Content uploaded by Bruce Alan Berkowitz
Author content
All content in this area was uploaded by Bruce Alan Berkowitz on Dec 01, 2014
Content may be subject to copyright.
Accepted Article
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/jdi.12312
This article is protected by copyright. All rights reserved.
Received Date : 13-Sep-2014
Revised Date : 07-Nov-2014
Accepted Date : 10-Nov-2014
Article type : Review
Photoreceptors in diabetic retinopathy
1,2
Timothy S. Kern and
3
Bruce A. Berkowitz
1
Case Western Reserve University, Department of Medicine and Center for Diabetes
Research, Cleveland, OH 44106
2
Veterans Administration Medical Center Research Service 151, Cleveland, OH 44106
3
Wayne State University School of Medicine, Departments of Anatomy and Cell Biology and
Ophthalmology, Detroit, MI, USA
*Address correspondence to: Timothy S. Kern, Ph.D., 441 Wood Building, Case Western Reserve
University, 10900 Euclid Ave., Cleveland, OH 44106; Tel: 1-(216)-368-6129
Fax: 1-(216)-368-5824 E-mail: tsk@case.edu.
Running title: Photoreceptors in diabetic retinopathy
Abstract
Although photoreceptors account for most of the mass and metabolic activity of the retina, their role
in the pathogenesis of diabetic retinopathy has been largely overlooked. Recent studies suggest that
photoreceptors may play a critical role in the diabetes-induced degeneration of retinal capillaries, and
thus can no longer be ignored. The present review summarizes diabetes-induced alterations in
Accepted Article
This article is protected by copyright. All rights reserved.
photoreceptor structure and function, and provides a rationale for further study of a role of
photoreceptors in the pathogenesis of the retinopathy.
Diabetic retinopathy (DR), a leading cause of visual impairment and blindness, is clinically defined as a
microvascular disease, but the unique susceptibility of the retina (compared to other tissues) to this
disease has never been explained (1). Here, we review the accumulating data that suggests a new
hypothesis that photoreceptors in the outer retina might play an important role in the development
of the retinopathy. Photoreceptors are light-sensing cells unique to the retina. The present review will
summarize current data linking retinal photoreceptors in the pathogenesis of early stages of diabetic
retinopathy. The discussion will focus primarily on rods, since most of the animal-based work on this
topic has been done in rodents (which have a rod-rich retina) (2). Less is known about how cone
function is affected with diabetes, although new animal models (such as nrl
-/-
mice (3, 4)) may be
useful in addressing this in the future.
A. Evidence suggesting that photoreceptors contribute to vascular disease in diabetic retinopathy.
Photoreceptors of the outer retina have not been usually regarded as important in the pathogenesis
of early diabetic retinopathy, likely due in part to the substantial distance between the
photoreceptors and the retinal microvasculature that is affected by diabetes (Fig 1). Neverthess,
available evidence raises a possibility that the unique susceptibility of the retina is to injury in
diabetes may in fact be due to the presence of photoreceptors. In support of the photoreceptor
hypothesis, Arden and colleagues sent a survey sent to a group of diabetic patients who also had
retinitis pigmentosa (5). The results of those responses suggested that DR was less severe in patients
who also had retinitis pigmentosa (and therefore, photoreceptor degeneration). Stitt and
collaborators (6) subsequently reported that diabetes did not cause the expected decrease in density
of the retinal microvasculature in mice lacking rhodopsin (Rho
-/-
), and thus lacking most
photoreceptors. These data suggest that loss of photoreceptors in the outer retina reduced the
severity of vascular degeneration in that model of diabetic retinopathy.
There are at least two hypotheses to explain how photoreceptors might influence the development of
DR, and they are not mutually exclusive:
a. Hypoxia. It is well known that photoreceptors account for much of the oxygen consumed by the
retina, and that this metabolism is increased during the dark (7, 8), when the rod dark current
becomes maximal (9-11). Studies in cat and macaque retinae in which oxygen microelectrodes were
inserted into the retina found a 30–40% PO
2
difference between inner retina and the vicinity of rods
Accepted Article
This article is protected by copyright. All rights reserved.
(12, 13). There was no detectable oxygen next to dark-adapted rods. In the dark, oxygen
consumption is greater than any other cell in the retina (14).
Arden (8, 15, 16) incorporated available data demonstrating the high metabolic activity of
photoreceptors at night (dark current), and postulated that in the presence of a compromised retinal
vasculature (such as in diabetes), photoreceptor activity in the dark would make the retina even more
hypoxic than usual. The extent to which this hypothesis applies also to the development of early
diabetic retinopathy (before the vasculature is compromised) requires additional study.
b. Oxidative stress. Diabetes results in increased generation of superoxide and other reactive oxygen
species in retina (17). This oxidative stress is important in the pathogenesis of at least the vascular
lesions of diabetic retinopathy, because inhibition of the oxidative stress has been shown to inhibit
development of inflammation and subsequent vascular lesions of early DR (18-21). It has commonly
been assumed that the diabetes-induced increases in oxidative stress arises in retinal cells known to
be affected by diabetes (including endothelial cells and pericytes), but recent data demonstrates that
photoreceptors are the major site of superoxide generation in diabetes (17). Consistent with a role of
photoreceptors in the oxidative stress, the presence or absence of light affects retinal oxidative stress
(the oxidative stress caused by diabetes is worsened in the dark), and the oxidative stress contributes
to the induction of pro-inflammatory proteins (which participate in the development of retinal
microvascular pathology in diabetes) (17). Photoreceptors express NADPH oxidase (22) and contain
most of the mitochondria found in the retina (23), and both of these sources of reactive oxygen
species seem to contribute to the observed retinal superoxide generation in diabetes (17, 24, 25).
Based on these considerations, our working model of how photoreceptors play a critical role in the
pathogenesis of diabetic retinopathy is summarized in Fig 2. Work is on-going to elucidate how
oxidative stress, inflammation, and microvascular disease in diabetes are linked and these are not the
central topic of this review. Here, we will largely focus on the impact of diabetes on rod morphology,
cell biology, and function as they related to oxidative stress generation in early stages of diabetic
retinopathy.
B. Morphologic changes to photoreceptors, retinal pigment epithelium (RPE), and choroid in
diabetes
A number of animal studies (summarized below) have reported that at least some photoreceptors
degenerate in diabetes. Nevertheless, it is important to recognize that diabetes has not been
reported to cause widespread degeneration of photoreceptors, unlike in several other important
retinal diseases.
