Multimodal Characterization of Proliferative Diabetic Retinopathy Reveals Alterations in Outer Retinal Function and Structure

Boynton, Grace E.; Stem, Maxwell S.; Kwark, Leon; Jackson, Gregory R.; Farsiu, Sina; Gardner, Thomas W.

doi:10.1016/j.ophtha.2014.12.001

Cited by 50 publications

(50 citation statements)

References 48 publications

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“…The accumulation of AGEs and glucose in the retina has been associated with other conditions of hyperglycemia, notably diabetic retinopathy, and some of the phenotypes noted in this work, such as RPE thinning, RPE vacuolation, photoreceptor degeneration, and thinning of the inner retinal layer, were also observed in humans and experimental models of diabetic retinopathy (33,(53)(54)(55)(56)(57)(58)(59). Glycation results in the dysfunction of structural proteins and impaired protein-editing machineries, including autophagy and the ubiquitin proteolytic systems, functions that are required for the degradation of phagosomes and AGEs (11,29,60).…”

Section: Discussionsupporting

confidence: 54%

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Rowan

Jiang

Korem

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

201

192

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Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf.LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet-and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD.age-related macular degeneration | glycemic index | advanced glycation end-product | gut microbiome | metabolomics A ge-related macular degeneration (AMD) is the leading cause of irremediable blindness in the industrialized world, with 200 million cases projected by 2020, at a cost of $300 billion (1, 2). Dry AMD accounts for the great majority of cases and is associated with photoreceptor cell loss, often preceded by compromise to the retina pigment epithelium (RPE) cells that nourish and remove waste from the photoreceptors. The etiology of AMD remains an enigma but is clearly multifactorial. Stresses associated with AMD include environment, age, and genetics (3). Frustratingly, there are no early biomarkers to anticipate AMD, and there are no therapies or cure.Recently, we and others observed in epidemiologic studies that, in addition to micronutrients (4-6), macronutrient quality [e.g., consuming a diet with a high glycemic index (GI)] is a significant risk factor for AMD onset and/or progress in nondiabetic humans (7)(8)(9). The GI appears to be an attractive dietary intervention target, because simple replacement of small amounts of high-index foods (such as white bread) with lower-index foods (such as wholegrain bread) can significantly reduce glycemic peaks without requiring ...

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Section: Discussionsupporting

confidence: 54%

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Rowan

Jiang

Korem

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

201

192

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“…We used Duke Optical Coherence Tomography Retinal Analysis Program (DOCTRAP) software to estimate the upper and lower boundaries of these seven layers 26 using a semiautomatic protocol described in our previous publication. 27 Fundus photographs (seven fields, 30°in each field) were taken of both eyes according to standard ETDRS protocol using the Zeiss FF 450 plus fundus camera (Carl Zeiss Meditec, Dublin, CA, USA). These images were used to grade the DR severity of each eye as none, mild, or moderate.…”

Section: Analysis Of Retinal Structurementioning

confidence: 99%

Glucose variability and inner retinal sensory neuropathy in persons with type 1 diabetes mellitus

Stem

Dunbar

Jackson³

et al. 2016

Eye

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Purpose To quantify early neuroretinal alterations in patients with type 1 diabetes mellitus (T1DM) and to assess whether glycemic variability contributes to alterations in neuroretinal structure or function. Methods Thirty patients with T1DM and 51 controls underwent comprehensive ophthalmic examination and assessment of retinal function or structure with frequency doubling perimetry (FDP), contrast sensitivity, dark adaptation, fundus photography, and optical coherence tomography (OCT). Diabetic participants wore a subcutaneous continuous glucose monitor for 5 days, from which makers of glycemic variability including the low blood glucose index (LGBI) and area under the curve (AUC) for hypoglycemia were derived. Results Sixteen patients had no diabetic retinopathy (DR), and 14 had mild or moderate DR. Log contrast sensitivity for the DM group was significantly reduced (mean ± SD = 1.63 ± 0.06) compared with controls (1.77 ± 0.13, Po0.001). OCT analysis revealed that the inner temporal inner nuclear layer (INL) was thinner in patients with T1DM (34.9 ± 2.8 μm) compared with controls (36.5 ± 2.9 μm) (P = 0.023), although this effect lost statistical significance after application of the Bonferroni correction for multiple comparisons. Both markers of glycemic variability, the AUC for hypoglycemia (R = − 0.458, P = 0.006) and LGBI (R = − 0.473, P = 0.004), were negatively correlated with inner temporal INL thickness. Conclusions Patients with T1DM and no to moderate DR exhibit alterations in inner retinal structure and function. Increased glycemic variability correlates with retinal thinning on OCT imaging, suggesting that fluctuations in blood glucose may contribute to neurodegeneration.

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“…Compared with controls, both PRP-treated PDR patients and untreated PDR patients had significant changes in retinal structure and function using multiple modalities, with untreated patients exhibiting more changes in inner and PRP-treated patients in outer retinal structure [122].…”

Section: Novel Utilizations Of Diagnosis and Testing Modalities In DImentioning

confidence: 91%

New Therapeutic Approaches in Diabetic Retinopathy

et al. 2015

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■ AbstractDiabetic retinopathy is a common microvascular complication of diabetes mellitus. It affects a substantial proportion of US adults over age 40. The condition is a leading cause of visual loss. Much attention has been given to expanding the role of current treatments along with investigating various novel therapies and drug delivery methods. In the treatment of diabetic macular edema (DME), intravitreal pharmacotherapies, especially anti-vascular endothelial growth factor (anti-VEGF) agents, have gained popularity. Currently, anti-VEGF agents are often used as first-line agents in centerinvolved DME, with recent data suggesting that among these agents, aflibercept leads to better visual outcomes in patients with worse baseline visual acuities. While photocoagulation remains the standard treatment for proliferative diabetic retinopathy (PDR), recent FDA approvals of ranibizumab and aflibercept in the management of diabetic retinopathy associated with DME may suggest a potential for pharmacologic treatments of PDR as well. Novel therapies, including small interfering RNAs, chemokines, kallikreinkinin inhibitors, and various anti-angiogenic agents, are currently being evaluated for the management of diabetic retinopathy and DME. In addition to these strategies, novel drug delivery methods such as sustained-release implants and refillable reservoir implants are either under active evaluation or have recently gained FDA approval. This review provides an update on the novel developments in the treatment of diabetic retinopathy.

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Multimodal Characterization of Proliferative Diabetic Retinopathy Reveals Alterations in Outer Retinal Function and Structure

Cited by 50 publications

References 48 publications

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Glucose variability and inner retinal sensory neuropathy in persons with type 1 diabetes mellitus

New Therapeutic Approaches in Diabetic Retinopathy

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