Академический Документы
Профессиональный Документы
Культура Документы
review article
medical progress
Diabetic Retinopathy
Robert N. Frank, M.D.
The earliest clinical signs of diabetic retinopathy are microaneurysms, small outpouch-
ings from retinal capillaries, and dot intraretinal hemorrhages. These signs are present
in nearly all persons who have had type 1 diabetes for 20 years2 and in nearly 80 percent
of those with type 2 disease of this duration.3 As the disease progresses, patients with
preproliferative retinopathy have an increase in the number and size of intraretinal
hemorrhages. This increase may be accompanied by cotton-wool spots; both of these
signs indicate regional failure of the retinal microvascular circulation, which results in
ischemia. On examination, retinal veins may appear dilated, tortuous, and irregular in
caliber. Arteries may appear white on inspection with an ophthalmoscope and are non-
perfused when examined with fluorescein angiography.
Proliferative diabetic retinopathy involves the formation of new blood vessels that
develop from the retinal circulation. Untreated, the process carries an ominous progno-
sis for vision. New vessels can extend into the vitreous cavity of the eye and can hemor-
rhage into the vitreous, resulting in visual loss, and they can cause tractional retinal de-
tachments from the accompanying contractile fibrous tissue. Late in the course of the
disease, new blood vessels may form within the stroma of the iris and may extend, with
accompanying fibrosis, into the structures that drain the anterior chamber angle of the
eye. This development blocks the outflow of aqueous humor, causing neovascular glau-
coma, with a devastating elevation of the intraocular pressure. Proliferative retinopathy
may occur in up to 50 percent of patients with type 1 diabetes2 and in about 10 percent
of patients with type 2 diabetes3 who have had the disease for 15 years. The prevalence
of proliferative retinopathy is somewhat higher among those with type 2 diabetes who
require insulin to control their disease and is lower among those who do not.
Another important change that can occur as diabetic retinopathy progresses is dia-
betic macular edema, which involves the breakdown of the blood–retinal barrier, with
leakage of plasma from small blood vessels in the macula, the central portion of the ret-
ina that is responsible for the major part of visual function. This causes swelling of the
central retina. Resorption of the fluid elements from plasma leads to the deposition of
its lipid and lipoprotein components and the formation of hard exudates. Although di-
abetic macular edema does not cause total blindness, it frequently leads to severe loss
of central vision. In a large population-based study, the incidence of macular edema over
a period of 10 years was 20.1 percent in patients with type 1 diabetes, 25.4 percent in pa-
tients with type 2 diabetes who required insulin, and 13.9 percent in patients with type
2 diabetes who did not require insulin.4 Some ophthalmologists who provide care for
* For all the proposed mechanisms, hyperglycemia accelerates the progression to diabetic retinopathy. VEGF denotes vascular endothelial
growth factor, PEDF pigment-epithelium–derived factor, and IGF-1 insulin-like growth factor 1.
sential for the formation of the fetal vascular system; from the basal surface of these cells,51 and perhaps
targeted disruption (knockout) of the VEGF gene in accounts in part for the richly vascular choriocapil-
mice leads to impaired vasculogenesis and death in laris, which lies opposite the basal surface of the ret-
utero.49 Normally, VEGF expression decreases sub- inal pigment epithelium (Fig. 2). The choriocapil-
stantially after birth, but some cells constitutively lary endothelium is itself asymmetrical, with a thin,
secrete picomolar amounts; cells in the neural reti- fenestrated inner portion facing the retinal pigment
na secrete 15 to 20 pg per milligram of protein, and epithelium and a thick, nonfenestrated outer por-
cells in the combined choroid and retinal pigment tion facing the deeper layers of the choroid.84 In vi-
epithelium secrete 50 pg per milligram of protein.50 tro experimentation has shown that VEGF appears
Constitutive VEGF secretion from the retinal pig- to induce endothelial fenestrations in cultured cap-
ment epithelium is asymmetric, occurring primarily illary endothelial cells that are derived from bo-
Muller
cell
VEGFR-1 VEGF
VEGF
VEGF
VEGF
Bipolar
cell
Amacrine Cone
cell
