Early structural and functional neurovascular changes in the retina in the prediabetic stage

Ratra, Dhanashree; Nagarajan, Rajesh; Dalan, Daleena; Prakash, Nandini; Kuppan, Kaviarasan; Thanikachalam, Sadagopan; Das, Undurti N.; Narayansamy, Angayarkanni

doi:10.1038/s41433-020-0984-z

Cited by 22 publications

(30 citation statements)

References 23 publications

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“…It is widely accepted that functional defects in the light evoked responses of the retina occur in rodent models of diabetes (Aung et al, 2013;Samuels et al, 2015) and in diabetic patients (Greenstein et al, 1993;Tyrberg et al, 2011;Bearse and Ozawa, 2014;Ratra et al, 2020), both of which also demonstrate increased polyol accumulation (Gabbay, 1973;Dagher et al, 2004;Lorenzi, 2007). In the STZ model of diabetes, reductions in ERG amplitudes were correlated with hyperglycemia, at both 2 weeks and 4 weeks of diabetes (Samuels et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

Reduction of Glut1 in the Neural Retina But Not the RPE Alleviates Polyol Accumulation and Normalizes Early Characteristics of Diabetic Retinopathy

et al. 2021

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Hyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization of glucose levels delays its progression. In hyperglycemia, hexokinase is saturated and excess glucose is metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies to reduce retinal polyol accumulation for the prevention of DR have been elusive due to low sorbitol dehydrogenase levels in the retina and inadequate inhibition of aldose reductase. Using systemic and conditional genetic inactivation, we targeted the primary facilitative glucose transporter in the retina, Glut1, as a preventative therapeutic in diabetic male and female mice.Unlike wildtype diabetics, diabetic Glut1 +/mice did not display elevated Glut1 levels in the retina. Furthermore, diabetic Glut1 +/mice exhibited ameliorated ERG defects, inflammation and oxidative stress, which was correlated with a significant reduction in retinal sorbitol accumulation. RPE-specific reduction of Glut1 did not prevent an increase in retinal sorbitol content or early hallmarks of DR. However, like diabetic Glut1 +/mice, reduction of Glut1 specifically in retinal neurons mitigated polyol accumulation and completely prevented retinal dysfunction and the elevation of markers for oxidative stress and inflammation associated with diabetes. These results suggest that modulation of retinal polyol accumulation via Glut1 in photoreceptors can circumvent the difficulties in regulating systemic glucose metabolism and be exploited to prevent DR.Significance: Diabetic retinopathy (DR) affects one third of diabetic patients and is the primary cause of vision loss in adults aged 20-74. While anti-VEGF and photocoagulation treatments for the late-stage vision threatening complications can prevent vision loss, a significant proportion of patients do not respond to anti-VEGF therapies and mechanisms to stop progression of early-stage symptoms remain elusive. Glut1 is the primary facilitative glucose transporter for the retina. We determined that a moderate reduction in Glut1 levels, specifically in retinal neurons, but not the RPE, was sufficient to prevent retinal

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Section: Resultsmentioning

confidence: 99%

Reduction of Glut1 in the Neural Retina But Not the RPE Alleviates Polyol Accumulation and Normalizes Early Characteristics of Diabetic Retinopathy

et al. 2021

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“…A growing body of literature has been devoted to analyzing and interpreting both the new OCT and OCTA data [16,17]. However, few studies have tried to correlate the new morphological and vascular findings to macular functional parameters [18][19][20][21][22][23]. The aim of this study was to evaluate and correlate the earliest structural and vascular retinal changes-obtained by means of OCT and OCTA-and the electrophysiological functional parameters-measured by multifocal electroretinogram (mfERG)-in diabetic eyes without or with early signs of DR, compared to healthy controls.…”

Section: Introductionmentioning

confidence: 99%

Early Retinal Changes by OCT Angiography and Multifocal Electroretinography in Diabetes

