from other RPE potentials showed that with maintained illumination the hyperpolarization begins approximately 2 s after light onset, peaks in 20 s, and slowly ends as the membrane repolarizes over the next 60 s. The delayed basal hyperpolarization is very small for stimuli less than 4 s in duration and grows with duration, becoming approximately 15% as large as the preceding apical hyperpolarization with stimuli longer than 20 s. Extracellularly, this response contributes to the transepithelial potential (TEP) across the RPE. In response to light the TEP first rises to a peak, the c-wave, as the apical membrane hyperpolarizes. For stimuli longer than approximately 4 s, the decline of the TEP from the peak of the c-wave results partly from the recovery of apical membrane potential and partly from the delayed basal hyperpolarization. For long periods of illumination (300 s) the delayed basal hyperpolarization leads to a trough in the TEP between the c-wave and light peak. This trough is largely responsible for a corresponding trough in vitreal recordings, which has been called the "fast oscillation." The term "fast oscillation" has also been used to denote the sequence of potential changes resulting from repeated stimuli approximately 1 min in duration. In addition to the delayed basal hyperpolarization, such responses also contain a basal off-response, a delayed depolarization.

Time-course changes in clinical features of early-onset Japanese type 1 and type 2 diabetes: TWMU hospital-based study

2008 ◽  
Vol 82 (1) ◽  
pp. 80-86 ◽  
Author(s):  
Yasuko Uchigata ◽  
Toshika Otani ◽  
Hiroko Takaike ◽  
Junnosuke Miura ◽  
Mari Osawa ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Features ◽  
Early Onset ◽  
Time Course ◽  
Course Changes

scholarly journals Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189

Diabetes ◽  
2019 ◽  
Vol 68 (11) ◽  
pp. 2143-2154 ◽  
Author(s):  
Corinne G. Jolivalt ◽  
Alexandra Marquez ◽  
David Quach ◽  
Michelle C. Navarro Diaz ◽  
Carlos Anaya ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Peripheral Neuropathy ◽  
Mouse Models

scholarly journals Apolipoprotein E isoform-specific phase transitions in the retinal pigment epithelium drive disease phenotypes in age-related macular degeneration

2020 ◽  
Author(s):  
Nilsa La Cunza ◽  
Li Xuan Tan ◽  
Gurugirijha Rathnasamy ◽  
Thushara Thamban ◽  
Colin J. Germer ◽  
...  
Keyword(s):  
Phase Transitions ◽  
Retinal Pigment Epithelium ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Human Donor ◽  
Age Related ◽  
Histopathological Studies

AbstractThe retinal pigment epithelium (RPE) is the site of initial damage leading to photoreceptor degeneration and vision loss in age-related macular degeneration (AMD). Genetic and histopathological studies implicate cholesterol dysregulation in AMD; yet mechanisms linking cholesterol to RPE injury and drusen formation remain poorly understood. Especially enigmatic are allelic variants of the cholesterol transporter APOE, major risk modifiers in Alzheimer’s disease that show reversed risk associations with AMD. Here, we investigated how ApoE isoforms modulate RPE health using live-cell imaging of primary RPE cultures and high-resolution imaging of human donor tissue. We show that the AMD-protective ApoE4 efficiently transports cholesterol and safeguards RPE homeostasis despite cellular stress. In contrast, ApoE2-expressing RPE accumulate cholesterol, which promotes autophagic deficits and complement-mediated mitochondrial fragmentation. Redox-related order-disorder phase transitions in ApoE2 drive the formation of intracellular biomolecular condensates as potential drusen precursors. Drugs that restore mitochondrial function limit condensate formation in ApoE2-RPE. Autophagic and mitochondrial defects correlate with intracellular ApoE aggregates in AMD donor RPE. Our study elucidates how AMD risk variants act as tipping points to divert the RPE from normal aging towards AMD by disrupting critical metabolic functions, and identifies mitochondrial stress-mediated aberrant phase transitions as a novel mechanism of drusen biogenesis.

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