Reactive
oxygen
species Rod
PEDF
PEDF PEDF
VEGF VEGF
VEGF Retinal pigment epithelium
VEGF VEGF VEGF
Choriocapillaris
vine adrenal cortex.55 Endothelial fenestrations are in the synthesis and secretion of VEGF.36,52,53 In-
thought to increase vascular permeability. deed, increased VEGF protein has been demonstrat-
VEGF expression is enhanced by hypoxia,56,57 ed by immunocytochemical analysis of nonvascular
which is a major stimulus for retinal neovasculariza- cells in the eyes of persons with diabetes even in the
tion.8,9 Reduced retinal blood flow and accompany- absence of retinopathy, supporting the hypothesis
ing hypoxia may be present even before the early that diabetic retinopathy begins as a disease of ret-
signs of retinopathy, such as loss of capillary peri- inal neurons and glia and only later involves the ret-
cytes and endothelial cells, are identified, and these inal vasculature.52,53
changes are likely to be accompanied by an increase An increase in levels of VEGF by a factor of more
than 20, as measured by radioimmunoassay or ra- primitive cultured retinoblastoma cells into neu-
dioreceptor assay, in the vitreous humor of patients ron-like structures. Subsequent work70 showed that
undergoing vitrectomy in the presence of active ret- PEDF substantially inhibits neovascularization. Ex-
inal or iris neovascularization provided initial evi- perimental studies indicated that systemic (intra-
dence that VEGF has a role in proliferative diabetic peritoneal) administration of PEDF protein inhibits
retinopathy.58 Experimental data support this ob- retinal neovascularization in the hyperoxygenated
servation. Exogenous VEGF injected into the vitre- neonatal mouse, an accepted model of human reti-
ous of the eyes of monkeys causes neovasculariza- nopathy of prematurity.71
tion of the iris59 or retina.60 In other animal models, PEDF and VEGF appear to have a reciprocal re-
interventions to block VEGF synthesis and intravit- lation in the eye. There is evidence that in prolifera-
real injection of anti-VEGF antibodies,61 a chimeric tive diabetic retinopathy, levels of VEGF increase,
fragment of a VEGF membrane receptor bound to whereas those of PEDF decrease.72 VEGF is consti-
an IgM fragment,62 or antisense VEGF DNA63 ap- tutively secreted from the basal surface of the retinal
pear to prevent retinal neovascularization. pigment epithelium, but the vascular anatomy of the
Strategies to block the formation of VEGF or to neural retina, whose outer layers are avascular (Fig.
prevent its action in the human eye might be prom- 2), retinal pigment epithelium, and choroid sug-
ising treatments for diabetic retinopathy. However, gests that PEDF is normally secreted from the apical
systemic anti-VEGF therapy would have potential surface of this cell layer, as was suggested by a pre-
clinical disadvantages.64 Whereas neovasculariza- liminary report.73
tion is harmful in several tissues of the eye, the for- The normal production and secretion of these
mation of new blood vessels is beneficial in the two factors may be critical for maintaining the nor-
coronary circulation and in the legs, which may be mal anatomy and function of the retinal and choroi-
affected in patients with diabetic vasculopathy. Thus, dal blood vessels, and PEDF may be important for
direct intraocular administration of agents that maintaining the neural architecture of the retina.
block neovascularization may be preferable, despite Abnormal production or secretion of VEGF and
the need for intravitreal injection, a potentially inju- PEDF in retinal tissues may be a major effector of
rious procedure. Because laser therapy has been so retinal disease. Both experimental retinal and cho-
effective in treating diabetic retinopathy, intravitreal roidal neovascularization in the mouse can be in-
injection has not generally been advised for the hibited after intravitreal injection of a replication-
treatment of diabetic retinopathy. However, a VEGF deficient adenovirus containing the PEDF gene74
aptamer consisting of a 28-base oligonucleotide — suggesting that gene therapy with this agent in
that binds to VEGF protein is now undergoing a clin- humans might be feasible. A phase 1 study of this
ical trial for the treatment of exudative, age-relat- approach in patients with very advanced neovascu-
ed macular degeneration, which also involves neo- lar age-related macular degeneration75 is now un-
vascularization through the choroidal circulation.65 der way.
The aptamer must be injected into the vitreous.
