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Published in:

01-02-2012 | Review Article

The pathogenesis of early retinal changes of diabetic retinopathy

Authors: G. B. Arden, S. Sivaprasad

Published in: Documenta Ophthalmologica | Issue 1/2012

Abstract

Recent successful trials of antibodies to vascular endothelial growth factor (VEGF) in diabetic retinopathy implicate this cytokine as a major cause of diabetic retinopathy (DR) and diabetic macular oedema (DME). The mechanisms which cause VEGF to be over-expressed to cause the vasculopathy are not entirely clear. This review explores the earliest changes to the retina in DR and the factors that predispose or prevent DR, including sleep apnoea, receptor degenerations laser treatment and VEGF polymorphism. The review also presents the evidence that retinal hypoxia, existing in the earliest stages, causes DR. This hypoxia is much increased by dark adaptation, indicating a new and possibly superior therapy.

Massin P, Bandello F, Garweg JG, Hansen LL, Harding SP, Larsen M, Mitchell P, Sharp D, Wolf-Schnurrbusch UE, Gekkieva M, Weichselberger A, Wolf S (2010) Safety and efficacy of ranibizumab in diabetic macular oedema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care 33:2399–2405PubMedCrossRef

Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, Ferris FL 3rd, Friedman SM, Glassman AR, Miller KM, Scott IU, Stockdale CR, Sun JK (2010) Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular oedema. Ophthalmology 117:1064–1077PubMedCrossRef

Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, Boos CJ, Xing W, Egan C, Peto T, Bunce C, Leslie RD, Hykin PG (2010) A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular oedema (BOLT study) 12-month data: report 2. Ophthalmology 117:1078–1086PubMedCrossRef

Madsen-Bouterse SA, Kowluru RA (2008) Oxidative stress and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Rev Endocr Metab Disord 9:315–327PubMedCrossRef

Droge W (2002) Free radicals and the physiological control of cell function. Physiol Rev 83:47–95

Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625PubMedCrossRef

Kowluru RA, Chan P-S (2007) Oxidative stress and diabetic retinopathy. Exp Diabetes Res 43603

Kowluru RA, Atasi L, Ho YS (2006) Role of mitochondrial superoxide dismutase in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci 47:1594–1599PubMedCrossRef

Clermont AC, Aiello LP, Mori F, Aiello LM, Bursell SE (1997) Vascular endothelial growth factor and severity of nonproliferative diabetic retinopathy mediate retinal hemodynamics in vivo: a potential role for vascular endothelial growth factor in the progression of non-proliferative diabetic retinopathy. Am J Ophthalmol 124:433–446PubMed

10.

Feit-Leichman RA, Kinouchi R, Takeda M, Fan Z, Mohr S, Kern TS, Chen DF (2005) Vascular damage in a mouse model of diabetic retinopathy: relation to neuronal and glial changes. Invest Ophthalmol Vis Sci 46:4281–4287PubMedCrossRef

11.

Segawa Y, Shirao Y, Yamagishi S, Higashide T, Kobayashi M, Katsuno K, Iyobe A, Harada H, Sato F, Miyata H, Asai H, Nishimura A, Takahira M, Souno T, Segawa Y, Maeda K, Shima K, Mizuno A, Yamamoto H, Kawasaki K (1998) Upregulation of vascular endothelial growth factor mRNAs in spontaneously diabetic rats without ophthalmoscopic retinopathy. A possible participation of advanced glycation end products in the early phase of diabetic retinopathy. Ophthalmic Res 30:333–339PubMedCrossRef

12.

Kern TS, Engerman RL (1996) Capillary lesions develop in retina rather than cerebral cortex in diabetes and experimental galactosemia. Arch Ophthalmol 114:306–310PubMedCrossRef

13.

Busik JV, Mohr S, Grant MB (2008) Hyperglycaemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators. Diabetes 57:1952–1965PubMedCrossRef

14.

Barber AJ, Lieth E, Khin SA, Antonetti DA, Buchanan AG, Gardner TW (1998) Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin. J Clin Invest 102:783–791PubMedCrossRef

15.

Rungger-Brändle E, Dosso AA, Leuenberger PM (2000) Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci 41:1971–1980PubMed

16.

Lieth E, Barber AJ, Xu B, Dice C, Ratz MJ, Tanase D, Strother JM (1998) Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Diabetes 47:815–820PubMedCrossRef

17.

Dowling JE (1987) The retina: an approachable part of the brain. Belknap Press of Harvard University Press, Cambridge, p 282

18.

Warburg O (1927) Uber die Klassifizierung tierischer Gewebe nach ihrem Stoffwechsel. Biochem Z 184:484–488

19.

