Diabetic retinopathy, an overview

Vision Research 139 (2017) 1–6

Contents lists available at ScienceDirect

Vision Research journal homepage: www.elsevier.com/locate/visres

Diabetic retinopathy, an overview a r t i c l e

i n f o

Article history: Available online 4 August 2017

a b s t r a c t This overview introduces contributions to a special issue on causes of vision loss from diabetes mellitus, focusing on the retina and also the cornea. Diabetic retinopathy is the most common and leading cause of vision loss among people with diabetes. Research to detect early symptoms, understand mechanisms leading to diabetic eye disease, and the development of treatments is a highly active research area, with currently about 2000 scientific publication per year. We provide a series of 27 comprehensive reviews and research articles from leading experts in the field. Ó 2017 Elsevier Ltd. All rights reserved.

Diabetes mellitus (DM) affects about 400 million adults worldwide (Lee, Wong, & Sabanayagam, 2015; Rowley, Bezold, Arikan, Byrne, & Krohe, 2017) a number that is anticipated to double by 2030 according to the World Health Organization (WHO, global report on diabetes 2016; accessed Feb 4, 2017). Diabetic eye disease is a major complication of DM and causes visual impairment and blindness, with diabetic retinopathy being a leading cause of vision loss among working-age adults. Even with mild to moderate vision loss, nonproliferative diabetic retinopathy (Fig. 1) and diabetic macular edema (Fig. 2) are associated with reduced quality of life (Mazhar et al., 2011). In the 1980’s, epidemiologic studies focused on diabetes mellitus in North America, but it is now recognized that diabetes is a global concern. From 1990 to 2010, blindness increased by 27% and visual impairment by 64% (Leasher et al., 2016). Although proliferative diabetic retinopathy (Fig. 3) is the most common form of vision threatening diabetic retinopathy in patients with type 1 DM, diabetic macular edema accounts for most of the vision loss in DM, because it is more common in the more prevalent type 2 DM (Lightman & Towler, 2003). Despite the growth of DM and diabetic retinopathy globally, our understanding and ability to successfully treat patients with DM have changed dramatically over the last few decades. For example, laser photocoagulation was the standard care for diabetic macular edema (DME) and was beneficial in maintaining visual acuity level in about a third of patients with DME compared to patients without treatment based on the multicenter (Early Treatment Diabetic Retinopathy Study Research Group, 1991). Panretinal photocoagulation was the standard for high-risk proliferative diabetic retinopathy (PDR) based on the earlier diabetic retinopathy study (Rand, Prud’homme, Ederer, & Canner, 1985). With the development of agents that block the bioactivity of vascular endothelial growth factor (VEGF), visual acuity has been shown to be improved in about 40% of patients with DME with anti-VEGF medications and is considered a standard treatment for many patients with http://dx.doi.org/10.1016/j.visres.2017.07.006 0042-6989/Ó 2017 Elsevier Ltd. All rights reserved.

DME given compliant follow up (Elman et al., 2010; Nguyen et al., 2012). The Diabetic Retinopathy Clinical Research Network (DRCR.net) funded by National Eye Institute found comparable outcomes for patients who had DME and visual acuity of 20/40 or better with monthly bevacizumab (1.25 mg), ranibizumab (0.3 mg), or aflibercept (2 mg), reported in Protocol T (Wells et al., 2015). Patients with 20/50 visual acuity had improved visual acuity and reduced number of injections with aflibercept treatment. Other multicenter clinical trials (VISTA and VIVID) found intravitreal aflibercept 2 mg monthly had equivalent outcomes to intravitreal aflibercept administered every two months (Brown et al., 2015; Heier et al., 2016). Corticosteroid formulations are also used to treat DME as it is recognized that inflammation plays a role in complications of DR, including DME. In addition, corticosteroids can affect angiogenic pathways. Formulations, such as triamcinolone (4 mg) (Elman et al., 2010), dexamethasone (0.7 mg) Boyer et al., 2014 or fluocinolone acetonide (0.2 lg) Campochiaro et al., 2012 improved vision and reduced macular thickness in multicenter clinical trials for DME. Triamcinolone is a suspension and causes floaters, whereas dexamethasone and fluocinolone are inserts causing usually one floater when the intravitreal insert is symptomatically visible to the patient. The reduced burden of injections is important for patient care and to reduce the risk of endophthalmitis. Triamcinolone and dexamethasone last about 3 months, whereas fluocinolone acetonide lasts up to 36 months. Bevacizumab and ranibizumab require monthly injections, whereas aflibercept is effective when delivered every two months. Anti-VEGF treatments have been associated with increased intraocular pressure (IOP) Bressler et al., 2015 and increased need for glaucoma surgery (Eadie, Etminan, Carleton, Maberley, & Mikelberg, 2017), but the risk for glaucoma following anti-VEGF treatment is not as apparent as with corticosteroids (Maturi et al., 2016). Before fluocinolone acetonide is offered for

