Hostname: page-component-78c5997874-xbtfd Total loading time: 0 Render date: 2024-11-10T19:54:30.632Z Has data issue: false hasContentIssue false
  • English
  • Français

Diabetic photoreceptors: Mechanisms underlying changes in structure and function

Published online by Cambridge University Press:  06 October 2020

Silke Becker ,
Lara S. Carroll  and
Frans Vinberg Open the ORCID record for Frans Vinberg [Opens in a new window]
Silke Becker
Affiliation:
John A. Moran Eye Center, University of Utah, Salt Lake City, Utah
Lara S. Carroll
Affiliation:
John A. Moran Eye Center, University of Utah, Salt Lake City, Utah
Frans Vinberg*
Affiliation:
John A. Moran Eye Center, University of Utah, Salt Lake City, Utah
*
Address correspondence to: Frans Vinberg, E-mail: frans.vinberg@utah.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

Based on clinical findings, diabetic retinopathy (DR) has traditionally been defined as a retinal microvasculopathy. Retinal neuronal dysfunction is now recognized as an early event in the diabetic retina before development of overt DR. While detrimental effects of diabetes on the survival and function of inner retinal cells, such as retinal ganglion cells and amacrine cells, are widely recognized, evidence that photoreceptors in the outer retina undergo early alterations in diabetes has emerged more recently. We review data from preclinical and clinical studies demonstrating a conserved reduction of electrophysiological function in diabetic retinas, as well as evidence for photoreceptor loss. Complementing in vivo studies, we discuss the ex vivo electroretinography technique as a useful method to investigate photoreceptor function in isolated retinas from diabetic animal models. Finally, we consider the possibility that early photoreceptor pathology contributes to the progression of DR, and discuss possible mechanisms of photoreceptor damage in the diabetic retina, such as enhanced production of reactive oxygen species and other inflammatory factors whose detrimental effects may be augmented by phototransduction.

Keywords

retinaphotoreceptorsdiabeteselectroretinogram
Type
Review Article
Information
Visual Neuroscience , Volume 37 , 2020 , E008
Check for updates
Copyright
© The Author(s), 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

Silke Becker and Lara S. Carroll contributed equally to this study.

References

Adhi, M., Brewer, E., Waheed, N.K. & Duker, J.S. (2013). Analysis of morphological features and vascular layers of choroid in diabetic retinopathy using spectral-domain optical coherence tomography. JAMA Ophthalmology 131, 1267–1274.CrossRefGoogle ScholarPubMed
Akimov, N.P. & Rentería, R.C. (2012). Spatial frequency threshold and contrast sensitivity of an optomotor behavior are impaired in the Ins2Akita mouse model of diabetes. Behavioural Brain Research 226, 601–605.CrossRefGoogle ScholarPubMed
Amemiya, T. (1977). Dark adaptation in diabetics. Ophthalmologica 174, 322–326.CrossRefGoogle ScholarPubMed
Andrawus, E., Veildbaum, G., Zemel, E., Leibu, R., Perlman, I. & Shehadeh, N. (2017). Light modulates ocular complications in an albino rat model of type 1 diabetes mellitus. Translational Vision Science & Technology 6, 1.CrossRefGoogle Scholar
Arden, G.B., Wolf, J.E. & Tsang, Y. (1998). Does dark adaptation exacerbate diabetic retinopathy? Evidence and a linking hypothesis. Vision Research 38, 1723–1729.CrossRefGoogle Scholar
Arend, O., Remky, A., Evans, D., Stüber, R. & Harris, A. (1997). Contrast sensitivity loss is coupled with capillary dropout in patients with diabetes. Investigative Ophthalmology & Visual Science 38, 1819–1824.Google ScholarPubMed
Aung, M.H., Kim, M.K., Olson, D.E., Thule, P.M. & Pardue, M.T. (2013). Early visual deficits in streptozotocin-induced diabetic long evans rats. Investigative Ophthalmology & Visual Science 54, 1370–1377.CrossRefGoogle ScholarPubMed
Bao, Y.K., Yan, Y., Gordon, M., McGill, J.B., Kass, M. & Rajagopal, R. (2019). Visual field loss in patients with diabetes in the absence of clinically-detectable vascular retinopathy in a nationally representative survey. Investigative Ophthalmology & Visual Science 60, 4711–4716.CrossRefGoogle Scholar
Barber, A.J., Lieth, E., Khin, S.A., Antonetti, D.A., Buchanan, A.G. & Gardner, T.W. (1998). Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. Journal of Clinical Investigation 102, 783–791.CrossRefGoogle ScholarPubMed
Bavinger, J.C., Dunbar, G.E., Stem, M.S., Blachley, T.S., Kwark, L., Farsiu, S., Jackson, G.R. & Gardner, T.W. (2016). The effects of diabetic retinopathy and pan-retinal photocoagulation on photoreceptor cell function as assessed by dark adaptometry. Investigative Ophthalmology & Visual Science 57, 208–217.CrossRefGoogle ScholarPubMed