The blockade of specific VEGF receptors is an- inhibitors of growth hormone action
other potentially useful therapeutic strategy. There The spontaneous resolution of proliferative diabetic
are three known VEGF receptors; the expression of retinopathy in a woman in whom acute panhypo-
two of them, designated VEGFR-1 and VEGFR-2, is pituitarism76 had developed stimulated interest in
altered in the vascular endothelium in humans with pituitary ablation as a treatment for vision-threaten-
diabetes.54 A drug that blocks VEGFR-2 has under- ing retinopathy. Destruction of the pituitary by sur-
gone initial tests as an angiogenesis inhibitor for the gery or radiation was used before the introduction
treatment of cancer,66 but it has not been tested as of photocoagulation, which is a more effective and
a treatment for diabetic retinopathy. far less hazardous therapy.77 The earlier method has
now largely been abandoned because of the high
pigment-epithelium–derived factor associated rates of morbidity and mortality. Because
First isolated from cultures of fetal retinal pigment the beneficial effect of hypophysectomy might be
epithelial cells,67,68 pigment-epithelium–derived due to the cessation of growth hormone secretion,
factor (PEDF) is also synthesized elsewhere in the therapies to block the actions of growth hormone
eye69 and throughout the body. The initial studies were initiated. A three-month, open-label trial
showed that PEDF promotes the differentiation of showed that pegvisomant, which blocks growth
hormone receptors,78 did not cause regression of tures of the eye disrupt the coherence of the two
the new retinal vessels in patients with “non–high- beams, producing an interference pattern detected
risk”18 proliferative diabetic retinopathy, although by the measuring system of the instrument and de-
plasma levels of insulin-like growth factor 1 (IGF-1) pendent on the optical reflectance and anatomical
decreased by 50 percent. A small-scale trial of octre- thickness of the retinal structures.87 In the most
otide, a somatostatin analogue, showed that at high commonly used protocol, the instrument produces
doses, the agent prevented progression to the prolif- a series of six radially oriented scans at equal inter-
erative stage of diabetic retinopathy over a 15-month vals around a circumference of 360 degrees. The
period.79 A larger trial, involving 30 clinical centers, scans pass through the fixation point of the patient’s
is in progress. eye (the center of the fovea). Each scan makes mul-
Growth hormone action is mediated primarily tiple measurements of retinal thickness; the most
through stimulation of the production of the insu- recent version of the instrument makes up to 768
lin-like growth factors.80 Studies by Smith and her measurements. The images produced appear to be
colleagues81,82 have suggested that IGF-1 is not it- good approximations of the cross-sectional anato-
self a vasoproliferative factor but, rather, is a per- my of the retina.
missive agent — that is, neovascularization cannot Measurements of mean retinal thickness along
occur in its absence, but it must be accompanied by these radii are plotted, along with a pseudocolor
other molecules such as VEGF in order to stimulate map of retinal thickness that enhances the visual
new vessel growth. These experiments may explain interpretability of the images. Optical coherence to-
why blocking IGF-1 secretion, either by destroying mography can therefore be used for the evaluation
the pituitary or by more specific inhibition of IGF-1 and follow-up of patients with diabetic macular ede-
production, appears to prevent retinal neovascular- ma (Fig. 3).88 Because the method requires the pro-
ization. jection of light onto the retina, it is subject to error
in the presence of interfering opacities such as cat-
aracts, corneal opacities, or vitreous hemorrhage.
genetic influences
on diabetic retinopathy However, day-to-day variation in the same patient
appears to be small.89 In diabetic macular edema,
Although the importance of chronic hyperglycemia optical coherence tomography can provide objec-
in the pathogenesis of retinopathy is now unques- tive, quantitative measurements that are not possi-
tioned, genetic factors appear to have important ble with other methods. An advanced version of this
roles in determining whether diabetic retinopathy device, involving a different optical system and a ti-
develops. Familial clustering of severe, vision-threat- tanium–aluminum oxide laser, provides even more
ening forms of diabetic retinopathy was observed striking images, which display the cellular anatomy
in the Diabetes Control and Complications Trial.48 of the retinal layers in nearly the detail of a histolog-
The continued progression of diabetic retinopathy ic section.90
after the institution of normoglycemia in human
subjects and in laboratory animals85,86 may be con- measurements of retinal blood flow,
sistent with the altered expression of one or more vascular leakage, and oxygenation
critical genes induced by chronic hyperglycemia. Alterations in retinal blood flow that modify the sup-
ply of oxygen and other nutrients to the retina may
new diagnostic methods be critical to the development of diabetic retinopa-
thy. There are several methods for measuring retinal
Several new, noninvasive techniques promise to im- blood flow. The laser Doppler flowmeter,91 which
prove diagnostic sensitivity and to enhance investi- involves a laser beam projected at right angles to the
gations into pathogenic mechanisms in diabetic ret- blood column in a retinal vessel, quantitates Dop-
inopathy. pler shifts in the column of moving erythrocytes.
The method can measure flow in only one vessel at
optical coherence tomography a time, however, and only in the largest vessels close
One new technique is optical coherence tomogra- to the optic-nerve head. The scanning laser ophthal-
phy, which projects a pair of near-infrared beams moscope can be used to produce a video fluorescein
from a diode through the pupil of the eye and then angiogram,92 from which the rate of flow of the
through the vitreous, retina, and choroid. The struc- plasma column in any blood vessel in the photo-
A B
C D
OCT Image—Diabetes OCT Image—Normal
Log reflection
Log reflection
325 219
395 242
376 486 492 320 295 204 233 181 241 237
405 241
331 219
250
30 0
150
200
350
40 0
0
0
0
0
0
0
500
0
10
10
20
30
40
50
graphic field can be calculated from the movement genation, free of the eye movement and blinking
of a point of fixed fluorescence intensity along the artifacts that produced inaccuracies when this tech-
course of the vessel over time. The scanning laser nique had initially been used in conscious human
ophthalmoscope produces a permanent electronic subjects. However, further development is required
record that can be subjected to many forms of analy- for clinical use.
sis, but it measures the movement of the plasma col-
umn, not the movement of the column of erythro- conclusions
cytes, which may be more physiologically relevant.