2

Editorial / Vision Research 139 (2017) 1–6

Fig. 1. Image of right eye showing scattered hemorrhage and microaneurysms. In the inferonasal quadrant there is subtle venous beading of a vein and some intraretinal microvascular abnormalities (IRMA). These are all characteristics of nonproliferative diabetic retinopathy (NPDR). (Courtesy of Danielle Princiotta, COA). Ó 2017 Mary Elizabeth Hartnett. All Rights Reserved.

DME, it is recommended that the patient receive a month trial of corticosteroids, such as prednisolone acetate 1% eye drops four times daily, to check for an increase in IOP in response to steroid treatment. Steroids also increase the risk of cataract formation progressing in almost all patients who received the fluocinolone acetonide and, in theory, may have increased risk of endophthalmitis. Imposed monthly injections of ranibizumab were reported to be associated with increased risks of a broad definition of cardiovascular risks (hypertension, vascular death, non-fatal myocardial infarction, stroke) in 17–19% (Bressler et al., 2014; Brown et al., 2013; Domalpally, Ip, & Ehrlich, 2015). In part, this may be due to reduced serum VEGF levels associated with intravitreal anti-VEGF treatment. However, currently many physicians base whether to administer treatment with an anti-VEGF treatment on the finding of macular thickening and cysts on optical coherence tomography (OCT). If response does not occur following a number of treatments, e.g., 4 monthly injections, there are other medications including steroid formulations that can be considered. Besides the benefit to DME, studies have also demonstrated that anti-VEGF treatment and some steroid formulations, e.g. fluocinolone acetonide, not only reduced progression of nonproliferative diabetic retinopathy but also reduced the severity of DR (Wykoff et al., 2016). Other aspects of glycemic and lipid control have been evaluated for general diabetic care. Good glycemic control and use of fenofibrate were associated with slowed progression of diabetic

Fig. 2. A. Image of right eye with scattered yellow exudates, blot hemorrhages and microaneurysms in macula. B. Accompanying scan from a spectral domain optical coherence tomogram (OCT) showing cysts and highly reflective material in the inner and outer nuclear and plexiform layers. Ó 2017 Mary Elizabeth Hartnett. All Rights Reserved.


3

retinopathy severity, others progress with anti-VEGF treatment. Even with improvements in DR severity scores, it is unknown how the improvement may affect an individual’s quality of life. Currently 95%; however compliance with yearly eye examinations remains 50% or less in many areas of the country. Therefore, screening of DR has evolved with fundus images initially and now the success with training medical assistants to obtain fundus images that can be interpreted in centers where a patient receives treatment to reduce the burden of examinations and to improve compliance with the recommendation for yearly eye examinations (Silva et al., 2016; Ting & Tan, 2017). There is still more work that needs to be done. Even with new treatments, only about 40% of patients with DME have improved vision. Even though some patients have improvement in diabetic