Bearse, M.A., Adams, A.J., Han, Y., Schneck, M.E., Ng, J., Bronson-Castain, K. & Barez, S. (2006). A multifocal electroretinogram model predicting the development of diabetic retinopathy. Progress in Retinal and Eye Research 25, 425–448.CrossRefGoogle ScholarPubMed
Becker, S., Carroll, L.S. & Vinberg, F. (2020). Rod phototransduction and light signal transmission during type 2 diabetes. BMJ Open Diabetes Research and Care 8, doi:10.1136/bmjdrc-2020-001571.CrossRefGoogle ScholarPubMed
Berkowitz, B.A., Kern, T.S., Bissig, D., Patel, P., Bhatia, A., Kefalov, V.J. & Roberts, R. (2015). Systemic retinaldehyde treatment corrects retinal oxidative stress, rod dysfunction, and impaired visual performance in diabetic mice. Investigative Ophthalmology & Visual Science 56 ,6294–6303.CrossRefGoogle ScholarPubMed
Bhatt, L., Groeger, G., McDermott, K. & Cotter, T.G. (2010). Rod and cone photoreceptor cells produce ROS in response to stress in a live retinal explant system. Molecular Vision 16, 283–293.Google Scholar
Bogdanov, P., Corraliza, L., Villena, J.A., Carvalho, A.R., Garcia-Arumí, J., Ramos, D., Ruberte, J., Simó, R. & Hernández, C. (2014). The db/db mouse: A useful model for the study of diabetic retinal neurodegeneration. PLoS One 9, e97302.CrossRefGoogle Scholar
Boynton, G.E., Stem, M.S., Kwark, L., Jackson, G.R., Farsiu, S. & Gardner, T.W. (2015). Multimodal characterization of proliferative diabetic retinopathy reveals alterations in outer retinal function and structure. Ophthalmology 122, 957–967.CrossRefGoogle ScholarPubMed
Calbiague, V.M., Vielma, A.H., Cadiz, B., Paquet-Durand, F. & Schmachtenberg, O. (2019). Physiological assessment of high glucose neurotoxicity in mouse and rat retinal explants. Journal of Comparative Neurology 528, 989–1002.CrossRefGoogle ScholarPubMed
Calligaro, H., Coutanson, C., Najjar, R.P., Mazzaro, N., Cooper, H.M., Haddjeri, N., Felder-Schmittbuhl, M.P. & Dkhissi-Benyahya, O. (2019). Rods contribute to the light-induced phase shift of the retinal clock in mammals. PLoS Biology 17, e2006211.CrossRefGoogle ScholarPubMed
Chakravarthy, H., Navitskaya, S., O'Reilly, S., Gallimore, J., Mize, H., Beli, E., Wang, Q., Kady, N., Huang, C., Blanchard, G.J., Grant, M.B. & Busik, J.V. (2016). Role of acid sphingomyelinase in shifting the balance between proinflammatory and reparative bone marrow cells in diabetic retinopathy. Stem Cells 34, 972–983.CrossRefGoogle ScholarPubMed
Chavez, J.A., Siddique, M.M., Wang, S.T., Ching, J., Shayman, J.A. & Summers, S.A. (2014). Ceramides and glucosylceramides are independent antagonists of insulin signaling. Journal of Biological Chemistry 289, 723–734.CrossRefGoogle ScholarPubMed
Chavez, J.A. & Summers, S.A. (2012). A ceramide-centric view of insulin resistance. Cell Metabolism 15, 585–594.CrossRefGoogle ScholarPubMed
Crognale, M.A., Switkes, E., Rabin, J., Schneck, M.E., Haegerström-Portnoy, G. & Adams, A.J. (1993). Application of the spatiochromatic visual evoked potential to detection of congenital and acquired color-vision deficiencies. Journal of Optical Society of America A: Optics, Image Science, and Vision 10, 1818–1825.CrossRefGoogle ScholarPubMed
Dawson, W.W., Hazariwala, K. & Karges, S. (2000). Human photopic response to circulating glucose. Documenta Ophthalmologica 101, 155–163.CrossRefGoogle ScholarPubMed
de Gooyer, T.E., Stevenson, K.A., Humphries, P., Simpson, D.A., Gardiner, T.A. & Stitt, A.W. (2006). Retinopathy is reduced during experimental diabetes in a mouse model of outer retinal degeneration. Investigative Ophthalmology & Visual Science 47, 5561–5568.CrossRefGoogle Scholar
Di Leo, M.A., Caputo, S., Falsini, B., Porciatti, V., Minnella, A., Greco, A.V. & Ghirlanda, G. (1992). Nonselective loss of contrast sensitivity in visual system testing in early type I diabetes. Diabetes Care 15, 620–625.CrossRefGoogle ScholarPubMed
Du, Y., Miller, C.M. & Kern, T.S. (2003). Hyperglycemia increases mitochondrial superoxide in retina and retinal cells. Free Radical Biology and Medicine 35, 1491–1499.CrossRefGoogle ScholarPubMed
Du, Y., Veenstra, A., Palczewski, K. & Kern, T.S. (2013). Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina. Proceedings of the National Academy of Sciences of the United States of America 110, 16586–16591.CrossRefGoogle ScholarPubMed
Felder-Schmittbuhl, M., Calligaro, H. & Dkhissi-Benyahya, O. (2017). The retinal clock in mammals: Role in health and disease. ChronoPhysiology and Therapy 7, 33–45.CrossRefGoogle Scholar
Findl, O., Dallinger, S., Rami, B., Polak, K., Schober, E., Wedrich, A., Ries, E., Eichler, H.G., Wolzt, M. & Schmetterer, L. (2000). Ocular haemodynamics and colour contrast sensitivity in patients with type 1 diabetes. British Journal of Ophthalmology 84, 493–498.CrossRefGoogle ScholarPubMed
Fong, D.S., Aiello, L., Gardner, T.W., King, G.L., Blankenship, G., Cavallerano, J.D., Ferris, F.L., Klein, R. & Association, A.D. (2004). Retinopathy in diabetes. Diabetes Care 27, S84–87.CrossRefGoogle ScholarPubMed