Retinal oxygenation has until recently been mea- Diabetic retinopathy, a major cause of blindness and
surable only with intraretinal oxygen electrodes, an visual disability in the United States, has been a fo-
invasive technique that cannot be used in humans. cus of extensive basic and clinical research since the
A new, noninvasive method, functional magnetic 1960s. The efficacy of retinal laser photocoagulation
resonance imaging (f MRI), does not measure reti- and vitrectomy for the treatment of this disease has
nal partial pressure of oxygen directly but, instead, been documented by large-scale randomized, con-
calculates the change in oxygenation by comparing trolled clinical trials. The value of blood glucose and
retinal oxygenation when the subject is breathing blood-pressure control for the prevention of reti-
room air and when he or she is breathing 100 per- nopathy in patients with type 1 or type 2 diabetes has
cent oxygen or a mixture of 95 percent oxygen and been documented in similar trials. New techniques
5 percent carbon dioxide.93 This technique can de- have enhanced the accuracy and sensitivity of diag-
tect differences in the change in retinal oxygenation nostic methods and may lead to a better understand-
even in very small regions of the retina, a few hun- ing of pathogenic mechanisms. The identification
dred micrometers on a side. In rats that had been of several such putative mechanisms has led to the
fed a high-galactose diet, which causes a diabetic- development of new drugs, none of which have as
like retinopathy, fMRI studies showed that oxygen- yet proved effective in randomized, controlled clin-
ation decreases as soon as three months after the ical trials. Additional therapeutic approaches that
onset of the metabolic abnormality94; this finding are being developed or evaluated in clinical trials
is consistent with the early up-regulation of VEGF may ultimately improve the outcome for patients
in the retina. Preliminary studies in humans95 have with diabetic retinopathy.
demonstrated that functional MRI can provide ac- Dr. Frank reports having received consulting fees from Pharma-
cia and GenVec and grant support from Eli Lilly.
curate measurements of the change in retinal oxy-
refer enc es
1. Kenny SJ, Aubert RE, Geiss LS. Preva- type 1 diabetes. Ophthalmology 1998;105: (UKPDS 33). Lancet 1998;352:837-53. [Erra-
lence and incidence of non-insulin-depen- 1801-15. tum, Lancet 1999;354:602.]
dent diabetes. In: Diabetes in America. 2nd 6. Kuwabara T, Cogan DG. Retinal vascular 12. Idem. Tight blood pressure control and
ed. Washington, D.C.: Government Printing patterns. VI. Mural cells of the retinal capil- risk of macrovascular and microvascular
Office, 1995. (NIH publication No. 95-1468.) laries. Arch Ophthalmol 1963;69:492-502. complications in type 2 diabetes: UKPDS 38.
2. Klein R, Klein BEK, Moss SE, Davis MD, 7. Mizutani M, Kern TS, Lorenzi M. Accel- BMJ 1998;317:703-13.
DeMets DL. The Wisconsin Epidemiologic erated death of retinal microvascular cells in 13. Early worsening of diabetic retinopathy
Study of Diabetic Retinopathy. II. Prevalence human and experimental diabetic retinopa- in the Diabetes Control and Complications
and risk of diabetic retinopathy when age at thy. J Clin Invest 1996;97:2883-90. Trial. Arch Ophthalmol 1998;116:874-86.
diagnosis is less than 30 years. Arch Oph- 8. Henkind P. Ocular neovascularization. [Erratum, Arch Ophthalmol 1998;116:
thalmol 1984;102:520-6. Am J Ophthalmol 1978;85:287-301. 1469.]
3. Idem. The Wisconsin Epidemiologic 9. Patz A. Clinical and experimental stud- 14. Chantelau E, Kohner EM. Why some cas-
Study of Diabetic Retinopathy. III. Preva- ies on retinal neovascularization. Am J Oph- es of retinopathy worsen when diabetic con-
lence and risk of diabetic retinopathy when thalmol 1982;94:715-43. trol improves. BMJ 1997;315:1105-6.
age at diagnosis is 30 or more years. Arch 10. The Diabetes Control and Complications 15. Lu M, Amano S, Miyamoto K, et al. Insu-
Ophthalmol 1984;102:527-32. Trial Research Group. The effect of intensive lin-induced vascular endothelial growth fac-
4. Klein R, Klein BE, Moss SE, Cruick- treatment of diabetes on the development tor expression in retina. Invest Ophthalmol
shanks KJ. The Wisconsin Epidemiologic and progression of long-term complica- Vis Sci 1999;40:3281-6.