In the thematic special Issue of Vision Research in which this introduction appears, we present reviews covering the basic understanding of mechanisms at a molecular, cell and tissue level in the eye and retina, genetic predisposition of DR, the effect of glucose and lipids on cell processes and diabetic models, the role of inflammation, diagnostic imaging, and new treatments on the horizon. As a great overview of known diabetic disease, Lechner, O’Leary, and Stitt (2017) provide a comprehensive review of complexity of molecular events and interplay among numerous cells of neuronal, glial, and microvascular origin that underpin pathophysiology and the features making up forms of diabetic retinopathy. A number of reviews cover mechanisms related to hyperglycemia and diabetic stresses. Ye and Steinle (2017) provide insight into a mechanism of potential therapeutic benefit regarding the microRNA, miR-146a, which inhibited high glucose-induced activation of the IL6 receptor that triggered the STAT3/VEGF signaling pathway to mediate apoptosis in cultured retinal microvascular endothelial cells. This review proposes a mechanism to reduce inflammation and apoptosis in retinal endothelial cells in high glucose. Ye, Liu and Steinle (2017) also provided in vitro and in vivo evidence that the microRNAs (miR-15a and miR-16) maintained retinal endothelial cell barrier integrity by inhibiting the TGFbeta3/SMAD signaling pathway. Kowluru (2017) describes mechanisms involved in metabolic memory, which is defined as the progression of DR after termination of hyperglycemia and the added deleterious effect of duration of prior hyperglycemia on further DR progression even after euglycemia is established. Reactive oxygen species (ROS) damage mitochondrial DNA and interfere with the transcription of proteins important in the electron transport change and subsequent oxidative phosphorylation. Hyperglycemia can lead to epigenetic modification of genes important for mitochondrial homeostasis and continues to proceed even after euglycemia is established. Therapies that combine methods to quench ROS or inhibit epigenetic modification, in combination with tight glycemic control, may reduce effects from metabolic memory. Xu and Chen (2017) review the role of the innate immune system in DR, in which early on the blood retinal barrier is intact and provides a means of defense against damage-associated molecular patterns (DAMPs), but with disease and increased DAMPs there is maladaptation of the innate immune system and later loss of immune privilege leading to chronic inflammation that may contribute to neuronal and vascular damage. Thus, the innate immune system, initially important in maintaining homeostasis, can be involved in later dysregulated inflammation that contributes to DR. Chen and Ma (2017) provide a comprehensive review of the canonical Wnt signaling pathway in health and its dysregulation in diseases highlighting mechanisms in DR pathophysiology. Jianyan Hu et al. in Qian Wu’s (Hu, Li, Du, Wu, & Le, 2017) group describe the potential role of the succinate-specific receptor, GPR91, in hypoxic retinal diseases, like DR. Experimental evidence supports the line of thinking that succinate builds up in the ganglion cells and triggers signaling through GPR91 to upregulate inflammatory cytokines through the ERK1/2-COX-2/PGE2 signaling pathway and pro-angiogenic VEGF through ERK1/2-CEBP beta (c-Fos). Kern (2017) reviews the role of photoreceptor cells in the development of DR potentially through increased metabolic demand,

4


hypoxia, reactive oxygen species and inflammation. He also described methods using various light strategies to reduce oxygen consumption incurred by the rod dark current with promising outcomes. Xia and Rizzolo (2017) describe the role of the RPE in maintaining retinal health by performing several functions in its role in the outer blood-retinal barrier including paracellular diffusion, facilitated diffusion, active transport, receptor mediated and bulk phase transcytosis and metabolic processing of solutes in transit. Late stages of DR are associated with reduced regulation of paracellular diffusion, active transport and metabolic processing. Also described are different model systems and controversies in the literature. Barber and Baccouche (2017) describe early changes in retinal neuronal structure by OCT and in experimental animal models, showing changes in synaptic proteins, axonal transport, neuronal morphology and neurotransmitter content and function and provides some neuroprotective approaches to preserve the integrity of the neural retina. Mohr & Coughlin, 2017 investigate the roles of Müller cells in maintaining a healthy and functioning retina and discuss their role in releasing beneficial and detrimental factors and inflammatory cytokines that impact adjacent cells, such as retinal neurons and endothelial cells, that may lead to progression of DR. Lynch and Abramoff (2017) describe a hypothesis in which diabetic neurodegeneration causes later microvasculopathy and proposes the need for further studies to test the hypothesis. Le (2017) describes how Müller cells modulate vascular function and neuronal integrity by regulating growth factors and that Müller cell-derived VEGF mediates diabetic retinopathy. However, achieving physiologic levels of VEGF through anti-VEGF treatments is challenging for each patient. In studies that knocked out VEGFR2 in Müller cells, photoreceptors and Müller cells died in part related to reduced neurotrophins, GDNF and BDNF, and to fewer VEGFR2induced Akt survival mechanisms. Roy, Kim, and Lim (2017) describes mechanisms of high glucose-mediated alterations in connexin expression that lead to disruption of Müller cell gap junctions and the effects on interacting endothelial cells and pericytes. Pathologic events are involved in apoptosis and compromise of the inner blood retinal barrier. Diaz-Coranguez, Ramos, and Antonetti (2017) review the basis of the blood retinal barrier including molecular mechanisms that regulate flux across the vascular bed that involve transcellular and paracellular fluxes and new understanding of the development of the blood retinal barrier that may lead to opportunities to restore barrier function in diabetic retinopathy. Ljubimov (2017) reviews the mechanisms of diabetic corneal abnormalities from models in animal tissue and organ cultures, and discusses emerging treatments to inhibit advanced glycation end products, including topical insulin, naltrexone, and aldose reductase inhibitors. Gardner and Sundstrom (2017) describe a novel line of study to prevent and treat early stage DR that involves patient specific classification of disease based on pathophysiologic adaptations determined from molecular diagnoses of proteomic analysis of inoffice vitreous fluid. The future directions include a personalized approach to therapy for patients with DM/DR. Early previous human studies show loss of choriocapillaris, tortuous vessels, microaneurysm, drusenoid deposits on Bruch’s membrane and neovascularization. Gerard Lutty (2017) describes diabetic choroidopathy as an inflammatory disease in which leukocyte adhesion molecules are elevated and neutrophils are found in areas of vascular loss. These pathologic observations are supported by imaging studies demonstrating reduced blood flow. Imaging studies now using enhanced depth imaging and swept source