Fox, T.E., Han, X., Kelly, S., Merrill, A.H., Martin, R.E., Anderson, R.E., Gardner, T.W. & Kester, M. (2006). Diabetes alters sphingolipid metabolism in the retina: A potential mechanism of cell death in diabetic retinopathy. Diabetes 55, 3573–3580.CrossRefGoogle ScholarPubMed
Frank, R.N. & Dowling, J.E. (1968). Rhodopsin photoproducts: Effects on electroretinogram sensitivity in isolated perfused rat retina. Science 161, 487–489.CrossRefGoogle ScholarPubMed
Frost-Larsen, K., Christiansen, J.S. & Parving, H.H. (1983). The effect of strict short-term metabolic control on retinal nervous system abnormalities in newly diagnosed type 1 (insulin-dependent) diabetic patients. Diabetologia 24, 207–209.CrossRefGoogle ScholarPubMed
Fu, Z., Chen, C.T., Cagnone, G., Heckel, E., Sun, Y., Cakir, B., Tomita, Y., Huang, S., Li, Q., Britton, W., Cho, S.S., Kern, T.S., Hellström, A., Joyal, J.S. & Smith, L.E. (2019). Dyslipidemia in retinal metabolic disorders. EMBO Molecular Medicine 11, e10473.CrossRefGoogle ScholarPubMed
Gastinger, M.J., Singh, R.S. & Barber, A.J. (2006). Loss of cholinergic and dopaminergic amacrine cells in streptozotocin-diabetic rat and Ins2Akita-diabetic mouse retinas. Investigative Ophthalmology & Visual Science 47, 3143–3150.CrossRefGoogle ScholarPubMed
Georgakopoulos, C.D., Eliopoulou, M.I., Exarchou, A.M., Tzimis, V., Pharmakakis, N.M. & Spiliotis, B.E. (2011). Decreased contrast sensitivity in children and adolescents with type 1 diabetes mellitus. Journal of Pediatric Ophthalmology and Strabismus 48, 92–97.CrossRefGoogle ScholarPubMed
German, O.L., Miranda, G.E., Abrahan, C.E. & Rotstein, N.P. (2006). Ceramide is a mediator of apoptosis in retina photoreceptors. Investigative Ophthalmology & Visual Science 47, 1658–1668.CrossRefGoogle ScholarPubMed
Giacco, F. & Brownlee, M. (2010). Oxidative stress and diabetic complications. Circulation Research 107, 1058–1070.CrossRefGoogle ScholarPubMed
Graham, M.L., Janecek, J.L., Kittredge, J.A., Hering, B.J. & Schuurman, H.J. (2011). The streptozotocin-induced diabetic nude mouse model: Differences between animals from different sources. Comparative Medine 61, 356–360.Google ScholarPubMed
Granit, R. (1933). The components of the retinal action potential in mammals and their relation to the discharge in the optic nerve. Journal of Physiology 77, 207–239.CrossRefGoogle ScholarPubMed
Greenstein, V., Sarter, B., Hood, D., Noble, K. & Carr, R. (1990). Hue discrimination and S cone pathway sensitivity in early diabetic retinopathy. Investigative Ophthalmology & Visual Science 31, 1008–1014.Google ScholarPubMed
Gurley, S.B., Clare, S.E., Snow, K.P., Hu, A., Meyer, T.W. & Coffman, T.M. (2006). Impact of genetic background on nephropathy in diabetic mice. American Journal of Physiology – Renal Physiology 290, F214–222.CrossRefGoogle ScholarPubMed
Hammad, S.M., Baker, N.L., El Abiad, J.M., Spassieva, S.D., Pierce, J.S., Rembiesa, B., Bielawski, J., Lopes-Virella, M.F., Klein, R.L. & Investigators, D.E.G.o. (2017). Increased plasma levels of select deoxy-ceramide and ceramide species are associated with increased odds of diabetic neuropathy in type 1 diabetes: A pilot study. Neuromolecular Medicine 19, 46–56.CrossRefGoogle ScholarPubMed
Hammer, S.S. & Busik, J.V. (2017). The role of dyslipidemia in diabetic retinopathy. Vision Reserach 139, 228–236.CrossRefGoogle ScholarPubMed
Han, G., Wood, J.P., Chidlow, G., Mammone, T. & Casson, R.J. (2013). Mechanisms of neuroprotection by glucose in rat retinal cell cultures subjected to respiratory inhibition. Investigative Ophthalmology & Visual Science 54, 7567–7577.CrossRefGoogle ScholarPubMed
Hao, W., Wenzel, A., Obin, M.S., Chen, C.K., Brill, E., Krasnoperova, N.V., Eversole-Cire, P., Kleyner, Y., Taylor, A., Simon, M.I., Grimm, C., Remé, C.E. & Lem, J. (2002). Evidence for two apoptotic pathways in light-induced retinal degeneration. Nature Genetics 32, 254–260.CrossRefGoogle ScholarPubMed
Harrison, W.W., Bearse, M.A., Ng, J.S., Jewell, N.P., Barez, S., Burger, D., Schneck, M.E. & Adams, A.J. (2011). Multifocal electroretinograms predict onset of diabetic retinopathy in adult patients with diabetes. Investigative Ophthalmology & Visual Science 52, 772–777.CrossRefGoogle ScholarPubMed
Haus, J.M., Kashyap, S.R., Kasumov, T., Zhang, R., Kelly, K.R., Defronzo, R.A. & Kirwan, J.P. (2009). Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes 58, 337–343.CrossRefGoogle ScholarPubMed
Henson, D.B. & North, R.V. (1979). Dark adaptation in diabetes mellitus. British Journal of Ophthalmology 63, 539–541.CrossRefGoogle ScholarPubMed
Hoang, Q.V., Linsenmeier, R.A., Chung, C.K. & Curcio, C.A. (2002). Photoreceptor inner segments in monkey and human retina: Mitochondrial density, optics, and regional variation. Visual Neuroscience 19, 395–407.CrossRefGoogle ScholarPubMed