Study of Diabetic Retinopathy. XV. The long- tions in insulin-dependent diabetes melli- 16. Diabetic Retinopathy Study Research
term incidence of macular edema. Ophthal- tus. N Engl J Med 1993;329:977-86. Group. Preliminary report on effects of pho-
mology 1995;102:7-16. 11. UK Prospective Diabetes Study (UKPDS) tocoagulation therapy. Am J Ophthalmol
5. Idem. The Wisconsin Epidemiologic Group. Intensive blood-glucose control with 1976;81:383-96.
Study of Diabetic Retinopathy. XVII. The 14- sulphonylureas or insulin compared with 17. Idem. Photocoagulation treatment of pro-
year incidence and progression of diabetic conventional treatment and risk of compli- liferative diabetic retinopathy: clinical appli-
retinopathy and associated risk factors in cations in patients with type 2 diabetes cation of Diabetic Retinopathy Study (DRS)
findings, DRS report number 8. Ophthal- diabetic macular edema. Ophthalmology al Research Group. Clustering of long-term
mology 1981;88:583-600. 2002;109:920-7. complications in families with diabetes in the
18. Idem. Four risk factors for severe visual 34. Xia P, Inoguchi T, Kern T, Engerman RL, Diabetes Control and Complications Trial.
loss in diabetic retinopathy: the third report Oates PJ, King GL. Characterization of the Diabetes 1997;46:1829-39.
from the Diabetic Retinopathy Study. Arch mechanism for the chronic activation of dia- 49. Carmeliet P, Ferreira V, Breier G, et al.
Ophthalmol 1979;97:654-5. cylglycerol-protein kinase C pathway in dia- Abnormal blood vessel development and le-
19. Early Treatment Diabetic Retinopathy betes and hypergalactosemia. Diabetes 1994; thality in embryos lacking a single VEGF al-
Study Research Group. Photocoagulation for 43:1122-9. lele. Nature 1996;380:435-9.
diabetic macular edema: Early Treatment Di- 35. Danis RP, Bingaman DP, Jirousek M, 50. Kim I, Ryan AM, Rohan R, et al. Consti-
abetic Retinopathy Study report number 1. Yang Y. Inhibition of intraocular neovascu- tutive expression of VEGF, VEGFR-1, and
Arch Ophthalmol 1985;103:1796-806. larization due to retinal ischemia in pigs by VEGFR-2 in normal eyes. Invest Ophthalmol
20. Idem. Early photocoagulation for diabetic PKCb inhibition with LY333531. Invest Oph- Vis Sci 1999;40:2115-21. [Erratum, Invest
retinopathy: ETDRS report number 9. Oph- thalmol Vis Sci 1998;39:171-9. Ophthalmol Vis Sci 2000;41:368.]
thalmology 1991;98:Suppl:766-85. 36. Ishii H, Jirousek MR, Koya D, et al. Amel- 51. Blaauwgeers HG, Holtkamp GM, Rut-
21. Frank RN. Visual fields and electroretin- ioration of vascular dysfunctions in diabetic ten H, et al. Polarized vascular endothelial
ography following extensive photocoagula- rats by an oral PKC beta inhibitor. Science growth factor secretion by human retinal
tion. Arch Ophthalmol 1975;93:591-8. 1996;272:728-31. pigment epithelium and localization of vas-
22. Machemer R, Buettner H, Norton EW, 37. Milton R, Aiello L, Davis M, et al. Initial cular endothelial growth factor receptors on
Parel JM. Vitrectomy: a pars plana approach. results of the Protein Kinase C b Inhibitor the inner choriocapillaris: evidence for a tro-
Trans Am Acad Ophthalmol Otolaryngol Diabetic Retinopathy Study (PKC-DRS). Di- phic paracrine relation. Am J Pathol 1999;
1971;75:813-20. abetes 2003;52:Suppl 1:A-127. abstract. 155:421-8.
23. The Diabetic Retinopathy Vitrectomy 38. Kunisaki M, Bursell SE, Clermont AC, et 52. Amin RH, Frank RN, Kennedy A, Eliott
Study Research Group. Early vitrectomy for al. Vitamin E prevents diabetes-induced ab- D, Puklin JE, Abrams GW. Vascular endothe-
severe vitreous hemorrhage in diabetic reti- normal retinal blood flow via the diacylglyc- lial growth factor is present in glial cells of
nopathy: two-year results of a randomized erol-protein kinase C pathway. Am J Physiol the retina and optic nerve of human subjects
trial: Diabetic Retinopathy Vitrectomy Study 1995;269:E239-E246. with nonproliferative diabetic retinopathy.
report 2. Arch Ophthalmol 1985;103:1644- 39. Kowluru RA, Tang J, Kern TS. Abnor- Invest Ophthalmol Vis Sci 1997;38:36-47.