Accepted Article
This article is protected by copyright. All rights reserved.
a. Animal studies. Some studies in diabetic rodents have reported photoreceptor degeneration early
in the course of diabetes. Retinas from diabetic rats have been found to have increased caspase-3, as
well as photoreceptor atrophy (26). A reduction in the thickness of the outer nuclear layer was seen
24 weeks after the onset of diabetes, resulting in only half of the normal cellular layers in the outer
nuclear layer remaining at 24 weeks of diabetes (27). A few photoreceptors showed evidence of
apoptosis at 4 weeks of diabetes, and the number of apoptotic photoreceptors increased thereafter
(27). Diabetes also has been reported to cause a reduction in the length of the rod outer segments
(27) in male Sprague Dawley rats over a study duration of 24 weeks. Morphologic signs of
degeneration in the outer segments of rods, most M-cones, and some S-cones has been reported in
Male Wistar and Sprague-Dawley rats killed 12 weeks after the induction of diabetes (28, 29).
These photoreceptor abnormalities seem not to be secondary to chemical induction of diabetes,
because they have been detected also in spontaneously diabetic animal models. A spontaneous
model of type 1 diabetes in Ins2Akita diabetic mice have been reported as showing cone but not rod
photoreceptor loss after only 3 months of diabetes, and severe impairment of synaptic connectivity at
the outer plexiform layer was detected in 9-month old animals, suggesting cone photoreceptor
degeneration (30). A model of type 2 diabetes, the db/db mouse, showed thinning of the inner and
outer nuclear (photoreceptor) layers, with defects in the integrity of the RPE over 8-24 weeks of
diabetes (31, 32).
Photoreceptors in less-studied animal models also have been reported to be affected by diabetes or
experimental hyperglycemia. In Otsuka Long-Evans Tokushima Fatty (OLETF) rats (duration of
diabetes not reported), the number of photoreceptor cell nuclei decreased, RPE decreased in height,
and basal infoldings were poorly developed (33). Retinas from (mRen2)27 rats (a transgenic model
showing greater than normal plasma prorenin levels) who were diabetic for only 3 weeks showed
increased apoptotic cell death of both inner retinal neurons and photoreceptors (34). Diabetes
narrowed the layers of rods and cones after 6 weeks in rabbits, and these changes were exacerbated
after 3-6 months diabetes (including atrophy of the RPE and damage to photoreceptor discs) (35, 36).
Adult zebrafish, in which the zebrafish were subjected to oscillating hyperglycemia for 30 days,
showed degeneration of cone photoreceptor neurons and dysfunction of cone-mediated
electroretinograms (37).
Diabetes-induced defects or degeneration of photoreceptors in animals have been reported to be
inhibited therapeutically. These defects have been reported to be inhibited by administration of
hesperetin (26), wolfberry (31), aliskiren (34), or exendin-4a, an agonist of glucagon-like factor-1 (29).
Accepted Article
This article is protected by copyright. All rights reserved.
Not all studies demonstrate photoreceptor death in diabetes. Studies of male Wistar and Sprague-
Dawley rats diabetic 12 weeks reported that retinal thickness, the number of apoptotic cells, and the
density of cones expressing middle (M)- and shortwave (S)-sensitive opsins was similar in diabetic and
control retinas (28). In male C57BL/6J mice diabetic for 2 months, no significant difference in the
number of layers in the outer nuclear layer was detected (17). Other morphological studies at
substantially longer durations of diabetes and in multiple species not found evidence of
photoreceptor loss (38), or have not commented on (or noticed) it (39-42). The lack of consistent
conclusions among investigators about whether or not photoreceptor loss occurs in diabetes raises
possibilities that some reports of photoreceptor loss might be due less to diabetes than to other
differences (including strain differences), or that duration of diabetes plays an important role in the
process.
b. Patient studies. Evidence demonstrating photoreceptor death is even less abundant in diabetic
patients. Occasional case reports suggest photoreceptor loss in diabetes or diabetic macular edema
(DME) (43), but there has been no systematic demonstration that photoreceptors are lost in diabetic
patients, with the exception of autopsy evidence showing that the S-cones selectively are lost in DR
(44).
Less severe changes to photoreceptor morphology have been associated with changes in visual acuity
in diabetes (45-48). Also, the photoreceptor inner and outer segment junction and external limiting
membrane have been identified as useful parameters for optical coherence tomography evaluation of
foveal photoreceptor layer integrity in DME (46, 47, 49). In DME, photoreceptor outer segment length
of the central subfield for was less (48) than the mean cone OS length in the fovea of healthy subjects
(50), suggesting shortening of the photoreceptor outer segment length in diabetes or macular edema.
Summarizing: Anatomical changes in the photoreceptors elicited by diabetes appear modest, but this
needs to be studied more, especially in patients.
C. Molecular changes in photoreceptors in diabetes
A. Animal studies: Molecular techniques provide evidence that proteins important for photoreceptor
function become altered before the appearance of microangiopathy in diabetes. For example, the
content of rhodopsin (51), transducin (28, 52, 53), recoverin (53) and optical density of photopigment
have been reported to become subnormal in diabetes. Reduced levels of genes involved in the
phototransduction pathway (photoreceptor-specific opsin (Opn1mw), arrestin (Arr3), and increased
transducin (Gnb3)) also suggests altered photoreceptor function (54), and whole transcriptome RNA
Sequencing (RNA-seq) has identified changes in transcripts including cyclic nucleotide gated channel
(Cngb3), arrestin (Arr), guanine nucleotide binding protein (Gnb3), and phosphodiesterase (Pde6h).
Accepted Article
This article is protected by copyright. All rights reserved.
Marginal decreases were also noticed in mRNA for RPE65, c transducin (Gnat2) and Crxos1 (55). A
significant decrease in RPE65 protein immunoreactivity was apparent in Wistar rats diabetic 12
weeks, but was less evident in diabetic Sprague Dawley rats (28). Rhodopsin kinase (Grk1) mRNA
was subnormal in diabetic Brown Norway and Sprague Dawley rats (but not in diabetic Long Evans
rats), but expression of rhodopsin kinase protein was reported to be increased in retinas of Sprague
Dawley rats diabetic for 6 weeks (53). Despite the changes in rhodopsin kinase and arrestin identified
above, diabetes of 12 weeks duration in rats did not alter the rate of deactivation of the
photoresponse (56).
Notably, insulin (independently of glucose uptake) has direct effects on photoreceptors. Insulin
directly binds to photoreceptors, and initiates signaling within those cells (57-62). Photoactivation of
rhodopsin causes tyrosine phosphorylation of the insulin receptor and subsequent activation of
phosphoinositide 3-kinase, a neuron survival factor (62, 63). This activation has been speculated to
protect the photoreceptors from light damage. The retinal insulin receptor exhibits a high level of
basal autophosphorylation, and this autophosphorylation is reduced in diabetic mouse retinas (64).
Thus, the absence or relative absence of insulin in diabetes might have effects on photoreceptors that
have not been fully characterized yet.
Na
+
/K
+
-ATPase activity, which is concentrated in outer segments of rods, plays a major role in a-wave
maintenance and is responsible for sustaining the dark current (65). Na
+/
K
+
-ATPase activity has been
found to be impaired in diabetes (66-69). It is possible that this diminished activity contributes to the
diabetes-induced reduction in photoreceptor amplitude.