Holfort, S.K., Jackson, G.R. & Larsen, M. (2010a). Dark adaptation during transient hyperglycemia in type 2 diabetes. Experimental Eye Research 91, 710–714.CrossRefGoogle Scholar
Holfort, S.K., Klemp, K., Kofoed, P.K., Sander, B. & Larsen, M. (2010b). Scotopic electrophysiology of the retina during transient hyperglycemia in type 2 diabetes. Investigative Ophthalmology & Visual Science 51, 2790–2794.CrossRefGoogle Scholar
Holfort, S.K., Nørgaard, K., Jackson, G.R., Hommel, E., Madsbad, S., Munch, I.C., Klemp, K., Sander, B. & Larsen, M. (2011). Retinal function in relation to improved glycaemic control in type 1 diabetes. Diabetologia 54, 1853–1861.CrossRefGoogle ScholarPubMed
Holopigian, K., Greenstein, V.C., Seiple, W., Hood, D.C. & Carr, R.E. (1997). Evidence for photoreceptor changes in patients with diabetic retinopathy. Investigative Ophthalmology & Visual Science 38, 2355–2365.Google ScholarPubMed
Holopigian, K., Seiple, W., Lorenzo, M. & Carr, R. (1992). A comparison of photopic and scotopic electroretinographic changes in early diabetic retinopathy. Investigative Ophthalmology & Visual Science 33, 2773–2780.Google ScholarPubMed
Hombrebueno, J.R., Chen, M., Penalva, R.G. & Xu, H. (2014). Loss of synaptic connectivity, particularly in second order neurons is a key feature of diabetic retinal neuropathy in the Ins2Akita mouse. PLoS One 9, e97970.CrossRefGoogle ScholarPubMed
Hudson, C., Flanagan, J.G., Turner, G.S., Chen, H.C., Young, L.B. & McLeod, D. (1998). Short-wavelength sensitive visual field loss in patients with clinically significant diabetic macular oedema. Diabetologia 41, 918–928.CrossRefGoogle ScholarPubMed
Iliescu, D.A., Ciubotaru, A., Ghiţă, M.A., Dumitru, A. & Zăgrean, L. (2018). Effect of sevoflurane preconditioning on light-induced retinal damage in diabetic rats. Romanian Journal of Ophthalmology 62, 24–33.CrossRefGoogle ScholarPubMed
Januschowski, K., Müller, S., Krupp, C., Spitzer, M.S., Hurst, J., Schultheiss, M., Bartz-Schmidt, K.U., Szurman, P. & Schnichels, S. (2015). Glutamate and hypoxia as a stress model for the isolated perfused vertebrate retina. Journal of Visualized Experiments 22, 52270.Google Scholar
Jiang, Y., Liu, L., Hainan, L., Wang, J.-M. & Steinle, J.J. (2019). Insulin signal transduction is impaired in the type 2 diabetic retina. bioRxiv.CrossRefGoogle Scholar
Jiang, Y., Thakran, S., Bheemreddy, R., Ye, E.A., He, H., Walker, R.J. & Steinle, J.J. (2014). Pioglitazone normalizes insulin signaling in the diabetic rat retina through reduction in tumor necrosis factor α and suppressor of cytokine signaling 3. Journal of Biological Chemistry 289, 26395–26405.CrossRefGoogle ScholarPubMed
Johnson, L.E., Larsen, M. & Perez, M.T. (2013). Retinal adaptation to changing glycemic levels in a rat model of type 2 diabetes. PLoS One 8, e55456.CrossRefGoogle Scholar
Jomary, C., Cullen, J. & Jones, S.E. (2006). Inactivation of the Akt survival pathway during photoreceptor apoptosis in the retinal degeneration mouse. Investigative Ophthalmology & Visual Science 47, 1620–1629.CrossRefGoogle ScholarPubMed
Kady, N.M., Liu, X., Lydic, T.A., Syed, M.H., Navitskaya, S., Wang, Q., Hammer, S.S., O'Reilly, S., Huang, C., Seregin, S.S., Amalfitano, A., Chiodo, V.A., Boye, S.L., Hauswirth, W.W., Antonetti, D.A. & Busik, J.V. (2018). ELOVL4-mediated production of very long-chain ceramides stabilizes tight junctions and prevents diabetes-induced retinal vascular permeability. Diabetes 67, 769–781.CrossRefGoogle ScholarPubMed
Kang Derwent, J.J. & Linsenmeier, R.A. (2001). Hypoglycemia increases the sensitivity of the cat electroretinogram to hypoxemia. Visual Neuroscience 18, 983–993.CrossRefGoogle ScholarPubMed
Kern, T.S. & Berkowitz, B.A. (2015). Photoreceptors in diabetic retinopathy. Journal of Diabetes Investigation 6, 371–380.CrossRefGoogle ScholarPubMed
Kim, Y.H., Kim, Y.S., Noh, H.S., Kang, S.S., Cheon, E.W., Park, S.K., Lee, B.J., Choi, W.S. & Cho, G.J. (2005). Changes in rhodopsin kinase and transducin in the rat retina in early-stage diabetes. Experimental Eye Research 80, 753–760.CrossRefGoogle ScholarPubMed
Kirwin, S.J., Kanaly, S.T., Linke, N.A. & Edelman, J.L. (2009). Strain-dependent increases in retinal inflammatory proteins and photoreceptor FGF-2 expression in streptozotocin-induced diabetic rats. Investigative Ophthalmology & Visual Science 50, 5396–5404.CrossRefGoogle ScholarPubMed
Klemp, K., Larsen, M., Sander, B., Vaag, A., Brockhoff, P.B. & Lund-Andersen, H. (2004). Effect of short-term hyperglycemia on multifocal electroretinogram in diabetic patients without retinopathy. Investigative Ophthalmology & Visual Science 45, 3812–3819.CrossRefGoogle ScholarPubMed
Klemp, K., Sander, B., Brockhoff, P.B., Vaag, A., Lund-Andersen, H. & Larsen, M. (2005). The multifocal ERG in diabetic patients without retinopathy during euglycemic clamping. Investigative Ophthalmology & Visual Science 46, 2620–2626.CrossRefGoogle ScholarPubMed