McFarland RA, Evans JN (1939) Dark adaptation and reduced oxygen tension. Am J Physiol 127:37–50

20.

McFarland RA, Forbes WH (1940) The effects of variations in the concentration of oxygen and of glucose on dark adaptation. J Gen Physiol 24:69–98PubMedCrossRef

21.

HechtS HendleyCD, Frank SR, Haig CJ (1946) Anoxia and brightness discrimination. Gen Physiol 29:335–351CrossRef

22.

Havelius U, Bergqvist D, Hindfelt B et al (1997) Improved dark adaptation after carotid endarterectomy. Evidence of a long-term ischaemic penumbra. Neurology 49:1360–1364PubMed

23.

Havelius U, Bergqvist D, Falke P, Hindfelt B, Krakau T (1997) Impaired dark adaptation in symptomatic carotid artery disease. Neurology 49:1353–1359PubMed

24.

Havelius U, Berglund S, Falke P, Hindfelt B, Krakau T (2000) Impaired dark adaptation in polycythaemia. Improvement after treatment. Acta Ophthalmol Scand 78:53–57PubMedCrossRef

25.

Linsenmeier RA (1986) The effect of light and darkness on oxygen distribution and consumption in the cat retina. J Gen Physiol 88:521–542PubMedCrossRef

26.

Braun RD, Linsenmeier RA, Goldstick TK (1995) Oxygen consumption in the inner and outer retina of the cat. Invest Ophthalmol Vis Sci 36:542–554PubMed

27.

Alder VA, Su EN, Yu DY, Cringle SJ, Yu PK (1997) Diabetic retinopathy: early functional changes. Clin Exp Pharmacol Physiol 24:785–830PubMedCrossRef

28.

Cringle S, Yu DY, Alder V, Su EN (1992) Oxygen tension and blood flow in the retina of normal and diabetic rats. Adv Exp Med Biol 317:787–791PubMedCrossRef

29.

Yu DY, Cringle SJ (2001) Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Prog Ret Eye Res 20:175–208CrossRef

30.

Birol G, Wang S, Budzynski E, Wangsa-Wirawan ND, Linsenmeier RA (2007) Oxygen distribution and consumption in the macaque retina. Am J Physiol Heart Circ Physiol 293:H1696–H1704PubMedCrossRef

31.

Linsenmeier RA (2007) Oxygen distribution and consumption in the macaque retina. Am J Physiol Heart Circ Physiol 293:H1696–H1704PubMedCrossRef

32.

Hagins WA, Penn RD, Yoshikami S (1970) Dark current and photocurrent in retinal rods. Biophys J 10:380–412PubMedCrossRef

33.

Pugh ENJ, Nikonov S, Lamb TD (1999) Molecular mechanisms of vertebrate photoreceptor light adaptation. Curr Opin Neurobiol 9:410–418PubMedCrossRef

34.

Demontis GC, Longoni B, Gorgini C, Cervetto L (1997) The energetic cost of phototransduction in retinal rods of some mammals Arch. Ital Biol 109:95–109

35.

Hagins Ross PD, Tate RL, Yoshikami S (1989) Transduction heats in retinal rods: tests of the role of cGMP by pyroelectric calorimetry. Proc Natl Acad Sci USA 86:1224–1228CrossRef

36.

de Gooyer TE, Stevenson KA, Humphries P, Simpson DA, Curtis TM, Gardiner TA, Stitt AW (2006) Rod photoreceptor loss in Rho −/− mice reduces retinal hypoxia and hypoxia-regulated gene expression. Invest Ophthalmol Vis Sci. 47:5553–5560PubMedCrossRef

37.

Cao J, McLeod S, Merges CA, Lutty GA (1998) Choriocapillaris degeneration and related pathologic changes in human diabetic eyes. Arch Ophthalmol 116:589–597PubMed

38.

Dai J, Vrensen GF, Schlingemann RO (2002) Blood-brain barrier integrity is unaltered in human brain cortex with diabetes mellitus. Brain Res 954:311–316PubMedCrossRef

39.

Arden GB, Hall MJ (1995) Does occupational exposure to argon laser radiation decrease colour contrast sensitivity in UK ophthalmologists? Eye 9:686–696PubMedCrossRef

40.

Harris A, Arend O, Danis RP, Evans D, Wolf S, Martin BJ (1996) Hyperoxia improves contrast sensitivity in early diabetic retinopathy. Br J Ophthalmol 80:209–213PubMedCrossRef

41.