Not all defects affecting to photoreceptor function in diabetes directly involve the photoreceptors.
Some investigators have demonstrated that the availability of vitamin A (retinol; the parent
compound for retinoids) is subnormal in diabetes (70, 71).
Summarizing: Diabetes causes a number of molecular alterations within photoreceptors, but there is
not yet a clear understanding of how these changes occur, or their significance with regard to
photoreceptor (and retinal) function. Whether these abnormalities are a cause or result of the
oxidative stress that develops in photoreceptors in diabetes is not known.
Accepted Article
This article is protected by copyright. All rights reserved.
D. Changes in photoreceptor/RPE unit function in diabetes
Photoreceptors are the most metabolically active neuron in the central nervous system (72). One
common method for evaluating the function of photoreceptors noninvasively is via electroretinogram
(ERG), and specifically by analysis of the ERG a-wave (73-75).
a. Animal studies: Diabetes-induced defects in both amplitude and latency of the a-wave have been
detected in some studies of diabetic rats. This defect has been reported to develop as rapidly as 2
days after the onset of diabetes (76), but whether this rapid development of a functional defect was
due to diabetes or the rapidly changing metabolic mileau immediately after the initiation of
hyperglycemia and insulin deficiency is not yet clear. Defects have been reported also at 4 weeks (77)
and 12 weeks of diabetes (76), and the defects in photoreceptor function detected at 12 weeks of
diabetes in rats encompassed several different parameters, including abnormal response amplitudes
in the presence of normal sensitivity (76, 78). Diabetes did not affect deactivation of the
photoreceptor response, and dark adaptation occurred faster than normal in those diabetic animals
(78). The authors interpreted this data as likely indicating a decrease in the amount of rhodopsin
present in the rod outer segments associated with a proportional decrease in outer segment lengths.
Likewise, some studies involving diabetic mice showed defects in the a-wave. Diabetic db/db mice
showed significant a-wave amplitude and implicit time defect in the interval of 8-24 weeks diabetes
(32). Spontaneously diabetic Ins2akita mice showed subnormal a-wave amplitude and implicit time at
9 months of age, but not at 3 or 6 months of age (30).
Diabetes has been reported to result in subnormal rhodopsin generation (51, 79). Rhodopsin
regeneration was also reported to be impaired by decreased pH in rod photoreceptors based on
studies in the excised mouse eye (51, 79). These data appear consistent with recent data from
Linsenmeier et al. who reported a significant acidosis in rod nuclei of rats diabetic for 1 month (80).
Not all investigators detected diabetes-induced alterations in a-wave. Responses of the a-wave were
not significantly reduced by experimental diabetes of 3 months duration in male Sprague Dawley rats
(81) or in male Long Evans rats (82). Likewise, the a-wave at the brightest luminous energy was
unaffected by 12 weeks diabetes in male SD rats (83), and amplitudes in such rats were significantly
reduced only at 10 and 15 weeks of diabetes, but not at 2, 6, 20 or 25 weeks (84). No significant
differences were observed in the sensitivity or amplitude of the a- or b-wave components of the ERG
between female diabetic and control rats (85), but this might be due to the less severe diabetes that
Accepted Article
This article is protected by copyright. All rights reserved.
developed in the female rats (compared to male rats). A-wave amplitudes were not subnormal in
C57Bl/6J mice (86) tested at 22 weeks of diabetes. Thus, there seems to be no consensus on a-wave
involvement in diabetic rodents at present.
b. Patient studies: Clinical data provide evidence for rod and cone receptor defects in patients with
diabetic retinopathy. Studies of diabetic patients by Holopigian and collaborators detected both rod-
isolated and cone-isolated changes in a-wave that were primarily in the log S (sensitivity) parameter
(87). Based on the mathematical model that they used to interpret the results, changes in the
sensitivity parameter indicate that the receptors may have transduction abnormalities, although this
was not confirmed experimentally. Losses of selective S-cone pathway sensitivity (88) have been
identified in diabetic patients. Alterations in rod and cone signaling have been detected in newly
onset type 2 diabetes patients with normal fundus appearance (89). Patients with diabetes exhibit
retinal regions with early neuroretinal dysfunction that are predictive of the eventual locations that
develop microvascular histopathology (90, 91), but the contributions of photoreceptors to the
multifocal ERG signal remains unclear. More light than usual is required to bleach an equivalent
amount of photopigment in some diabetic patients, suggesting that the photopigment is not
bleaching normally (92).
Elevations of glucose in diabetes seems itself to play an important role in the development of
photoreceptor defects, since rod adaptation (but not cone adaptation) was enhanced by transiently
increased blood glucose (93).
Photoreceptors and the RPE have multiple close interactions related to many important functions of
the outer retina including recovery of photoreceptor sensitivity following a bleach (94).
Rod sensitivity was subnormal in patients with early diabetic retinopathy, and mean thresholds were
abnormal at all eccentricities and in all four quadrants of retina (95). Abnormalities in dark
adaptation and absolute threshold have also been reported in human subjects with diabetes (7, 95-
97). Electrooculogram amplitudes (thought to reflect ionic fluxes across the RPE) have been shown to
fluctuate with elevation of blood glucose in healthy human subjects (98). In addition, the RPE
response was found to be abnormal in diabetic mice with prolonged diabetes (86).
Summarizing: The electrophysiology data suggest that photoreceptors and/or RPE show variable
impairments in diabetes. Whether or not these changes can serve as biomarkers for impending
development of aspects of diabetic retinopathy is still unclear.
Accepted Article
This article is protected by copyright. All rights reserved.
E. Diabetes-induced alterations in ion flux in photoreceptors
As discussed above, electrophysiologic and biochemical (ATPase) evidence suggests that diabetes
alters photoreceptor ion homeostasis. However, these data focus on the entire retina and movement
of monovalent ions like sodium. L-type calcium channels (LTCCs) are the major entry route of calcium
into photoreceptors, and play a major role in photoreceptor function. For example, sustained influx
of calcium into photoreceptors via open LTCCs is essential for the regulated release of the
neurotransmitter glutamate (among many other critical functions) (99). Photoreceptors also have a
relatively weak calcium buffering capacity (100-102), and contain at least 75% of total retinal
mitochondria (103-107). Together, these calcium handling features greatly facilitate rapid signaling in
photoreceptors but also substantially promote susceptibility to increased reactive oxygen species
production relative to other cell types in the retina.
Manganese-enhanced MRI (MEMRI) is a new method that measures aspects of photoreceptor
function not evaluated using electrophysiology, such as the influx of divalent ions like calcium into
central retinal photoreceptors of awake and freely moving animals. Manganese (Mn
2+
, a strong MRI
contrast agent) is a calcium ion surrogate that is taken into excitable cells via in L-type calcium
channels (LTCCs) (20, 108-117). After systemic injection of a nontoxic dose of MnCl
2
, manganese
uptake into photoreceptors and other retinal cells can be non-invasively and quantitatively measured
using MEMRI. This technique is being used to investigate diabetes-induced changes in calcium
channels in photoreceptors.