Kohzaki, K., Vingrys, A.J. & Bui, B.V. (2008). Early inner retinal dysfunction in streptozotocin-induced diabetic rats. Investigative Ophthalmology & Visual Science 49, 3595–3604.CrossRefGoogle ScholarPubMed
Kong, H., Ren, X., Zhang, H., Wang, N., Zhang, C., Li, L., Xia, X., Kong, L., Zhang, M. & Xu, M. (2019). Thioredoxin is a potential therapy for light-induced photoreceptor degeneration in diabetic mice. Neuro Endocrinology Letters 39, 561–566.Google ScholarPubMed
Kowluru, R.A. & Chan, P.S. (2007). Oxidative stress and diabetic retinopathy. Experimental Diabetes Research 2007, 43603.CrossRefGoogle ScholarPubMed
Kumar, B., Gupta, S.K., Srinivasan, B.P., Nag, T.C., Srivastava, S., Saxena, R. & Jha, K.A. (2013). Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvascular Research 87, 65–74.CrossRefGoogle ScholarPubMed
Kur, J., Burian, M.A. & Newman, E.A. (2016). Light adaptation does not prevent early retinal abnormalities in diabetic rats. Scientific Reports 6, 21075.CrossRefGoogle Scholar
Kurtenbach, A., Mayser, H.M., Jägle, H., Fritsche, A. & Zrenner, E. (2006). Hyperoxia, hyperglycemia, and photoreceptor sensitivity in normal and diabetic subjects. Visual Neuroscience 23, 651–661.CrossRefGoogle ScholarPubMed
Lau, J.C. & Linsenmeier, R.A. (2014). Increased intraretinal PO2 in short-term diabetic rats. Diabetes 63, 4338–4342.CrossRefGoogle ScholarPubMed
Layton, C.J. (2015). Diabetic levels of glucose increase cellular reducing equivalents but reduce survival in three models of 661W photoreceptor-like cell injury. BMC Ophthalmology 15, 174.CrossRefGoogle ScholarPubMed
Lecleire-Collet, A., Audo, I., Aout, M., Girmens, J.F., Sofroni, R., Erginay, A., Le Gargasson, J.F., Mohand-Saïd, S., Meas, T., Guillausseau, P.J., Vicaut, E., Paques, M. & Massin, P. (2011). Evaluation of retinal function and flicker light-induced retinal vascular response in normotensive patients with diabetes without retinopathy. Investigative Ophthalmology & Visual Science 52, 2861–2867.CrossRefGoogle ScholarPubMed
Leskova, W., Watts, M.N., Carter, P.R., Eshaq, R.S. & Harris, N.R. (2013). Measurement of retinal blood flow rate in diabetic rats: Disparity between techniques due to redistribution of flow. Investigative Ophthalmology & Visual Science 54, 2992–2999.CrossRefGoogle Scholar
Lin, Y.B., Liu, J.H. & Chang, Y. (2012). Hypoxia reduces the effect of photoreceptor bleaching. Journal of Physiological Sciences 62, 309–315.CrossRefGoogle ScholarPubMed
Linsenmeier, R.A., Braun, R.D., McRipley, M.A., Padnick, L.B., Ahmed, J., Hatchell, D.L., McLeod, D.S. & Lutty, G.A. (1998). Retinal hypoxia in long-term diabetic cats. Investigative Ophthalmology & Visual Science 39, 1647–1657.Google ScholarPubMed
Liu, H., Tang, J., Du, Y., Saadane, A., Samuels, I., Veenstra, A., Kiser, J.Z., Palczewski, K. & Kern, T.S. (2019). Transducin1, phototransduction and the development of early diabetic retinopathy. Investigative Ophthalmology & Visual Science 60, 1538–1546.CrossRefGoogle ScholarPubMed
Liu, H., Tang, J., Du, Y., Saadane, A., Tonade, D., Samuels, I., Veenstra, A., Palczewski, K. & Kern, T.S. (2016). Photoreceptor cells influence retinal vascular degeneration in mouse models of retinal degeneration and diabetes. Investigative Ophthalmology & Visual Science 57, 4272–4281.CrossRefGoogle ScholarPubMed
Lovasik, J.V. & Spafford, M.M. (1988). An electrophysiological investigation of visual function in juvenile insulin-dependent diabetes mellitus. American Journal of Optometry and Physiological Optics 65, 236–253.CrossRefGoogle ScholarPubMed
Luu, C.D., Szental, J.A., Lee, S.Y., Lavanya, R. & Wong, T.Y. (2010). Correlation between retinal oscillatory potentials and retinal vascular caliber in type 2 diabetes. Investigative Ophthalmology & Visual Science 51, 482–486.CrossRefGoogle ScholarPubMed
Macaluso, C., Onoe, S. & Niemeyer, G. (1992). Changes in glucose level affect rod function more than cone function in the isolated, perfused cat eye. Investigative Ophthalmology & Visual Science 33, 2798–2808.Google ScholarPubMed
Malechka, V.V., Moiseyev, G., Takahashi, Y., Shin, Y. & Ma, J.X. (2017). Impaired rhodopsin generation in the rat model of diabetic retinopathy. American Journal of Pathology 187, 2222–2231.CrossRefGoogle ScholarPubMed
Martin, P.M., Roon, P., Van Ells, T.K., Ganapathy, V. & Smith, S.B. (2004). Death of retinal neurons in streptozotocin-induced diabetic mice. Investigative Ophthalmology & Visual Science 45, 3330–3336.CrossRefGoogle ScholarPubMed
Matteucci, A., Varano, M., Mallozzi, C., Gaddini, L., Villa, M., Gabrielli, S., Formisano, G., Pricci, F. & Malchiodi-Albedi, F. (2015). Primary retinal cultures as a tool for modeling diabetic retinopathy: An overview. BioMed Research International 2015, 364924.CrossRefGoogle ScholarPubMed
Naeser, P. (1997). Insulin receptors in human ocular tissues. Immunohistochemical demonstration in normal and diabetic eyes. Upsala Journal of Medical Sciences 102, 35–40.CrossRefGoogle ScholarPubMed