Arden GB, Wolf JE, Collier J, Wolff C, Rosenberg M (1999) Dark adaptation is impaired in diabetics before photopic visual losses can be seen. In: Hollyfield et al. (ed) Retinal degenerative diseases and experimental therapy, Ch. 29. Kluwer Academic, Plenumn, pp 305–316

42.

Drasdo N, Chiti Z, Owens DR, North RV (2002) Effect of darkness on inner retinal hypoxia in diabetes. Lancet 359(9325):2251–2253PubMedCrossRef

43.

Juen S, Kieselbach GF (1990) Electrophysiological changes in juvenile diabetics without retinopathy. Arch Ophthalmol 1083:372–375CrossRef

44.

Dean FM, Arden GB, Dornhorst A (1997) Partial reversal of protan and tritan colour defects with inhaled oxygen in insulin dependent diabetic subjects. Br J Ophthalmol 81:27–30PubMedCrossRef

45.

Linsenmeier RA, Braun RD, McRipley MA, Padnick LB, Ahmed J, Hatchell DL, McLeod DS, Lutty GA (1998) Retinal hypoxia in long-term diabetic cats. Invest Ophthalmol Vis Sci 39:1647–1657PubMed

46.

Berkowitz BA, Ito Y, Kern TS, McDonald C, Hawkins R (2001) Correction of early subnormal superior hemiretinal Delta PO(2) predicts therapeutic efficacy in experimental diabetic retinopathy. Invest Ophthalmol Vis Sci 42:2964–2969PubMed

47.

Yu DY, Cringle SJ (2001) Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Prog Retin Eye Res 20:175–208PubMedCrossRef

48.

Patel V, Rassam S, Newsom R, Wiek J, Kohner E (1992) Retinal blood flow in diabetic retinopathy. Br Med J 305:678–683CrossRef

49.

Padnick-Silver L, Linsenmeier RA (2003) Effect of acute hyperglycemia on oxygen and oxidative metabolism in the intact cat retina. Invest Ophthalmol Vis Sci 44:745–750PubMedCrossRef

50.

Arden GB (2001) Absence of diabetic retinopathy in patients with retinitis pigmentosa: implications for pathophysiology and possible treatment. Brit J Ophthalmol 85:366–370CrossRef

51.

Lahdenranta J, Pasqualini R, Schlingemann RO, Hagedorn M, Stallcup WB, Bucana CD, Sidman RL, Arap W (2001) An anti-angiogenic state in mice and humans with retinal photoreceptor cell degeneration. Proc Natl Acad Sci USA 98:10368–10373PubMedCrossRef

52.

Uliss AE, Gregor ZJ, Bird AC (1986) Retinitis pigmentosa and retinal neovascularization. Ophthalmology 93:1599–1603PubMed

53.

Stefansson E (2006) Ocular oxygenation and the treatment of diabetic retinopathy. Surv Ophthalmol 51:364–380PubMedCrossRef

54.

Holmes-Walker DJ, Mitchell P, Boyages SC (1998) Does mitochondrial genome mutation in subjects with maternally inherited diabetes and deafness decrease severity of diabetic retinopathy? Diabet Med 15:946–952PubMedCrossRef

55.

Massin P, Dubois-Laforgue D, Meas T, Laloi-Michelin M, Gin H, GEDIAM (Mitochondrial Diabetes French Study Group) (2008) Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3, 243 (maternally inherited diabetes and deafness). A case–control study. Diabetologia 51:1664–1670PubMedCrossRef

56.

Yu DY, Cringle SJ, Su E, Yu PK, Humayun MS, Dorin G (2005) Laser-induced changes in intraretinal oxygen distribution in pigmented rabbits. Invest Ophthalmol Vis Sci 46:988–999PubMedCrossRef

57.

Shiba T, Sato Y, Takahashi M (2009) Relationship between diabetic retinopathy and sleep-disordered breathing. Am J Ophthalmol 147:1017–1021PubMedCrossRef

58.

West SD, Groves DC, Lipinski HJ, Nicoll DJ, Mason RH, Scanlon PH, Stradling JR (2010) The prevalence of retinopathy in men with type 2 diabetes and obstructive sleep apnoea. Diabet Med 27:423–430PubMedCrossRef

59.

Kosseifi S, Bailey B, Price R, Roy TM, Byrd RP Jr, Peiris AN (2010) The association between obstructive sleep apnea syndrome and microvascular complications in well-controlled diabetic patients. Mil Med 175(11):913–916PubMed

60.

Tolentino MJ, McLeod DS, Taomoto M, Otsuji T, Adamis AP, Lutty GA (2002) Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol 133:373–385PubMedCrossRef

61.