Early in the course of diabetes, MEMRI studies have demonstrated that photoreceptor uptake of
manganese is significantly reduced in dark-adapted mice and rats, suggesting that diabetes causes a
paradoxical closure of LTCCs in the dark (as if the photoreceptors were light adapted) (20, 112, 118).
Because these ion channels are essential for regulated release of neurotransmitter at the
photoreceptor synapse, paradoxically closed photoreceptor LTCCs in the dark (together with the
normally closed LTCCs in the light) likely have significant consequences on function of photoreceptors
and the whole retina.
Several possibilities exist as to how diabetes might inhibit opening of ion channels in dark:
a. The diabetes-induced defect in photoreceptor ion channel regulation apparently is secondary to
oxidative stress. Preventing oxidative stress in diabetic mice or rats, using either genetic
overexpression of Cu,Zn superoxide dismutase or systemic administration of α-lipoic acid,
respectively, corrected the diabetes-induced reduction in ion flux into photoreceptors in the dark (20,
112). Interestingly, both of these treatments also have been shown to inhibit the diabetes-induced
Accepted Article
This article is protected by copyright. All rights reserved.
degeneration of retinal capillaries (20, 119). On-going experiments are testing the possibility that
closed LTCCs might also contribute to the oxidative stress.
b. Diabetes alters electron chain efficiency, resulting in excessive generation of superoxide. Thus, the
reduction in mitochondrial function might reduce the energy available for keeping the cyclic
guanosine monophosphate (cGMP) channels open in the dark (112, 120). Available data does not
provide support for this hypothesis, however, since retinal adenosine triphosphate (ATP) levels
(measured during daylight hours) have not been found to be abnormal in diabetes (69, 121).
Moreover, 11-cis-retinal supplementation partly restored manganese uptake, suggesting that enough
energy was available to maintain open channels, at least to some degree (118).
c. Activated protein kinase C (PKC) suppresses L-type calcium channel activity (at least in cardiac
tissue) (122). PKC activity is known to be increased in retina in diabetes, and has been implicated in
diabetes-induced reductions in visual function (123, 124).
Summarizing: Accumulating evidence demonstrates that diabetes alters ion flux in photoreceptors,
and that these abnormalities are linked to oxidative stress. The contribution of photoreceptor
calcium channels and ion flux to the oxidative stress and to the development of the lesions clinically
accepted as diabetic retinopathy is vastly unexplored, and is actively being investigated.
Conclusion:
Photoreceptors are unique to the retina, and thus might account for the unique susceptibility of the
retina to damage in diabetes. Although photoreceptors account for most of the mass and metabolic
activity of the retina and they clearly influence the function of all other cell types in the retina, their
role in DR has not been clearly delineated. The present review provides a rationale for further study
of a role of photoreceptors in the pathogenesis of diabetic retinopathy. The contributions of
surrounding cells, such as RPE and choriocapillaris, to the photoreceptor alterations in diabetes
remain to be investigated.
Acknowledgments. This work was supported by grants from the National Eye Institute (R01EY00300
and R01EY022938 to TSK, and R21 EY021619 to BAB), the Medical Research Service of the
Department of Veteran Affairs (to TSK), NIH Animal Models of Diabetic Complications Consortium and
Mouse Metabolic Phenotyping Centers Pilot and Feasibility Programs (to BAB), and an unrestricted
grant from Research to Prevent Blindness (Kresge Eye Institute).
Duality of interest. None
Accepted Article
This article is protected by copyright. All rights reserved.
Literature cited
1. Kern TS, Engerman RL. Capillary lesions develop in retina rather than cerebral cortex in
diabetes and experimental galactosemia. Arch Ophthalmol. 1996;114:306-10.
2. Carter-Dawson LD, LaVail MM. Rods and cones in the mouse retina. I. Structural analysis using
light and electron microscopy. J Comp Neurol. 1979;188(2):245-62. Epub 1979/11/15.
3. Nikonov SS, Daniele LL, Zhu X, et al. Photoreceptors of Nrl -/- mice coexpress functional S- and
M-cone opsins having distinct inactivation mechanisms. The Journal of general physiology.
2005;125(3):287-304. Epub 2005/03/02.
4. Mears AJ, Kondo M, Swain PK, et al. Nrl is required for rod photoreceptor development. Nat
Genet. 2001;29(4):447-52. Epub 2001/11/06.
5. Arden GB. The absence of diabetic retinopathy in patients with retinitis pigmentosa:
implications for pathophysiology and possible treatment. Br J Ophthalmol. 2001;85(3):366-70. Epub
2001/02/27.
6. de Gooyer TE, Stevenson KA, Humphries P, et al. Retinopathy is reduced during experimental
diabetes in a mouse model of outer retinal degeneration. Invest Ophthalmol Vis Sci.
2006;47(12):5561-8.
7. Arden GB, Wolf JE, Tsang Y. Does dark adaptation exacerbate diabetic retinopathy? Evidence
and a linking hypothesis. Vision Res. 1998;38(11):1723-9. Epub 1998/09/25.
8. Arden GB, Sidman RL, Arap W, et al. Spare the rod and spoil the eye. Br J Ophthalmol.
2005;89(6):764-9. Epub 2005/06/01.
9. Linsenmeier RA. Effects of light and darkness on oxygen distribution and consumption in the
cat retina. The Journal of general physiology. 1986;88(4):521-42. Epub 1986/10/01.
10. Haugh LM, Linsenmeier RA, Goldstick TK. Mathematical models of the spatial distribution of
retinal oxygen tension and consumption, including changes upon illumination. Ann Biomed Eng.
1990;18(1):19-36. Epub 1990/01/01.
11. Yu DY, Cringle SJ. Oxygen distribution and consumption within the retina in vascularised and
avascular retinas and in animal models of retinal disease. Prog Retin Eye Res. 2001;20(2):175-208.
Epub 2001/02/15.
12. Linsenmeier RA, Braun RD. Oxygen distribution and consumption in the cat retina during
normoxia and hypoxemia. The Journal of general physiology. 1992;99(2):177-97. Epub 1992/02/01.
13. Ahmed J, Braun RD, Dunn R, Jr., et al. Oxygen distribution in the macaque retina. Invest
Ophthalmol Vis Sci. 1993;34(3):516-21. Epub 1993/03/01.
Accepted Article
This article is protected by copyright. All rights reserved.
14. Wang S, Birol G, Budzynski E, et al. Metabolic responses to light in monkey photoreceptors.
Curr Eye Res. 2010;35(6):510-8. Epub 2010/05/15.
15. Arden GB, Sivaprasad S. Hypoxia and oxidative stress in the causation of diabetic retinopathy.
Curr Diabetes Rev. 2011;7(5):291-304. Epub 2011/09/16.