forms of OCT permit better analysis of the choroid and may complement OCTA to assess the choriocapillaris. Ung et al., 2017 performed whole exome sequencing on patients with phenotypic extremes of diabetic retinal complications and identified 7 genes that were validated and had reduced expression in human retinal microvascular endothelial cells under high glucose, suggesting a possible role for these in proliferative DR. A number of studies review different current imaging techniques that correlate with pathologic features and can be helpful in understanding the current diabetic pathology in the individual patient’s retina. Richard Rosen (Krawitz et al., 2017) compared two methods, the acircularity index and axis ratio, that measure the superimposed superficial and deep plexi at the foveal avascular zone in patients without DR, with nonproliferative DR or with proliferative DR using noninvasive optical coherence tomography angiography (OCTA) and found them useful to stage DR with OCTA, avoid invasive fluorescein angiography and offer a means to monitor disease progression and response to treatment. Ghasemi, Tsui, and Sadda, 2017 describe the technique of ultrawide-field images to study DR. Ultra-wide-field images cover up to 82% of the fundus and with ocular steering can image almost 100% of the eye. This technique allows more precise imaging of the peripheral retina and potentially may be important in precise diagnosis and targeted treatment. However, studies to date have not provided evidence that targeted treatment improves current management of DR or diabetic macular edema although identification of peripheral retinal findings is increased with ultra-wide-field images in patients with DR (Silva et al., 2016). Nesper, Soetikno, Zhang, and Fawzi, 2017 describe a new method of OCTA using visible light, which permits measurement of retinal oxygen delivery and metabolic rates. Future steps require consensus on the most reliable parameters with consistent outcome measurements for multicenter studies to be done to test them in DR. Gerendas et al., 2017 in Ursula Schmidt-Erfurth’s group evaluated a computational machine learning approach that analyzed features from OCT data to assess prognosis for visual acuity following treatment of diabetic macular edema with anti-VEGF therapy. The study found intraretinal cystoid fluid in the outer nuclear layer and total retinal thickness within the 3-mm area surrounding the fovea 12 and 24 weeks following treatment to have the greatest predictive values for best-corrected visual acuity at one year. Several future potential treatments were posed, some already in clinical trials. Bhatwadekar et al., 2017 in Maria Grant’s laboratory describe how DM damages bone marrow and reduces bone marrow-hematopoietic stem/progenitor cells (HS/PCs), which provide microvascular repair during diabetic disease. Damage to the autonomic nervous system initiates and propagates bone marrow dysfunction. Potential therapies to protect HS/PCs from oxidative stress and advanced glycation end product accumulation may reduce risk of vascular degeneration in the retina. Urias, Urias, Monickaraj, McGuire, and Das (2017) describe inflammatory mechanisms in diabetic macular edema that involve chemokines and cytokines. These chemokines are potential targets being considered in clinical trials to improve outcomes in diabetic macular edema that are in addition to targeting VEGF. Hammer and Busik (2017) describe several mechanisms behind dyslipidemia and their role in the development of DR, suggesting potential therapies, based currently on experimental studies, through activation of liver X receptor, miR-15a mediated inhibition of VEGF or acid sphingomylenases, lipoxins, resolvins and protectins. Reid and Lois (2017) highlight non-erythroid effects from the hormone erythropoietin and the potential protective effects in early DR, including non-erythropoietic erythropoietin-derived