Amin RH, Frank RN, Kennedy A, Eliott D, Puklin JE, Abrams GW (1997) Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 38:36–47PubMed

62.

Duh E, Aiello LP (1999) Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes 48:1899–1906PubMedCrossRef

63.

Matsuoka M, Ogata N, Minamino K, Matsumura M (2007) Leukostasis and pigment epithelium-derived factor in rat models of diabetic retinopathy. Mol Vis 13:1058–1065PubMed

64.

Chen P, Guo AM, Edwards PA, Trick G, Scicli AG (2007) Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis. Am J Physiol Regul Integr Comp Physiol 293:R1619–R1629PubMedCrossRef

65.

Kaji Y, Usui T, Ishida S, Yamashiro K, Moore TC, Moore J, Yamamoto Y, Yamamoto H, Adamis AP (2007) Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products. Invest Ophthalmol Vis Sci. 48:858–865PubMedCrossRef

66.

Wang J, Xu X, Elliott MH, Zhu M, Le YZ (2010) Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes 59:2297–2305PubMedCrossRef

67.

Zhang B, Hu Y, Ma JX (2009) Anti-inflammatory and antioxidant effects of SERPINA3 K in the retina. Invest Ophthalmol Vis Sci 50:3943–3952PubMedCrossRef

68.

Miyamoto K, Khosrof S, Bursell SE, Moromizato Y, Aiello LP, Ogura Y, Adamis AP (2000) Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol 156:1733–1739PubMedCrossRef

69.

Adamis AP, Berman AJ (2008) Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin Immunopathol 30:65–84PubMedCrossRef

70.

Nakamura S, Iwasaki N, Funatsu H, Kitano S, Iwamoto Y (2009) Impact of variants in the VEGF gene on progression of proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 247:21–26PubMedCrossRef

71.

Churchill AJ, Carter JG, Ramsden C, Turner SJ, Yeung A, Brenchley PE, Ray DW (2008) VEGF polymorphisms are associated with severity of diabetic retinopathy. Invest Ophthalmol Vis Sci 49:3611–3616PubMedCrossRef

72.

Arden GB, Sidman RL, Arap W, Schlingemann RO (2005) Spare the rod and spoil the eye. Br J Ophthalmol 89:764–769PubMedCrossRef

73.

Wirostko B, Wong TY, Simó R (2008) Vascular endothelial growth factor and diabetic complications. Prog Retin Eye Res 27:608–621PubMedCrossRef

74.

Lee JH, Lee W, Kwon OH, Kim JH, Kwon OW, Kim KH, Lim JB (2008) Cytokine profile of peripheral blood in type 2 diabetes mellitus patients with diabetic retinopathy. Ann Clin Lab Sci 38:361–367PubMed

75.

Adamiec-Mroczek J, Oficjalska-Młyńczak (2008) Assessment of selected adhesion molecule and proinflammatory cytokine levels in the vitreous body of patients with type 2 diabetes—role of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 246:1665–1670PubMedCrossRef

76.

Murata T, Ishibashi T, Khalil A, Hata Y, Yoshikawa H, Inomata H (1995) Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels. Ophthalmic Res 27:48–52PubMedCrossRef

77.

Ozaki H, Seo MS, Ozaki K, Yamada H, Yamada E, Okamoto N, Hofmann F, Wood JM, Campochiaro PA (2000) Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. Am J Pathol 156:697–707PubMedCrossRef

78.

Murohara T, Horowitz JR, Silver M, Tsurumi Y, Chen D, Sullivan A, Isner JM (1998) Vascular endothelial growth factor/vascular permeability factor enhances vascular permeability via nitric oxide and prostacyclin. Circulation 97:99–107PubMed

79.

van Eeden PE, Tee LB, Lukehurst S, Lai CM, Rakoczy EP, Beazley LD, Dunlop SA (2006) Early vascular and neuronal changes in a VEGF transgenic mouse model of retinal neovascularization. Invest Ophthalmol Vis Sci 47:4638–4645PubMedCrossRef

80.

Tilton RG, Kawamura T, Chang KC, Ido Y, Bjercke RJ, Stephan CC, Brock TA, Williamson JR (1997) Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor. J Clin Invest 99:2192–2202PubMedCrossRef

81.

Cohen MP, Hud E, Shea E, Shearman CW (2008) Vitreous fluid of db/db mice exhibits alterations in angiogenic and metabolic factors consistent with early diabetic retinopathy. Ophthalmic Res 40:5–9PubMedCrossRef

82.