16. Arden GB, Sivaprasad S. The pathogenesis of early retinal changes of diabetic retinopathy.
Documenta ophthalmologica Advances in ophthalmology. 2012;124(1):15-26. Epub 2012/02/04.
17. Du Y, Veenstra A, Palczewski K, et al. Photoreceptor cells are major contributors to diabetes-
induced oxidative stress and local inflammation in the retina. Proc Natl Acad Sci U S A.
2013;110:16586-91. Epub 2013/09/27.
18. Kowluru RA, Tang J, Kern TS. Abnormalities of retinal metabolism in diabetes and
experimental galactosemia. VII. Effect of long-term administration of antioxidants on the
development of retinopathy. Diabetes. 2001;50(8):1938-42.
19. Kanwar M, Chan PS, Kern TS, et al. Oxidative damage in the retinal mitochondria of diabetic
mice: possible protection by superoxide dismutase. Invest Ophthalmol Vis Sci. 2007;48:3805-11.
20. Berkowitz BA, Gradianu M, Bissig D, et al. Retinal ion regulation in a mouse model of diabetic
retinopathy: natural history and the effect of Cu/Zn superoxide dismutase overexpression. Invest
Ophthalmol Vis Sci. 2009;50:2351-8.
21. Zheng L, Kern T. Role of nitric oxide, superoxide, peroxynitrite and poly(ADP-ribose)
polymerase in diabetic retinopathy. Front Biosci. 2009;14:3974-87.
22. Lee SG, Lee CG, Yun IH, et al. Effect of lipoic acid on expression of angiogenic factors in
diabetic rat retina. Clin Experiment Ophthalmol. 2012;40(1):e47-57. Epub 2011/09/10.
23. Hoang QV, Linsenmeier RA, Chung CK, et al. Photoreceptor inner segments in monkey and
human retina: mitochondrial density, optics, and regional variation. Vis Neurosci. 2002;19(4):395-407.
Epub 2003/01/04.
24. Kowluru RA, Kowluru A, Veluthakal R, et al. TIAM1-RAC1 signalling axis-mediated activation of
NADPH oxidase-2 initiates mitochondrial damage in the development of diabetic retinopathy.
Diabetologia. 2014;57(5):1047-56. Epub 2014/02/21.
25. Santos JM, Tewari S, Lin JY, et al. Interrelationship between activation of matrix
metalloproteinases and mitochondrial dysfunction in the development of diabetic retinopathy.
Biochem Biophys Res Commun. 2013;438(4):760-4. Epub 2013/07/31.
26. Kumar B, Gupta SK, Srinivasan BP, et al. Hesperetin rescues retinal oxidative stress,
neuroinflammation and apoptosis in diabetic rats. Microvasc Res. 2013;87:65-74. Epub 2013/02/05.
Accepted Article
This article is protected by copyright. All rights reserved.
27. Park SH, Park JW, Park SJ, et al. Apoptotic death of photoreceptors in the streptozotocin-
induced diabetic rat retina. Diabetologia. 2003;46(9):1260-8. Epub 2003/08/05.
28. Enzsoly A, Szabo A, Kantor O, et al. Pathologic alterations of the outer retina in
streptozotocin-induced diabetes. Invest Ophthalmol Vis Sci. 2014;55(6):3686-99. Epub 2014/05/23.
29. Zhang Y, Wang Q, Zhang J, et al. Protection of exendin-4 analogue in early experimental
diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2009;247(5):699-706. Epub 2008/12/17.
30. Hombrebueno JR, Chen M, Penalva RG, et al. Loss of synaptic connectivity, particularly in
second order neurons is a key feature of diabetic retinal neuropathy in the Ins2Akita mouse. PLoS
One. 2014;9(5):e97970. Epub 2014/05/23.
31. Tang L, Zhang Y, Jiang Y, et al. Dietary wolfberry ameliorates retinal structure abnormalities in
db/db mice at the early stage of diabetes. Experimental biology and medicine. 2011;236(9):1051-63.
Epub 2011/07/14.
32. Bogdanov P, Corraliza L, A Villena J, et al. The db/db mouse: a useful model for the study of
diabetic retinal neurodegeneration. PLoS One. 2014;9(5):e97302. Epub 2014/05/20.
33. Lu ZY, Bhutto IA, Amemiya T. Retinal changes in Otsuka long-evans Tokushima Fatty rats
(spontaneously diabetic rat)--possibility of a new experimental model for diabetic retinopathy. Jpn J
Ophthalmol. 2003;47(1):28-35. Epub 2003/02/15.
34. Batenburg WW, Verma A, Wang Y, et al. Combined Renin Inhibition/(Pro)Renin Receptor
Blockade in Diabetic Retinopathy- A Study in Transgenic (mREN2)27 Rats. PLoS One.
2014;9(6):e100954. Epub 2014/06/27.
35. Zarebska A, Czerny K, Bakiera K, et al. Histological changes in the retina in experimental
alloxan-induced diabetes in rabbits. Annales Universitatis Mariae Curie-Sklodowska Sectio D:
Medicina. 2001;56:81-4. Epub 2002/04/30.
36. Zarebska A, Lancut M, Bakiera K, et al. Ultrastructural changes in the receptor parts of retinal
rods in experimental alloxan-induced diabetes in rabbits. Annales Universitatis Mariae Curie-
Sklodowska Sectio D: Medicina. 2001;56:77-80. Epub 2002/04/30.
37. Alvarez Y, Chen K, Reynolds AL, et al. Predominant cone photoreceptor dysfunction in a
hyperglycaemic model of non-proliferative diabetic retinopathy. Disease models & mechanisms.
2010;3(3-4):236-45. Epub 2010/02/10.
38. Barber AJ, Lieth E, Khin SA, et al. Neural apoptosis in the retina during experimental and
human diabetes. Early onset and effect of insulin. J Clin Invest. 1998;102:783-91.
Accepted Article
This article is protected by copyright. All rights reserved.
39. Kern TS, Kowluru R, Engerman RL. Dog and rat models of diabetic retinopathy. In: Shafrir E,
editor. Lessons from Animal Diabetes. London: Smith-Gordon; 1996. p. 395-408.
40. Joussen AM, Poulaki V, Le ML, et al. A central role for inflammation in the pathogenesis of
diabetic retinopathy. Faseb J. 2004;18:1450-2.
41. Barber AJ, Antonetti DA, Kern TS, et al. The Ins2Akita Mouse as a Model of Early Retinal
Complications in Diabetes. Invest Ophthalmol Vis Sci. 2005;46(6):2210-8.
42. Kern TS. In vivo models of diabetic retinopathy. In: Duh EJ, editor. Diabetic Retinopathy.
Totowa, New Jersey: Humana Press; 2008. p. 137-56.
43. Frank RN. The Optic UK Lecture: bench-to-bedside adventures of a diabetes researcher:
results past, results present. Eye (Lond). 2011;25(3):331-41. Epub 2011/01/08.