peptides to reduce side effects. These compounds are currently in investigation in early phase clinical trials. We are excited to provide this series of timely and comprehensive reviews from leading experts and scientists, and we hope the reviews are informative for basic researchers, clinician scientists and patients affected by diabetic retinopathy. Acknowledgments This work was supported by NIH grants EY015130 and EY017011 (MEH), EY08123 and EY019298 (WB); GM122744 and EY26970 (YZL), EY014800-039003 (NEI core grant to the Department of Ophthalmology, University of Utah); unrestricted grants to the University of Utah Department of Ophthalmology from Research to Prevent Blindness (RPB; New York), and grants form Oklahoma Center for Adult Stem Cell Research. WB is the recipient an RPB Nelson Trust Award, and an award from the Retina Research Foundation (Alice McPherson, MD), Houston. References Barber A.J. and Baccouche B. (2017). Neurodegeneration in Diabetic Retinopathy: potential for novel therapies. Vision Research, 139, 82–92. Bhatwadekar, A., Duan, Y., Korah, M., Thinschmidt, J., Hu, P., Leley, S. P., Cabellero, S., Shaw, L. C., Busik, J., and Grant, M. (2017). Hematopoietic stem/progenitor involvement in retinal microvascular repair during diabetes: implications for bone marrow rejuvenation. Vision Research, 139, 211–220. Boyer, D. S., Yoon, Y. H., Belfort, R., Jr., Bandello, F., Maturi, R. K., Augustin, A. J., et al (2014). Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology, 121, 1904–1914. Bressler, S. B., Almukhtar, T., Bhorade, A., Bressler, N. M., Glassman, A. R., Huang, S. S., et al (2015). Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure or the need for ocular hypotensive treatment. JAMA Ophthalmology, 133, 589–597 (PMC4496789). Bressler, N. M., Varma, R., Suner, I. J., Dolan, C. M., Ward, J., Ehrlich, J. S., et al (2014). Vision-related function after ranibizumab treatment for diabetic macular edema: results from RIDE and RISE. Ophthalmology, 121, 2461–2472. Brown, D. M., Nguyen, Q. D., Marcus, D. M., Boyer, D. S., Patel, S., Feiner, L., et al (2013). Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology, 120, 2013–2022. Brown, D. M., Schmidt-Erfurth, U., Do, D. V., Holz, F. G., Boyer, D. S., Midena, E., et al (2015). Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology, 122, 2044–2052. Campochiaro, P. A., Brown, D. M., Pearson, A., Chen, S., Boyer, D., Ruiz-Moreno, J., et al (2012). Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology, 119, 2125–2132. Chen, Q. and Ma, J. X. (2017). Canonical Wnt signaling in diabetic retinopathy. Vision Research, 139, 47–58. Chew, E. Y., Davis, M. D., Danis, R. P., Lovato, J. F., Perdue, L. H., Greven, C., et al (2014). The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. JAMA Ophthalmology, 121, 2443 (PMC4252767). Diaz-Coranguez, M., Ramos, C., and Antonetti, D. A. (2017). The inner blood-retinal barrier: Cellular basis and development. Vision Research, 139, 123–137. Domalpally, A., Ip, M. S., & Ehrlich, J. S. (2015). Effects of intravitreal ranibizumab on retinal hard exudate in diabetic macular edema: findings from the RIDE and RISE phase III clinical trials. Ophthalmology, 122, 779–786. Eadie, B. D., Etminan, M., Carleton, B. C., Maberley, D. A., & Mikelberg, F. S. (2017). Association of repeated intravitreous bevacizumab injections with risk for glaucoma surgery. JAMA Ophthalmology, 135, 363–368 (PMC5470402). Early Treatment Diabetic Retinopathy Study Research Group (1991). Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology, 98, 766–785. Elman, M. J., Aiello, L. P., Beck, R. W., Bressler, N. M., Bressler, S. B., Edwards, A. R., ... Sun, J. K. (2010). Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology, 117(6), 1064–1077 (e1035). Gardner, T. W. and Sundstrom, J. M. (2017). A proposal for early and personalized treatment of diabetic retinopathy based on clinical pathophysiology and molecular phenotyping. Vision Research, 139, 153–160. Gerendas, B. S., Bogunovic, H., Sadeghipour, A., Schlegl, T., Langs, G., Waldstein, S. M., and Schmidt-Erfurth, U. (2017). Computational image analysis for prognosis determination in DME. Vision Research, 139, 204–210.