Frizziero

Midena

Longhin

et al. 2020

JCM

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Background: To evaluate the earliest retinal morphological and functional changes in diabetic eyes without or with early signs of diabetic retinopathy (DR). Methods: Twenty-two eyes with no DR (noDR group), 22 eyes with mild DR (DR group), and 18 healthy nondiabetic eyes (controls) were enrolled. All eyes were studied by means of spectral domain optical coherence tomography (OCT), OCT angiography (OCTA), and multifocal electroretinogram (mfERG). Results: A significantly higher number of OCT hyperreflective intraretinal foci (HRF) was found in both noDR and DR groups versus controls, but not between DR groups. The OCTA parameters of the superficial vascular plexus (SVP) were significantly reduced in the noDR group both versus controls and DR group (p < 0.05). The OCTA parameters of the intermediate capillary plexus (ICP) were significantly reduced in the DR group versus controls. An increased number of altered hexagons on mfERG was found in the noDR versus the DR group (p = 0.0192). Conclusions: Retinal vascular and functional parameters are differently involved in diabetic eyes; major vascular changes in the SVP and functional alterations of the mfERG are present in diabetic eyes with no clinical microvascular signs of DR, while ICP is mainly involved when early ophthalmoscopic signs of DR are present. The integrated use of mfERG and OCTA provides new significant insights into the pathogenesis of diabetic related retinal disease.

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Section: Resultsmentioning

confidence: 99%

“…We previously correlated the time course and extent of ERG defects in STZ-induced diabetic mice with hyperglycemia (Samuels et al, 2015). Reduced ERG amplitudes and increased ERG latencies occur prior to structural changes to the retina and are predictive of microaneurysm development and DR severity (Ng et al, 2008;Ratra et al, 2020). Molecular targets that prevent ERG defects could be utilized for preventative or interventional therapies.…”

mentioning

confidence: 99%

Reduction of Glut1 in retinal neurons but not the RPE alleviates polyol accumulation and normalizes early characteristics of diabetic retinopathy

Holoman

Aiello

Trobenter

et al. 2020

Preprint

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Hyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization of glucose levels delays its progression. In hyperglycemia, hexokinase is saturated and excess glucose is metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies to reduce retinal polyol accumulation for the prevention of DR have been elusive due to low sorbitol dehydrogenase levels in the retina and inadequate inhibition of aldose reductase. Using systemic and conditional genetic inactivation, we targeted the primary facilitative glucose transporter in the retina, Glut1, as a preventative therapeutic in diabetic male and female mice. Unlike wildtype diabetics, diabetic Glut1+/− mice did not display elevated Glut1 levels in the retina. Furthermore, diabetic Glut1+/− mice exhibited ameliorated ERG defects, inflammation and oxidative stress, which was correlated with a significant reduction in retinal sorbitol accumulation. RPE-specific reduction of Glut1 did not prevent an increase in retinal sorbitol content or early hallmarks of DR. However, like diabetic Glut1+/− mice, reduction of Glut1 specifically in retinal neurons mitigated polyol accumulation and completely prevented retinal dysfunction and the elevation of markers for oxidative stress and inflammation associated with diabetes. These results suggest that modulation of retinal polyol accumulation via Glut1 in photoreceptors can circumvent the difficulties in regulating systemic glucose metabolism and be exploited to prevent DR.SignificanceDiabetic retinopathy (DR) affects one third of diabetic patients and is the primary cause of vision loss in adults aged 20-74. While anti-VEGF and photocoagulation treatments for the late-stage vision threatening complications can prevent vision loss, a significant proportion of patients do not respond to anti-VEGF therapies and mechanisms to stop progression of early-stage symptoms remain elusive. Glut1 is the primary facilitative glucose transporter for the retina. We determined that a moderate reduction in Glut1 levels, specifically in retinal neurons, but not the RPE, was sufficient to prevent retinal polyol accumulation and the earliest functional defects to be identified in the diabetic retina. Our study defines modulation of Glut1 in retinal neurons as a targetable molecule for prevention of DR.

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Early structural and functional neurovascular changes in the retina in the prediabetic stage

Cited by 22 publications

References 23 publications

Reduction of Glut1 in the Neural Retina But Not the RPE Alleviates Polyol Accumulation and Normalizes Early Characteristics of Diabetic Retinopathy

Reduction of Glut1 in the Neural Retina But Not the RPE Alleviates Polyol Accumulation and Normalizes Early Characteristics of Diabetic Retinopathy

Early Retinal Changes by OCT Angiography and Multifocal Electroretinography in Diabetes

Reduction of Glut1 in retinal neurons but not the RPE alleviates polyol accumulation and normalizes early characteristics of diabetic retinopathy

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