44. Cho NC, Poulsen GL, Ver Hoeve JN, et al. Selective loss of S-cones in diabetic retinopathy. Arch
Ophthalmol. 2000;118(10):1393-400. Epub 2000/10/13.
45. Uji A, Murakami T, Unoki N, et al. Parallelism as a novel marker for structural integrity of
retinal layers in optical coherence tomographic images in eyes with epiretinal membrane. Am J
Ophthalmol. 2014;157(1):227-36 e4. Epub 2013/10/22.
46. Murakami T, Yoshimura N. Structural changes in individual retinal layers in diabetic macular
edema. Journal of diabetes research. 2013;2013:920713. Epub 2013/09/28.
47. Shin HJ, Lee SH, Chung H, et al. Association between photoreceptor integrity and visual
outcome in diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 2012;250(1):61-70. Epub
2011/08/30.
48. Forooghian F, Stetson PF, Meyer SA, et al. Relationship between photoreceptor outer
segment length and visual acuity in diabetic macular edema. Retina. 2010;30(1):63-70. Epub
2009/12/03.
49. Ito S, Miyamoto N, Ishida K, et al. Association between external limiting membrane status and
visual acuity in diabetic macular oedema. Br J Ophthalmol. 2013;97(2):228-32. Epub 2012/11/23.
50. Srinivasan VJ, Adler DC, Chen Y, et al. Ultrahigh-speed optical coherence tomography for
three-dimensional and en face imaging of the retina and optic nerve head. Invest Ophthalmol Vis Sci.
2008;49(11):5103-10. Epub 2008/07/29.
51. Ostroy SE, Frede SM, Wagner EF, et al. Decreased rhodopsin regeneration in diabetic mouse
eyes. Invest Ophthalmol Vis Sci. 1994;35(11):3905-9. Epub 1994/10/01.
Accepted Article
This article is protected by copyright. All rights reserved.
52. Kowluru A, Kowluru RA, Yamazaki A. Functional alterations of G-proteins in diabetic rat retina:
a possible explanation for the early visual abnormalities in diabetes mellitus. Diabetologia.
1992;35:624-31.
53. Kim YH, Kim YS, Noh HS, et al. Changes in rhodopsin kinase and transducin in the rat retina in
early-stage diabetes. Exp Eye Res. 2005;80(6):753-60. Epub 2005/06/09.
54. Kirwin SJ, Kanaly ST, Linke NA, et al. Strain-dependent increases in retinal inflammatory
proteins and photoreceptor FGF-2 expression in streptozotocin-induced diabetic rats. Invest
Ophthalmol Vis Sci. 2009;50(11):5396-404. Epub 2009/05/29.
55. Kandpal RP, Rajasimha HK, Brooks MJ, et al. Transcriptome analysis using next generation
sequencing reveals molecular signatures of diabetic retinopathy and efficacy of candidate drugs. Mol
Vis. 2012;18:1123-46. Epub 2012/05/19.
56. Phipps JA, Yee P, Fletcher EL, et al. Rod photoreceptor dysfunction in diabetes: activation,
deactivation, and dark adaptation. Invest Ophthalmol Vis Sci. 2006;47(7):3187-94.
57. Stella SL, Jr., Bryson EJ, Thoreson WB. Insulin inhibits voltage-dependent calcium influx into
rod photoreceptors. Neuroreport. 2001;12(5):947-51. Epub 2001/04/17.
58. Rajala A, Dighe R, Agbaga MP, et al. Insulin receptor signaling in cones. J Biol Chem.
2013;288(27):19503-15. Epub 2013/05/16.
59. Gupta VK, Rajala A, Rajala RV. Insulin receptor regulates photoreceptor CNG channel activity.
Am J Physiol Endocrinol Metab. 2012;303(11):E1363-72. Epub 2012/10/04.
60. Rajala A, Tanito M, Le YZ, et al. Loss of neuroprotective survival signal in mice lacking insulin
receptor gene in rod photoreceptor cells. J Biol Chem. 2008;283(28):19781-92. Epub 2008/05/16.
61. Yu X, Rajala RV, McGinnis JF, et al. Involvement of insulin/phosphoinositide 3-kinase/Akt
signal pathway in 17 beta-estradiol-mediated neuroprotection. J Biol Chem. 2004;279(13):13086-94.
Epub 2004/01/09.
62. Rajala RV, McClellan ME, Chan MD, et al. Interaction of the retinal insulin receptor beta-
subunit with the p85 subunit of phosphoinositide 3-kinase. Biochemistry. 2004;43(19):5637-50. Epub
2004/05/12.
63. Rajala A, Gupta VK, Anderson RE, et al. Light activation of the insulin receptor regulates
mitochondrial hexokinase. A possible mechanism of retinal neuroprotection. Mitochondrion.
2013;13(6):566-76. Epub 2013/09/03.
Accepted Article
This article is protected by copyright. All rights reserved.
64. Rajala RV, Wiskur B, Tanito M, et al. Diabetes reduces autophosphorylation of retinal insulin
receptor and increases protein-tyrosine phosphatase-1B activity. Invest Ophthalmol Vis Sci.
2009;50(3):1033-40. Epub 2008/11/26.
65. Wetzel RK, Arystarkhova E, Sweadner KJ. Cellular and subcellular specification of Na,K-ATPase
alpha and beta isoforms in the postnatal development of mouse retina. J Neurosci. 1999;19(22):9878-
89. Epub 1999/11/13.
66. Ottlecz A, Garcia CA, Eichberg J, et al. Alterations in retinal Na+, K(+)-ATPase in diabetes:
streptozotocin-induced and Zucker diabetic fatty rats. Curr Eye Res. 1993;12(12):1111-21. Epub
1993/12/01.
67. Bensaoula T, Ottlecz A. Decreased activity of retinal ATPases and Na+, K+-ATPase isozymes in
the microvascular and neural compartments of the experimentally diabetic retina. ARVO abstracts.
Invest Ophthalmol Vis Sci. 1995;36:S897.
68. Ottlecz A, Bensaoula T. Captopril ameliorates the decreased Na+, K+-ATPase activity in the
retina of streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci. 1996;37:1633-41.
69. Kern TS, Kowluru R, Engerman RL. Abnormalities of retinal metabolism in diabetes or
galactosemia. ATPases and glutathione. Invest Ophthalmol Vis Sci. 1994;35:2962-7.
70. Tuitoek PJ, Lakey JR, Rajotte RV, et al. Strain variation in vitamin A (retinol) status of
streptozotocin-induced diabetic rats. International journal for vitamin and nutrition research
Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung Journal international de
vitaminologie et de nutrition. 1996;66(2):101-5. Epub 1996/01/01.