Nair, G., Kim, M., Nagaoka, T., Olson, D.E., Thulé, P.M., Pardue, M.T. & Duong, T.Q. (2011). Effects of common anesthetics on eye movement and electroretinogram. Documenta Ophthalmologica 122, 163–176.CrossRefGoogle ScholarPubMed
Narayan, D.S., Chidlow, G., Wood, J.P. & Casson, R.J. (2017). Glucose metabolism in mammalian photoreceptor inner and outer segments. Journal of Clinical and Experimental Ophthalmology 45, 730–741.CrossRefGoogle ScholarPubMed
Natoli, R., Fernando, N., Dahlenburg, T., Jiao, H., Aggio-Bruce, R., Barnett, N.L., Chao de la Barca, J.M., Tcherkez, G., Reynier, P., Fang, J., Chu-Tan, J.A., Valter, K., Provis, J. & Rutar, M. (2018). Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment. Molecular Vision 24, 201–217.Google ScholarPubMed
Nesper, P.L., Scarinci, F. & Fawzi, A.A. (2017). Adaptive optics reveals photoreceptor abnormalities in diabetic macular ischemia. PLoS One 12, e0169926.CrossRefGoogle ScholarPubMed
Ng, J.S., Bearse, M.A., Schneck, M.E., Barez, S. & Adams, A.J. (2008). Local diabetic retinopathy prediction by multifocal ERG delays over 3 years. Investigative Ophthalmology & Visual Science 49, 1622–1628.CrossRefGoogle ScholarPubMed
Ng, S.K., Wood, J.P., Chidlow, G., Han, G., Kittipassorn, T., Peet, D.J. & Casson, R.J. (2015). Cancer-like metabolism of the mammalian retina. Journal of Clinical and Experimental Ophthalmology 43, 367–376.CrossRefGoogle ScholarPubMed
Opreanu, M., Tikhonenko, M., Bozack, S., Lydic, T.A., Reid, G.E., McSorley, K.M., Sochacki, A., Perez, G.I., Esselman, W.J., Kern, T., Kolesnick, R., Grant, M.B. & Busik, J.V. (2011). The unconventional role of acid sphingomyelinase in regulation of retinal microangiopathy in diabetic human and animal models. Diabetes 60, 2370–2378.CrossRefGoogle ScholarPubMed
Organisciak, D.T. & Vaughan, D.K. (2010). Retinal light damage: Mechanisms and protection. Progress in Retinal Eye Research 29, 113–134.CrossRefGoogle ScholarPubMed
Ostroy, S.E., Frede, S.M., Wagner, E.F., Gaitatzes, C.G. & Janle, E.M. (1994). Decreased rhodopsin regeneration in diabetic mouse eyes. Investigative Ophthalmology & Visual Science 35, 3905–3909.Google ScholarPubMed
Owsley, C., McGwin, G., Clark, M.E., Jackson, G.R., Callahan, M.A., Kline, L.B., Witherspoon, C.D. & Curcio, C.A. (2016). Delayed rod-mediated dark adaptation is a functional biomarker for incident early age-related macular degeneration. Ophthalmology 123, 344–351.CrossRefGoogle ScholarPubMed
Park, S.H., Park, J.W., Park, S.J., Kim, K.Y., Chung, J.W., Chun, M.H. & Oh, S.J. (2003). Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina. Diabetologia 46, 1260–1268.CrossRefGoogle ScholarPubMed
Phipps, J.A., Fletcher, E.L. & Vingrys, A.J. (2004). Paired-flash identification of rod and cone dysfunction in the diabetic rat. Investigative Ophthalmology & Visual Science 45, 4592–4600.CrossRefGoogle ScholarPubMed
Phipps, J.A., Yee, P., Fletcher, E.L. & Vingrys, A.J. (2006). Rod photoreceptor dysfunction in diabetes: Activation, deactivation, and dark adaptation. Investigative Ophthalmology & Visual Science 47, 3187–3194.CrossRefGoogle ScholarPubMed
Piano, I., Novelli, E., Della Santina, L., Strettoi, E., Cervetto, L. & Gargini, C. (2016). Involvement of autophagic pathway in the progression of retinal degeneration in a mouse model of diabetes. Frontiers in Cellular Neuroscience 10, 42.CrossRefGoogle Scholar
Puro, D.G. (2002). Diabetes-induced dysfunction of retinal Müller cells. Transactions of the American Ophthalmological Society 100, 339–352.Google ScholarPubMed
Rajagopal, R., Bligard, G.W., Zhang, S., Yin, L., Lukasiewicz, P. & Semenkovich, C.F. (2016). Functional deficits precede structural lesions in mice with high-fat diet-induced diabetic retinopathy. Diabetes 65, 1072–1084.CrossRefGoogle ScholarPubMed
Rajala, A., Anderson, R.E., Ma, J.X., Lem, J., Al-Ubaidi, M.R. & Rajala, R.V. (2007). G-protein-coupled receptor rhodopsin regulates the phosphorylation of retinal insulin receptor. Journal of Biological Chemistry 282, 9865–9873.CrossRefGoogle ScholarPubMed
Rajala, A., Tanito, M., Le, Y.Z., Kahn, C.R. & Rajala, R.V. (2008). Loss of neuroprotective survival signal in mice lacking insulin receptor gene in rod photoreceptor cells. Journal of Biological Chemistry 283, 19781–19792.CrossRefGoogle ScholarPubMed
Rajala, R.V. & Anderson, R.E. (2010). Rhodopsin-regulated insulin receptor signaling pathway in rod photoreceptor neurons. Molecular Neurobiology 42, 39–47.CrossRefGoogle ScholarPubMed
Rajala, R.V., McClellan, M.E., Ash, J.D. & Anderson, R.E. (2002). In vivo regulation of phosphoinositide 3-kinase in retina through light-induced tyrosine phosphorylation of the insulin receptor beta-subunit. Journal of Biological Chemistry 277, 43319–43326.CrossRefGoogle ScholarPubMed