El-Remessy AB, Behzadian MA, Abou-Mohamed G, Franklin T, Caldwell RW, Caldwell RB (2003) Experimental diabetes causes breakdown of the blood-retina barrier by a mechanism involving tyrosine nitration and increases in expression of vascular endothelial growth factor and urokinase plasminogen activator receptor. Am J Pathol 162:1995–2004PubMedCrossRef

83.

Ellis EA, Guberski DL, Somogyi-Mann M, Grant MB (2000) Increased H₂O₂, vascular endothelial growth factor and receptors in the retina of the BBZ/Wor diabetic rat. Free Radic Biol Med 28:91–101PubMedCrossRef

84.

Vedula SS, Krzystolik MG (2008) Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration. Cochrane Database Syst Rev CD005139

85.

Hussain N, Ghanekar Y, Kaur I (2007) The future implications and indications of anti-vascular endothelial growth factor therapy in ophthalmic practice. Ind J Ophthalmol 55:445–450CrossRef

86.

Nicholson BP, Schachat AP (2010) A review of clinical trials of anti-VEGF agents for diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 248:915–930PubMedCrossRef

87.

Simó R, Hernández C (2008) Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy. Diabetologia 51:1574–1580PubMedCrossRef

88.

Salam A, DaCosta J, Sivaprasad S (2010) Anti-vascular endothelial growth factor agents for diabetic maculopathy. Br J Ophthalmol 94:821–826PubMedCrossRef

89.

Waisbourd M, Goldstein M, Loewenstein A (2011) Treatment of diabetic retinopathy with anti-VEGF drugs. Acta Ophthalmol 89:203–207PubMedCrossRef

90.

Kennedy A, Frank RN (2011) The influence of glucose concentration and hypoxia on VEGF secretion by cultured retinal cells. Curr Eye Res 36:168–177PubMedCrossRef

91.

Frank RN (2011) The optic UK lecture: bench-to-bedside adventures of a diabetes researcher: results past, results present. Eye 25:331–341PubMedCrossRef

92.

Davis MD, Beck RW, Home PD, Sandow J, Ferris FL (2007) Early retinopathy progression in four randomized trials comparing insulin glargine and NPH [corrected] insulin. Exp Clin Endocrinol Diabetes 115:240–243PubMedCrossRef

93.

Awata T, Kurihara S, Takata N et al (2005) Functional VEGF C-634G polymorphism is associated with development of diabetic macular edema and correlated with macular retinal thickness in type 2 diabetes. Biochem Biophys Res Commun 333:679–685PubMedCrossRef

94.

Marsh S, Nakhoul FM, Skorecki K, Rubin A, Miller BP, Leibu R, Levy NS, Levy AP (2000) Hypoxic induction of vascular endothelial growth factor is markedly decreased in diabetic individuals who do not develop retinopathy. Diabetes Care 23:1375–1380PubMedCrossRef

95.

Nguyen QD, Shah SM, Van Anden E, Sung JU, Vitale S, Campochiaro PA (2004) Supplemental oxygen improves diabetic macular oedema: a pilot study. Invest Ophthalmol Vis Sci 45:617–624PubMedCrossRef

96.

Gaynon M (2007) Should people with prethreshold ROP, BDR or ARMD sleep with a nightlight? Review of factors contributing to retinal hypoxia in retinal and choroidal vascular disease Arvo abstract 2007 # 4653

97.

Arden GB, Gündüz MK, Kurtenbach A, Völker M, Zrenner E, Gündüz SB, Kamis Ü, Öztürk BT, Okudan S (2010) A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy. Eye 24:1149–1155PubMedCrossRef

98.

Jyothi S, Arden GB, Sivaprasad S (2011) 2101 Light adaptation improves diabetic maculopathy Arvo abstract, # 5847

99.

Arden GB, Jyothi S, Hogg CH, Lee YF, Sivaprasad S (2011) Regression of early diabetic macular oedema associated with prevention of dark—adaptation. Eye 25. e-published Oct 20th 2011

100.

Brainard GC, Hanifin JP, Greeson JM, Byrne B, Glickman G, Edward Gerner E, Rollag MD (2001) Action Spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. J Neurosci 21:6405–6412PubMed

Title: The pathogenesis of early retinal changes of diabetic retinopathy
Authors: G. B. Arden
S. Sivaprasad
Publication date: 01-02-2012
Publisher: Springer-Verlag
Published in: Documenta Ophthalmologica / Issue 1/2012
Print ISSN: 0012-4486
Electronic ISSN: 1573-2622
DOI: https://doi.org/10.1007/s10633-011-9305-y

At a glance: The STEP trials

Springer Medicine

The pathogenesis of early retinal changes of diabetic retinopathy

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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