71. Tuitoek PJ, Ziari S, Tsin AT, et al. Streptozotocin-induced diabetes in rats is associated with
impaired metabolic availability of vitamin A (retinol). The British journal of nutrition. 1996;75(4):615-
22. Epub 1996/04/01.
72. Ames A, 3rd, Li YY, Heher EC, et al. Energy metabolism of rabbit retina as related to function:
high cost of Na+ transport. J Neurosci. 1992;12(3):840-53. Epub 1992/03/01.
73. Hood DC, Birch DG. A quantitative measure of the electrical activity of human rod
photoreceptors using electroretinography. Vis Neurosci. 1990;5(4):379-87. Epub 1990/10/01.
74. Hood DC, Birch DG. Rod phototransduction in retinitis pigmentosa: estimation and
interpretation of parameters derived from the rod a-wave. Invest Ophthalmol Vis Sci.
1994;35(7):2948-61. Epub 1994/06/01.
75. Breton ME, Schueller AW, Lamb TD, et al. Analysis of ERG a-wave amplification and kinetics in
terms of the G-protein cascade of phototransduction. Invest Ophthalmol Vis Sci. 1994;35(1):295-309.
Epub 1994/01/01.
Accepted Article
This article is protected by copyright. All rights reserved.
76. Phipps JA, Fletcher EL, Vingrys AJ. Paired-flash identification of rod and cone dysfunction in
the diabetic rat. Invest Ophthalmol Vis Sci. 2004;45:4592-600.
77. Kusari J, Zhou S, Padillo E, et al. Effect of memantine on neuroretinal function and retinal
vascular changes of streptozotocin-induced diabetic rats. Invest Ophthalmol Vis Sci. 2007;48:5152-9.
78. Phipps JA, Yee P, Fletcher EL, et al. Rod photoreceptor dysfunction in diabetes: activation,
deactivation, and dark adaptation. Invest Ophthalmol Vis Sci. 2006;47:3187-94.
79. Ostroy SE. Altered rhodopsin regeneration in diabetic mice caused by acid conditions within
the rod photoreceptors. Curr Eye Res. 1998;17(10):979-85. Epub 1998/10/27.
80. Dmitriev AV, Henderson D, Lau JC, et al. Retinal Acidosis at an Early Stage of Diabetes in the
Rat. Invest Ophthalmol Vis Sci. 2014;55(5):1049-.
81. Kohzaki K, Vingrys AJ, Bui BV. Early inner retinal dysfunction in streptozotocin-induced
diabetic rats. Invest Ophthalmol Vis Sci. 2008;49:3595-604.
82. Aung MH, Kim MK, Olson DE, et al. Early visual deficits in streptozotocin-induced diabetic long
evans rats. Invest Ophthalmol Vis Sci. 2013;54(2):1370-7. Epub 2013/02/02.
83. Bui BV, Loeliger M, Thomas M, et al. Investigating structural and biochemical correlates of
ganglion cell dysfunction in streptozotocin-induced diabetic rats. Exp Eye Res. 2009;88(6):1076-83.
Epub 2009/05/20.
84. Li Q, Zemel E, Miller B, et al. Early retinal damage in experimental diabetes:
electroretinographical and morphological observations. Exp Eye Res. 2002;74:615-25.
85. Ramsey DJ, Ripps H, Qian H. An electrophysiological study of retinal function in the diabetic
female rat. Invest Ophthalmol Vis Sci. 2006;47:5116-24.
86. Samuels IS, Lee CA, Petrash JM, et al. Exclusion of Aldose Reductase as a mediator of ERG
deficits in a mouse model of diabetic eye disease. Visual Neuroscience. 2012;29:267-74.
87. Holopigian K, Greenstein VC, Seiple W, et al. Evidence for photoreceptor changes in patients
with diabetic retinopathy. Invest Ophthalmol Vis Sci. 1997;38(11):2355-65. Epub 1997/10/31.
88. Greenstein V, Sarter B, Hood D, et al. Hue discrimination and S cone pathway sensitivity in
early diabetic retinopathy. Invest Ophthalmol Vis Sci. 1990;31(6):1008-14. Epub 1990/06/01.
89. Tyrberg M, Lindblad U, Melander A, et al. Electrophysiological studies in newly onset type 2
diabetes without visible vascular retinopathy. Documenta ophthalmologica Advances in
ophthalmology. 2011;123(3):193-8. Epub 2011/11/08.
Accepted Article
This article is protected by copyright. All rights reserved.
90. Harrison WW, Bearse MA, Jr., Ng JS, et al. Multifocal electroretinograms predict onset of
diabetic retinopathy in adult patients with diabetes. Invest Ophthalmol Vis Sci. 2011;52(2):772-7.
Epub 2010/10/12.
91. Harrison WW, Bearse MA, Jr., Schneck ME, et al. Prediction, by retinal location, of the onset
of diabetic edema in patients with nonproliferative diabetic retinopathy. Invest Ophthalmol Vis Sci.
2011;52(9):6825-31. Epub 2011/07/12.
92. Elsner AE, Burns SA, Lobes LA, Jr., et al. Cone photopigment bleaching abnormalities in
diabetes. Invest Ophthalmol Vis Sci. 1987;28(4):718-24. Epub 1987/04/01.
93. Holfort SK, Jackson GR, Larsen M. Dark adaptation during transient hyperglycemia in type 2
diabetes. Exp Eye Res. 2010;91(5):710-4. Epub 2010/08/25.
94. Strauss O. The retinal pigment epithelium in visual function. Physiological reviews.
2005;85(3):845-81. Epub 2005/07/01.
95. Greenstein VC, Thomas SR, Blaustein H, et al. Effects of early diabetic retinopathy on rod
system sensitivity. Optometry and vision science : official publication of the American Academy of
Optometry. 1993;70(1):18-23. Epub 1993/01/01.
96. Henson DB, North RV. Dark adaptation in diabetes mellitus. Br J Ophthalmol. 1979;63(8):539-
41. Epub 1979/08/01.
97. Amemiya T. Dark adaptation in diabetics. Ophthalmologica. 1977;174(6):322-6. Epub
1977/01/01.
98. Schneck ME, Fortune B, Adams AJ. The fast oscillation of the electrooculogram reveals
sensitivity of the human outer retina/retinal pigment epithelium to glucose level. Vision Res.
2000;40(24):3447-53. Epub 2000/11/04.
99. Schmitz Y, Witkovsky P. Dependence of photoreceptor glutamate release on a
dihydropyridine-sensitive calcium channel. Neuroscience. 1997;78(4):1209-16. Epub 1997/06/01.
100. Mann M, Haq W, Zabel T, et al. Age-dependent changes in the regulation mechanisms for
intracellular calcium ions in ganglion cells of the mouse retina. Eur J Neurosci. 2005;22(11):2735-43.
Epub 2005/12/06.
101. Nikonov S, Engheta N, Pugh EN, Jr. Kinetics of recovery of the dark-adapted salamander rod
photoresponse. The Journal of general physiology. 1998;111(1):7-37. Epub 1998/02/14.