Regatieri, C.V., Branchini, L., Carmody, J., Fujimoto, J.G. & Duker, J.S. (2012). Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina 32, 563–568.CrossRefGoogle ScholarPubMed
Reiter, C.E., Sandirasegarane, L., Wolpert, E.B., Klinger, M., Simpson, I.A., Barber, A.J., Antonetti, D.A., Kester, M. & Gardner, T.W. (2003). Characterization of insulin signaling in rat retina in vivo and ex vivo. American Journal of Physiology – Endocrinology and Metabolism 285, E763–774.CrossRefGoogle ScholarPubMed
Reiter, C.E., Wu, X., Sandirasegarane, L., Nakamura, M., Gilbert, K.A., Singh, R.S., Fort, P.E., Antonetti, D.A. & Gardner, T.W. (2006). Diabetes reduces basal retinal insulin receptor signaling: Reversal with systemic and local insulin. Diabetes 55, 1148–1156.CrossRefGoogle ScholarPubMed
Ren, X., Li, C., Liu, J., Zhang, C., Fu, Y., Wang, N., Ma, H., Lu, H., Kong, H. & Kong, L. (2017). Thioredoxin plays a key role in retinal neuropathy prior to endothelial damage in diabetic mice. Oncotarget 8, 61350–61364.CrossRefGoogle Scholar
Rockett, M., Anderle, D. & Bessman, A.N. (1987). Blue-yellow vision deficits in patients with diabetes. Western Journal of Medicine 146, 431–433.Google ScholarPubMed
Rodrigues, M., Waldbillig, R.J., Rajagopalan, S., Hackett, J., LeRoith, D. & Chader, G.J. (1988). Retinal insulin receptors: Localization using a polyclonal anti-insulin receptor antibody. Brain Research 443, 389–394.CrossRefGoogle ScholarPubMed
Roy, M.S., Gunkel, R.D. & Podgor, M.J. (1986). Color vision defects in early diabetic retinopathy. Archives of Ophthalmology 104, 225–228.CrossRefGoogle ScholarPubMed
Salido, E.M., de Zavalía, N., Schreier, L., De Laurentiis, A., Rettori, V., Chianelli, M., Keller Sarmiento, M.I., Arias, P. & Rosenstein, R.E. (2012). Retinal changes in an experimental model of early type 2 diabetes in rats characterized by non-fasting hyperglycemia. Experimental Neurology 236, 151–160.CrossRefGoogle Scholar
Sas, K.M., Lin, J., Rajendiran, T.M., Soni, T., Nair, V., Hinder, L.M., Jagadish, H.V., Gardner, T.W., Abcouwer, S.F., Brosius, F.C., Feldman, E.L., Kretzler, M., Michailidis, G. & Pennathur, S. (2018). Shared and distinct lipid-lipid interactions in plasma and affected tissues in a diabetic mouse model. Journal of Lipid Research 59, 173–183.CrossRefGoogle Scholar
Scott, G.I. (1953). Ocular complications of diabetes mellitus. British Journal of Ophthalmology 37, 705–715.CrossRefGoogle ScholarPubMed
Sharma, S., Saxena, S., Srivastav, K., Shukla, R.K., Mishra, N., Meyer, C.H., Kruzliak, P. & Khanna, V.K. (2015). Nitric oxide and oxidative stress is associated with severity of diabetic retinopathy and retinal structural alterations. Clinical and Experimental Ophthalmology 43, 429–436.CrossRefGoogle ScholarPubMed
Shinoda, K., Rejdak, R., Schuettauf, F., Blatsios, G., Völker, M., Tanimoto, N., Olcay, T., Gekeler, F., Lehaci, C., Naskar, R., Zagorski, Z. & Zrenner, E. (2007). Early electroretinographic features of streptozotocin-induced diabetic retinopathy. Clinical and Experimental Ophthalmology 35, 847–854.CrossRefGoogle ScholarPubMed
Sivaprasad, S., Vasconcelos, J.C., Prevost, A.T., Holmes, H., Hykin, P., George, S., Murphy, C., Kelly, J., Arden, G.B. & Group, C. S. (2018). Clinical efficacy and safety of a light mask for prevention of dark adaptation in treating and preventing progression of early diabetic macular oedema at 24 months (CLEOPATRA): A multicentre, phase 3, randomised controlled trial. Lancet Diabetes and Endocrinology 6, 382–391.CrossRefGoogle ScholarPubMed
Sohn, E.H., van Dijk, H.W., Jiao, C., Kok, P.H., Jeong, W., Demirkaya, N., Garmager, A., Wit, F., Kucukevcilioglu, M., van Velthoven, M.E., DeVries, J.H., Mullins, R.F., Kuehn, M.H., Schlingemann, R.O., Sonka, M., Verbraak, F.D. & Abràmoff, M.D. (2016). Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus. Proceedings of the National Academy of Sciences of the United States of America 113, E2655–2664.CrossRefGoogle ScholarPubMed
Sokol, S., Moskowitz, A., Skarf, B., Evans, R., Molitch, M. & Senior, B. (1985). Contrast sensitivity in diabetics with and without background retinopathy. Archives of Ophthalmology 103, 51–54.CrossRefGoogle ScholarPubMed
Sokolowska, E. & Blachnio-Zabielska, A. (2019). The role of ceramides in insulin resistance. Frontiers in Endocrinology (Lausanne) 10, 577.CrossRefGoogle ScholarPubMed
Stem, M.S., Dunbar, G.E., Jackson, G.R., Farsiu, S., Pop-Busui, R. & Gardner, T.W. (2016). Glucose variability and inner retinal sensory neuropathy in persons with type 1 diabetes mellitus. Eye (Lond) 30, 825–832.CrossRefGoogle ScholarPubMed
Sternberg, P., Landers, M.B. & Wolbarsht, M. (1984). The negative coincidence of retinitis pigmentosa and proliferative diabetic retinopathy. American Journal of Ophthalmology 97, 788–789.CrossRefGoogle ScholarPubMed