5

Ghasemi, F. K., Tsui, I., and Sadda, S. R. (2017). Ultra-wide-field imaging in diabetic retinopathy. Vision Research, 139, 187–190. Hammer, S. S. and Busik, J. V. (2017). The role of dyslipidemia in diabetic retinopathy. Vision Research, 139, 228–236. Heier, J. S., Korobelnik, J. F., Brown, D. M., Schmidt-Erfurth, U., Do, D. V., Midena, E., et al (2016). Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies. Ophthalmology, 123, 2376–2385. Hu, J., Li, T., Du, X., Wu, Q., and Le, Y. Z. (2017). G protein-coupled receptor 91 signaling in diabetic retinopathy and hypoxic retinal diseases. Vision Research, 139, 59–64. Keech, A. C., Mitchell, P., Summanen, P. A., O’Day, J., Davis, T. M., Moffitt, M. S., et al (2007). Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet, 370, 1687–1697. Kern, T. S. (2017). Do photoreceptor cells cause the development of retinal vascular disease? Vision Research, 139, 65–71. Kowluru, R. A. (2017). Diabetic Retinopathy, Metabolic Memory and Epigenetic Modifications. Vision Research, 139, 30–38. Krawitz, B. D., Mo, S., Geyman, L. S., Agemy, S. A., Scripsema, N. K., Garcia, P. M., Chui, T. Y., and Rosen, R. B. (2017). Acircularity index and axis ratio of the foveal avascular zone in diabetic eyes and healthy controls measured by optical coherence tomography angiography. Vision Research, 139, 177–186. Le, Y. Z. (2017). VEGF production and signaling in Muller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases. Vision Research, 139, 108–114. Leasher, J. L., Bourne, R. R., Flaxman, S. R., Jonas, J. B., Keeffe, J., Naidoo, N., et al (2016). Erratum. global estimates on the number of people blind or visually impaired by diabetic retinopathy: a meta-analysis from 1990-2010. Diabetes Care, 39, 2096. Lechner, J., O’Leary, O. E., and Stitt, A. W. (2017). The pathology associated with diabetic retinopathy. Vision Research, 139, 7–14. Lee, R., Wong, T. Y., & Sabanayagam, C. (2015). Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vision (Lond), 2, 17 (PMC4657234). Lightman, S., & Towler, H. M. (2003). Diabetic retinopathy. Clinical Cornerstone, 5, 12–21. Ljubimov, A. V. (2017). Diabetic complications in the cornea. Vision Research, 139, 138–152. Lutty, G. (2017). Diabetic choroidopathy. Vision Research, 139, 161–167. Lynch, S. K. and Abramoff, M. D. (2017). Diabetic retinopathy is a neurodegenerative disorder. Vision Research, 139, 101–107. Maturi, R. K., Pollack, A., Uy, H. S., Varano, M., Gomes, A. M., Li, X. Y., et al (2016). Intraocular pressure in patients with diabetic macular edema treated with dexamethasone intravitreal implant in the 3-year mead study. Retina, 36, 1143–1152. Mazhar, K., Varma, R., Choudhury, F., McKean-Cowdin, R., Shtir, C. J., & Azen, S. P. (2011). Severity of diabetic retinopathy and health-related quality of life: the Los Angeles Latino Eye Study. Ophthalmology, 118, 649–655 (PMC3070833). Mohr, S. and Coughlin, B. (2017). Müller Cells and Diabetic Retinopathy. Vision Research, 139, 93–100. Nesper, P. L., Soetikno, B. T., Zhang, H. F., and Fawzi, A. A. (2017). OCT angiography and visible-light OCT in diabetic retinopathy. Vision Research, 139, 191–203. Nguyen, Q. D., Brown, D. M., Marcus, D. M., Boyer, D. S., Patel, S., Feiner, L., et al (2012). Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology, 119, 789–801. Rand, L. I., Prud’homme, G. J., Ederer, F., & Canner, P. L. (1985). Factors influencing the development of visual loss in advanced diabetic retinopathy. Diabetic Retinopathy Study (DRS) Report No. 10. Investigative Ophthalmology & Visual Science, 26, 983–991. Reid, G. and Lois, N. (2017). Erythropoietin in diabetic retinopathy. Vision Research, 139, 237–242. Rowley, W. R., Bezold, C., Arikan, Y., Byrne, E., & Krohe, S. (2017). Diabetes 2030: insights from yesterday, today, and future trends. Population Health Management, 20, 6–12 (PMC5278808). Roy, S., Kim, D., and Lim, R. (2017). Cell-cell communication in diabetic retinopathy. Vision Research, 139, 115–122. Silva, P. S., Cavallerano, J. D., Haddad, N. M., Tolls, D., Thakore, K., Patel, B., et al (2016). Comparison of nondiabetic retinal findings identified with nonmydriatic fundus photography vs ultrawide field imaging in an ocular telehealth program. JAMA Ophthalmology, 134, 330–334. Silva, P. S., Horton, M. B., Clary, D., Lewis, D. G., Sun, J. K., Cavallerano, J. D., et al (2016). Identification of diabetic retinopathy and ungradable image rate with ultrawide field imaging in a national teleophthalmology program. Ophthalmology, 123, 1360–1367. Ting, D. S. W., & Tan, G. S. W. (2017). Telemedicine for diabetic retinopathy screening. JAMA Ophthalmology, 135, 722–723. Ung, C., Sanchez, A. V., Shen, L., Davoudi, S., Ahmadi, T., Navarro-Gomez, D., Chen, C. J., Hancock, H., Penman, A., Hoadley, S., Consugar, M., Restrepo, C., Shah, V. A., Arboleda-Velasquez, J. F., Sobrin, L., Gai, X., and Kim, L. A. (2017). Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy. Vision Research, 139, 168–176. Urias, E. A., Urias, G. A., Monickaraj, F., McGuire, P. G., and Das, A. (2017). Novel Therapeutic Targets in Diabetic Macular Edema: Beyond VEGF. Vision Research, 139, 221–227.