52. malities of retinal metabolism in diabetes 53. Lutty GA, McLeod DS, Merges C, Diggs
24. Idem. Early vitrectomy for severe prolif- and experimental galactosemia. VII. Effect A, Plouét J. Localization of vascular endothe-
erative diabetic retinopathy in eyes with use- of long-term administration of antioxidants lial growth factor in human retina and cho-
ful vision: clinical application of results of a on the development of retinopathy. Diabetes roid. Arch Ophthalmol 1996;114:971-7.
randomized trial — Diabetic Retinopathy 2001;50:1938-42. 54. Witmer AN, Blaauwgeers HG, Weich
Vitrectomy Study report 4. Ophthalmology 40. Age-Related Eye Disease Study Research HA, Alitalo K, Vrensen GF, Schlingemann
1988;95:1321-34. Group. A randomized, placebo-controlled, RO. Altered expression patterns of VEGF
25. Nathan DM. Long-term complications clinical trial of high-dose supplementation receptors in human diabetic retina and in
of diabetes mellitus. N Engl J Med 1993;328: with vitamins C and E, beta carotene, and experimental VEGF-induced retinopathy in
1676-85. zinc for age-related macular degeneration monkey. Invest Ophthalmol Vis Sci 2002;
26. Ferris FL III, Davis MD, Aiello LM. and vision loss: AREDS report no. 8. Arch 43:849-57.
Treatment of diabetic retinopathy. N Engl J Ophthalmol 2001;119:1417-36. 55. Esser S, Wolburg K, Wolburg H, Breier
Med 1999;341:667-78. 41. Cusick M, Chew EY, Clemons TE, Klein G, Kurzchalia T, Risau W. Vascular endothe-
27. Sorbinil Retinopathy Trial Research R, Klein BEK, Hubbard LD. Effect of antiox- lial growth factor induces endothelial fenes-
Group. A randomized trial of sorbinil, an al- idant and zinc supplements on development trations in vitro. J Cell Biol 1998;140:947-
dose reductase inhibitor, in diabetic retinop- of diabetic retinopathy in the Age-Related Eye 59.
athy. Arch Ophthalmol 1990;108:1234-44. Disease Study (AREDS). Invest Ophthalmol 56. Shweiki D, Itin A, Soffer D, Keshet E.
28. Sundkvist G, Armstrong FM, Bradbury Vis Sci 2002;43:E-abstract 1909. (Accessed Vascular endothelial growth factor induced
JE, et al. Peripheral and autonomic nerve December 3, 2003, at http://www.iovs.org.) by hypoxia may mediate hypoxia-initiated
function in 259 diabetic patients with periph- 42. Brownlee M, Cerami A. The biochemis- angiogenesis. Nature 1992;359:843-5.
eral neuropathy treated with ponalrestat (an try of the complications of diabetes mellitus. 57. Aiello LP, Northrup JM, Keyt BA, Takagi
aldose reductase inhibitor) or placebo for 18 Annu Rev Biochem 1981;50:385-432. H, Iwamoto MA. Hypoxic regulation of vas-
months. J Diabetes Complications 1992;6: 43. Du Y, Smith MA, Miller CM, Kern TS. cular endothelial growth factor in retinal
123-30. Diabetes-induced nitrative stress in the ret- cells. Arch Ophthalmol 1995;113:1538-44.
29. Early Treatment Diabetic Retinopathy ina, and correction by aminoguanidine. 58. Aiello LP, Avery RL, Arrigg PG, et al. Vas-
Study Research Group. Effects of aspirin J Neurochem 2002;80:771-9. cular endothelial growth factor in ocular flu-
treatment on diabetic retinopathy: ETDRS 44. Brownlee M, Vlassara H, Kooney A, Ul- id of patients with diabetic retinopathy and
report number 8. Ophthalmology 1991;98: rich P, Cerami A. Aminoguanidine prevents other retinal disorders. N Engl J Med 1994;
Suppl:757-65. diabetes-induced arterial wall protein cross- 331:1480-7.
30. Adamis AP. Is diabetic retinopathy an in- linking. Science 1986;232:1629-32. 59. Tolentino MJ, Miller JW, Gragoudas ES,
flammatory disease? Br J Ophthalmol 2002; 45. Freedman BI, Wuerth JP, Cartwright K, Chatzistefanou K, Ferrara N, Adamis AP.