Stitt, A.W., Curtis, T.M., Chen, M., Medina, R.J., McKay, G.J., Jenkins, A., Gardiner, T.A., Lyons, T.J., Hammes, H.P., Simó, R. & Lois, N. (2016). The progress in understanding and treatment of diabetic retinopathy. Progress in Retinal and Eye Research 51, 156–186.CrossRefGoogle ScholarPubMed
Strettoi, E., Gargini, C., Novelli, E., Sala, G., Piano, I., Gasco, P. & Ghidoni, R. (2010). Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa. Proceedings of the National Academy of Sciences of the United States of America 107, 18706–18711.CrossRefGoogle Scholar
Szabó, K., Énzsöly, A., Dékány, B., Szabó, A., Hajdú, R.I., Radovits, T., Mátyás, C., Oláh, A., Laurik, L.K., Somfai, G.M., Merkely, B., Szél, Á. & Lukáts, Á. (2017). Histological evaluation of diabetic neurodegeneration in the retina of zucker diabetic fatty (ZDF) rats. Scientific Reports 7, 8891.CrossRefGoogle ScholarPubMed
Sánchez-Chávez, G., Peña-Rangel, M.T., Riesgo-Escovar, J.R., Martínez-Martínez, A. & Salceda, R. (2012). Insulin stimulated-glucose transporter Glut 4 is expressed in the retina. PLoS One 7, e52959.CrossRefGoogle ScholarPubMed
Tan, N.C., Yip, W.F., Kallakuri, S., Sankari, U. & Koh, Y.L.E. (2017). Factors associated with impaired color vision without retinopathy amongst people with type 2 diabetes mellitus: A cross-sectional study. BMC Endocrine Disorders 17, 29.CrossRefGoogle ScholarPubMed
Tang, J., Du, Y., Lee, C.A., Talahalli, R., Eells, J.T. & Kern, T.S. (2013). Low-intensity far-red light inhibits early lesions that contribute to diabetic retinopathy: in vivo and in vitro. Investigative Ophthalmology & Visual Science 54, 3681–3690.CrossRefGoogle ScholarPubMed
Tanvir, Z., Nelson, R.F., DeCicco-Skinner, K. & Connaughton, V.P. (2018). One month of hyperglycemia alters spectral responses of the zebrafish photopic electroretinogram. Disease Models & Mechanisms 11.CrossRefGoogle ScholarPubMed
Tarchick, M.J., Bassiri, P., Rohwer, R.M. & Samuels, I.S. (2016). Early functional and morphologic abnormalities in the diabetic nyxnob mouse retina. Investigative Ophthalmology & Visual Science 57, 3496–3508.CrossRefGoogle ScholarPubMed
The Diabetic Retinopathy Study Research Group. (1981). Photocoagulation treatment of proliferative diabetic retinopathy: clinical applications of diabetic retinopathy study (DRS) findings, DRS report number 8. Ophthalmology 88(7), 583–600.CrossRefGoogle Scholar
Thebeau, C., Zhang, S., Kolesnikov, A.V., Kefalov, V.J., Semenkovich, C.F. & Rajagopal, R. (2020). Light deprivation reduces the severity of experimental diabetic retinopathy. Neurobiology of Disease 137, 104754.CrossRefGoogle ScholarPubMed
Tomlinson, D.R. & Gardiner, N.J. (2008). Glucose neurotoxicity. Nature Reviews Neuroscience 9, 36–45.CrossRefGoogle ScholarPubMed
Tonade, D. & Kern, T.S. (2017). Diabetes of 5 years duration does not lead to photoreceptor degeneration in the canine non-tapetal inferior-nasal retina. Experimental Eye Research 162, 126–128.CrossRefGoogle Scholar
Vicente-Tejedor, J., Marchena, M., Ramírez, L., García-Ayuso, D., Gómez-Vicente, V., Sánchez-Ramos, C., de la Villa, P. & Germain, F. (2018). Removal of the blue component of light significantly decreases retinal damage after high intensity exposure. PLoS One 13, e0194218.CrossRefGoogle ScholarPubMed
Vinberg, F. & Kefalov, V. (2015). Simultaneous ex vivo functional testing of two retinas by in vivo electroretinogram system. Journal of Visualized Experiments 99, e52855.Google Scholar
Waldbillig, R.J., Fletcher, R.T., Chader, G.J., Rajagopalan, S., Rodrigues, M. & LeRoith, D. (1987). Retinal insulin receptors. 2. Characterization and insulin-induced tyrosine kinase activity in bovine retinal rod outer segments. Experimental Eye Research 45, 837–844.CrossRefGoogle ScholarPubMed
Wang, J.S. & Kefalov, V.J. (2009). An alternative pathway mediates the mouse and human cone visual cycle. Current Biology 19, 1665–1669.CrossRefGoogle ScholarPubMed
Wolff, B.E., Bearse, M.A., Schneck, M.E., Dhamdhere, K., Harrison, W.W., Barez, S. & Adams, A.J. (2015). Color vision and neuroretinal function in diabetes. Documenta Ophthalmology 130, 131–139.CrossRefGoogle ScholarPubMed
Woodruff, M.L., Rajala, A., Fain, G.L. & Rajala, R.V. (2015). Effect of knocking down the insulin receptor on mouse rod responses. Scientific Reports 5, 7858.CrossRefGoogle ScholarPubMed
Yang, Q., Xu, Y., Xie, P., Cheng, H., Song, Q., Su, T., Yuan, S. & Liu, Q. (2015). Retinal neurodegeneration in db/db mice at the early period of diabetes. Journal of Ophthalmology 2015, 757412.CrossRefGoogle ScholarPubMed
Yu, D.Y. & Cringle, S.J. (2001). Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Progress in Retinal and Eye Research 20, 175–208.CrossRefGoogle ScholarPubMed
Zhang, J., Wu, L., Chen, J., Lin, S., Cai, D., Chen, C. & Chen, Z. (2018). Downregulation of MicroRNA 29a/b exacerbated diabetic retinopathy by impairing the function of Müller cells via Forkhead box protein O4. Diabetes and Vascular Disease Research 15, 214–222.CrossRefGoogle ScholarPubMed