102. Chiquet C, Dkhissi-Benyahya O, Cooper HM. Calcium-binding protein distribution in the retina
of strepsirhine and haplorhine primates. Brain Res Bull. 2005;68(3):185-94. Epub 2005/12/06.
Accepted Article
This article is protected by copyright. All rights reserved.
103. Demontis GC, Longoni B, Marchiafava PL. Molecular steps involved in light-induced oxidative
damage to retinal rods. Invest Ophthalmol Vis Sci. 2002;43(7):2421-7. Epub 2002/07/02.
104. Yang JH, Basinger SF, Gross RL, et al. Blue light-induced generation of reactive oxygen species
in photoreceptor ellipsoids requires mitochondrial electron transport. Invest Ophthalmol Vis Sci.
2003;44(3):1312-9. Epub 2003/02/26.
105. Krizaj D, Copenhagen DR. Calcium regulation in photoreceptors. Front Biosci. 2002;7:d2023-
44. Epub 2002/08/06.
106. Morgans CW, El Far O, Berntson A, et al. Calcium extrusion from mammalian photoreceptor
terminals. J Neurosci. 1998;18(7):2467-74. Epub 1998/04/16.
107. Johnson JE, Jr., Perkins GA, Giddabasappa A, et al. Spatiotemporal regulation of ATP and Ca2+
dynamics in vertebrate rod and cone ribbon synapses. Mol Vis. 2007;13:887-919. Epub 2007/07/27.
108. Drapeau P, Nachshen DA. Manganese fluxes and manganese-dependent neurotransmitter
release in presynaptic nerve endings isolated from rat brain. The Journal of physiology. 1984;348:493-
510. Epub 1984/03/01.
109. Lin YJ, Koretsky AP. Manganese ion enhances T1-weighted MRI during brain activation: an
approach to direct imaging of brain function. Magnetic resonance in medicine : official journal of the
Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine.
1997;38(3):378-88. Epub 1997/10/27.
110. Berkowitz BA, Roberts R, Goebel DJ, et al. Noninvasive and simultaneous imaging of layer-
specific retinal functional adaptation by manganese-enhanced MRI. Invest Ophthalmol Vis Sci.
2006;47:2668-74.
111. Berkowitz BA, Roberts R, Luan H, et al. Manganese-enhanced MRI studies of alterations of
intraretinal ion demand in models of ocular injury. Invest Ophthalmol Vis Sci. 2007;48:3796-804.
112. Berkowitz BA, Roberts R, Stemmler A, et al. Impaired apparent ion demand in experimental
diabetic retinopathy: correction by lipoic Acid. Invest Ophthalmol Vis Sci. 2007;48:4753-8.
113. Berkowitz BA, Roberts R, Oleske DA, et al. Quantitative mapping of ion channel regulation by
visual cycle activity in rodent photoreceptors in vivo. Invest Ophthalmol Vis Sci. 2009;50:1880-5.
114. Ivanova E, Roberts R, Bissig D, et al. Retinal channelrhodopsin-2-mediated activity in vivo
evaluated with manganese-enhanced magnetic resonance imaging. Mol Vis. 2010;16:1059-67. Epub
2010/07/03.
Accepted Article
This article is protected by copyright. All rights reserved.
115. Berkowitz BA, Roberts R, Bissig D. Light-dependant intraretinal ion regulation by melanopsin
in young awake and free moving mice evaluated with manganese-enhanced MRI. Mol Vis.
2010;16:1776-80. Epub 2010/09/03.
116. Bissig D, Goebel D, Berkowitz BA. Diminished vision in healthy aging is associated with
increased retinal L-type voltage gated calcium channel ion influx. PLoS One. 2013;8(2):e56340. Epub
2013/03/05.
117. Berkowitz BA, Grady EM, Roberts R. Confirming a prediction of the calcium hypothesis of
photoreceptor aging in mice. Neurobiol Aging. 2014;35(8):1883-91. Epub 2014/04/01.
118. Berkowitz BA, Bissig D, Patel P, et al. Acute systemic 11-cis-retinal intervention improves
abnormal outer retinal ion channel closure in diabetic mice. Mol Vis. 2012;18:372-6. Epub
2012/02/23.
119. Kowluru RA, Odenbach S. Effect of long-term administration of alpha-lipoic acid on retinal
capillary cell death and the development of retinopathy in diabetic rats. Diabetes. 2004;53(12):3233-
8. Epub 2004/11/25.
120. Braun RD, Gradianu M, Vistisen KS, et al. Manganese-enhanced MRI of human choroidal
melanoma xenografts. Invest Ophthalmol Vis Sci. 2007;48:963-7.
121. Diederen RM, Starnes CA, Berkowitz BA, et al. Reexamining the hyperglycemic pseudohypoxia
hypothesis of diabetic oculopathy. Invest Ophthalmol Vis Sci. 2006;47(6):2726-31.
122. Kamp TJ, Hell JW. Regulation of cardiac L-type calcium channels by protein kinase A and
protein kinase C. Circ Res. 2000;87(12):1095-102. Epub 2000/01/11.
123. Aiello LP, Davis MD, Girach A, et al. Effect of ruboxistaurin on visual loss in patients with
diabetic retinopathy. Ophthalmology. 2006;113(12):2221-30.
124. Davis MD, Sheetz MJ, Aiello LP, et al. Effect of ruboxistaurin on the visual acuity decline
associated with long-standing diabetic macular edema. Invest Ophthalmol Vis Sci. 2009;50:1-4.
LEGEND
Fig 1. Structure of the mouse retina, and localization of photoreceptors and microvasculature within
the retina. The retina is highly organized, and cells in the Ganglion Cell Layer (GCL), Inner Nuclear
Layer (INL), and Outer Nuclear Layer (ONL) appear in discrete layers. Between these nuclear layers are
plexiform layers where processes from various neural and glial cell types interdigitate. Retinal
photoreceptors (that absorb light) interact with the Retinal Pigment Epithelium (RPE) to maintain the
visual cycle, and thus, vision. The vasculature supplying the retina comes from two different sides,
Accepted Article
This article is protected by copyright. All rights reserved.
with the photoreceptors supplied by choroidal vessels below the retina, and the inner retina supplied
by interconnected vascular networks (radial peripapillary network, and inner and deep vascular
networks). The retinal microvasculature is a major site of damage in diabetes. These vascular beds are
indicated in cartoon form (red) on the figure.
Fig 2. Postulated mechanism by which retinal photoreceptors contribute to the development of the
vascular lesions that are typical of the nonproliferative stage of diabetic retinopathy (NPDR).
Diabetes causes oxidative stress and perhaps other adaptive changes in photoreceptors, in part via
diabetes-induced alterations in ion flux. These abnormalities likely affect intermediate cells (such as
Müller cells and leukocytes), which result in characteristic pathologic alterations to the retinal
vasculature, including increased permeability and nonperfusion.
Accepted Article
This article is protected by copyright. All rights reserved.