86:363-5. et al. Design and baseline characteristics for Vascular endothelial growth factor is suffi-
31. Kern TS, Engerman RL. Pharmacologi- the Aminoguanidine Clinical Trial in Overt cient to produce iris neovascularization and
cal inhibition of diabetic retinopathy: ami- Type 2 Diabetic Nephropathy (ACTION II). neovascular glaucoma in a nonhuman pri-
noguanidine and aspirin. Diabetes 2001;50: Control Clin Trials 1999;20:493-510. mate. Arch Ophthalmol 1996;114:964-70.
1636-42. 46. A curious stopping rule from Hoechst 60. Tolentino MJ, McLeod DS, Taomoto M,
32. Joussen AM, Poulaki V, Mitsiades N, et al. Marion Roussel. Lancet 1997;350:155. Otsuji T, Adamis AP, Lutty GA. Pathologic fea-
Nonsteroidal anti-inflammatory drugs pre- 47. Williamson JR, Chang K, Franzos M, et tures of vascular endothelial growth factor-
vent early diabetic retinopathy via TNF-alpha al. Hyperglycemic pseudohypoxia and dia- induced retinopathy in the nonhuman pri-
suppression. FASEB J 2002;16:438-40. betic complications. Diabetes 1993;42:801- mate. Am J Ophthalmol 2002;133:373-85.
33. Martidis A, Duker JS, Greenberg PB, et 13. 61. Adamis AP, Shima DT, Tolentino MJ, et
al. Intravitreal triamcinolone for refractory 48. Diabetes Control and Complications Tri- al. Inhibition of vascular endothelial growth
factor prevents retinal ischemia-associated cretion from the retinal pigment epithelium. 85. The Diabetes Control and Complica-
iris neovascularization in a nonhuman pri- Invest Ophthalmol Vis Sci 2001;42:Suppl: tions Trial/Epidemiology of Diabetes Inter-
mate. Arch Ophthalmol 1996;114:66-71. S772. abstract. ventions and Complications Research Group.
62. Aiello LP, Pierce EA, Foley ED, et al. Sup- 74. Mori K, Duh E, Gehlbach P, et al. Pig- Retinopathy and nephropathy in patients
pression of retinal neovascularization in vivo ment epithelium-derived factor inhibits reti- with type 1 diabetes for four years after a tri-
by inhibition of vascular endothelial growth nal and choroidal neovascularization. J Cell al of intensive therapy. N Engl J Med 2000;
factor (VEGF) using soluble VEGF-receptor Physiol 2001;188:253-63. 342:381-9.
chimeric proteins. Proc Natl Acad Sci U S A 75. Rasmussen H, Chu KW, Campochiaro 86. Engerman RL, Kern TS. Progression of
1995;92:10457-61. P, et al. An open-label, phase I, single ad- incipient diabetic retinopathy during good
63. Robinson GS, Pierce EA, Rook SL, Foley ministration, dose-escalation study of glycemic control. Diabetes 1987;36:808-12.
E, Webb R, Smith LE. Oligodeoxynucleotides ADGVPEDF.11D (ADPEDF) in neovascular 87. Huang D, Swanson EA, Lin CP, et al. Op-
inhibit retinal neovascularization in a mu- age-related macular degeneration (AMD). tical coherence tomography. Science 1991;
rine model of proliferative retinopathy. Proc Hum Gene Ther 2001;12:2029-32. 254:1178-81.
Natl Acad Sci U S A 1996;93:4851-6. 76. Poulsen JE. Recovery from retinopathy 88. Rivellese M, George A, Sulkes D, Reich-
64. Duh E, Aiello LP. Vascular endothelial in a case of diabetes with Simmonds’ dis- el E, Puliafito C. Optical coherence tomog-
growth factor and diabetes: the agonist ver- ease. Diabetes 1953;2:7-12. raphy after laser photocoagulation for clini-
sus antagonist paradox. Diabetes 1999;48: 77. Lundbaek K, Malmros R, Andersen HC, cally significant macular edema. Ophthalmic
1899-906. et al. Hypophysectomy for diabetic angiopa- Surg Lasers 2000;31:192-7.
65. The Eyetech Study Group. Preclinical thy: a controlled clinical trial. In: Goldberg 89. Massin P, Vicaut E, Haouchine B, Ergin-
and phase 1A clinical evaluation of an anti- MF, Fine SL, eds. Symposium on the treat- ay A, Paques M, Gaudric A. Reproducibility
VEGF pegylated aptamer (EYE001) for the ment of diabetic retinopathy. Washington, of retinal mapping using optical coherence
treatment of exudative age-related macular D.C.: Government Printing Office, 1968. tomography. Arch Ophthalmol 2001;119:
degeneration. Retina 2002;22:143-52. (Public Health Service publication no. 1890.) 1135-42.