6


Wells, J. A., Glassman, A. R., Ayala, A. R., Jampol, L. M., Aiello, L. P., Antoszyk, A. N., et al (2015). Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. New England Journal of Medicine, 372, 1193–1203 (PMC4422053). Wykoff, C. C., Marcus, D. M., Midena, E., Korobelnik, J. F., Saroj, N., Gibson, A., et al (2016). Intravitreal aflibercept injection in eyes with substantial vision loss after laser photocoagulation for diabetic macular edema: subanalysis of the VISTA and VIVID randomized clinical trials. JAMA Ophthalmology. http://dx.doi. org/10.1001/jamaophthalmol.2016.4912. epub ahead of print. Xia, T. and Rizzolo, L. J. (2017). Effects of diabetic retinopathy on the barrier functions of the retinal pigment epithelium. Vision Research, 139, 72–81. Xu, H. and Chen, M. (2017). Diabetic retinopathy and dysregulated innate immunity. Vision Research, 139, 39–46. Ye, E. A. and Steinle, J. J. (2017). miR-146a suppresses STAT3/VEGF pathways and reduces apoptosis through IL-6 signaling in primary human retinal microvascular endothelial cells in high glucose conditions. Vision Research, 139, 15–22. Ye, E.-A., Liu, L., and Steinle, J. J. (2017). miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins. Vision Research, 139, 23–29.

⇑

M. Elizabeth Hartnett Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Sciences, Salt Lake City, UT 84132, United States ⇑ Corresponding author. E-mail address: [email protected] Wolfgang Baehr Department of Ophthalmology, John A. Moran Eye Center, University of Utah Health Sciences, Salt Lake City, UT 84132, United States Yun Z. Le Section of Endocrinology and Diabetes, Departments of Medicine, Cell Biology and Ophthalmology and Harold Hamm Diabetes Center, University of Oklahoma, Oklahoma City, OK 73104-5020, United States