66. Rosen LS. Clinical experience with an- 78. Growth Hormone Antagonist for Prolif- 90. Drexler W, Morgner U, Ghanta RK,
giogenesis signaling inhibitors: focus on erative Diabetic Retinopathy Study Group. Kartner FX, Schuman JS, Fujimoto JG. Ultra-
vascular endothelial growth factor (VEGF) The effect of a growth hormone receptor an- high-resolution ophthalmic optical coher-
blockers. Cancer Control 2002;9:Suppl 2: tagonist drug on proliferative diabetic reti- ence tomography. Nat Med 2001;7:502-7.
36-44. nopathy. Ophthalmology 2001;108:2266-72. 91. Grunwald JE, Riva CE, Sinclair SH,
67. King GL, Suzuma K. Pigment-epitheli- 79. Grant MB, Mames RN, Fitzgerald C, et Brucker AJ, Petrig BL. Laser Doppler velo-
um–derived factor — a key coordinator of al. The efficacy of octreotide in the therapy cimetry study of retinal circulation in dia-
retinal neuronal and vascular functions. of severe nonproliferative and early prolifer- betes mellitus. Arch Ophthalmol 1986;104:
N Engl J Med 2000;342:349-51. ative diabetic retinopathy: a randomized con- 991-6.
68. Chader GJ. PEDF: raising both hopes trolled study. Diabetes Care 2000;23:504-9. 92. Aiello LP, Bursell SE, Devries T, et al.
and questions in controlling angiogenesis. 80. Van Wyk JJ, Underwood LE, Hintz RL, Amelioration of abnormal retinal hemody-
Proc Natl Acad Sci U S A 2001;98:2122-4. Clemmons DR, Voina SJ, Weaver RP. The so- namics by a protein kinase C b selective
69. Ogata N, Wada M, Otsuji T, Jo N, Tom- matomedins: a family of insulinlike hor- inhibitor (LY333531) in patients with diabe-
bran-Tink J, Matsumura M. Expression of mones under growth hormone control. Re- tes: results of a Phase 1 safety and pharma-
pigment epithelium-derived factor in normal cent Prog Horm Res 1974;30:259-318. codynamic clinical trial. Invest Ophthalmol
adult rat eye and experimental choroidal 81. Smith LE, Shen W, Perruzzi C, et al. Reg- Vis Sci 1999;40:Suppl:S192. abstract.
neovascularization. Invest Ophthalmol Vis ulation of vascular endothelial growth fac- 93. Berkowitz BA. Adult and newborn rat
Sci 2002;43:1168-75. tor-dependent retinal neovascularization by inner retinal oxygenation during carbogen
70. Dawson DW, Volpert OV, Gillis P, et al. insulin-like growth factor-1 receptor. Nat and 100% oxygen breathing: comparison
Pigment epithelium-derived factor: a potent Med 1999;5:1390-5. using magnetic resonance imaging delta
inhibitor of angiogenesis. Science 1999;285: 82. Smith LEH, Kopchick JJ, Chen W, et al. pO2 mapping. Invest Ophthalmol Vis Sci
245-8. Essential role of growth hormone in ische- 1996;37:2089-98.
71. Stellmach V, Crawford SE, Zhou W, mia-induced retinal neovascularization. Sci- 94. Berkowitz BA, Kowluru RA, Frank RN,
Bouck N. Prevention of ischemia-induced ence 1997;276:1706-9. Kern TS, Hohman TC, Prakash M. Subnor-
retinopathy by the natural ocular antiangio- 83. Hammes HP, Du X, Edelstein D, et al. mal retinal oxygenation response precedes
genic agent pigment epithelium-derived fac- Benfotiamine blocks three major pathways diabetic-like retinopathy. Invest Ophthalmol
tor. Proc Natl Acad Sci U S A 2001;98:2593-7. of hyperglycemic damage and prevents ex- Vis Sci 1999;40:2100-5.
72. Gao G, Li Y, Zhang D, Gee S, Crosson C, perimental diabetic retinopathy. Nat Med 95. Berkowitz BA, McDonald C, Ito Y, Tofts
Ma J. Unbalanced expression of VEGF and 2003;9:294-9. PS, Latif Z, Gross J. Measuring the human
PEDF in ischemia-induced retinal neovascu- 84. Mancini MA, Frank RN, Keirn RJ, retinal oxygenation response to a hyperoxic
larization. FEBS Lett 2001;489:270-6. Kennedy A, Khoury JK. Does the retinal pig- challenge using MRI: eliminating blinking
73. Becerra SP, Wu YQ, Montuenga L, Wong ment epithelium polarize the choriocapil- artifacts and demonstrating proof of con-
P, Pfeffer B. Pigment epithelium-derived laris? Invest Ophthalmol Vis Sci 1986;27: cept. Magn Reson Med 2001;46:412-6.
factor (PEDF) in the monkey eye: apical se- 336-45. Copyright © 2004 Massachusetts Medical Society.