See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/272422216

Ocular complications of diabetes mellitus

Article  in  World Journal of Diabetes · February 2015

DOI: 10.4239/wjd.v6.i1.92 · Source: PubMed

CITATIONS READS

224 2,508

3 authors:

Nihat Sayın Necip Kara

Kanuni Sultan Süleyman Training and Research Hospital Istanbul Gaziantep University
26 PUBLICATIONS   660 CITATIONS    85 PUBLICATIONS   1,543 CITATIONS   

SEE PROFILE SEE PROFILE

Gökhan Pekel
Pamukkale University
118 PUBLICATIONS   1,036 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Spectral Domain OCT-Based Evaluation of the Sclera and Its Adjacent Layers. View project

Vitrectomy View project

All content following this page was uploaded by Nihat Sayın on 14 July 2019.

The user has requested enhancement of the downloaded file.

 Submit a Manuscript: http://www.wjgnet.com/esps/ World J Diabetes 2015 February 15; 6(1): 92-108
Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 1948-9358 (online)
DOI: 10.4239/wjd.v6.i1.92 © 2015 Baishideng Publishing Group Inc. All rights reserved.

REVIEW

Ocular complications of diabetes mellitus

Nihat Sayin, Necip Kara, Gökhan Pekel

Nihat Sayin, Department of Ophthalmology, Kanuni Sultan is becoming more common. Ocular complications
Suleyman Education and Research Hospital, 34303 Istanbul, associated with DM are progressive and rapidly
Turkey becoming the world’s most significant cause of morbidity
Necip Kara, Department of Ophthalmology, Gaziantep and are preventable with early detection and timely
University, 27000 Gaziantep, Turkey
treatment. This review provides an overview of five
Gökhan Pekel, Department of Ophthalmology, Pamukkale
main ocular complications associated with DM, diabetic
University, 20070 Denizli, Turkey
Author contributions: Sayin N, Kara N and Pekel G contributed retinopathy and papillopathy, cataract, glaucoma, and
to this paper. ocular surface diseases.
Conflict-of-interest: The authors declare no conflicts of interest
regarding this manuscript. Key words: Diabetes mellitus; Diabetic retinopathy;
Open-Access: This article is an open-access article which was Ocular complication; Neovascular glaucoma; Cataract;
selected by an in-house editor and fully peer-reviewed by external Ocular diseases
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license, © The Author(s) 2015. Published by Baishideng Publishing
which permits others to distribute, remix, adapt, build upon this Group Inc. All rights reserved.
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and
the use is non-commercial. See: http://creativecommons.org/
Core tip: Ocular complications associated with diabetes
licenses/by-nc/4.0/ mellitus (DM) are progressive and rapidly becoming
Correspondence to: Nihat Sayin, MD, Department of the world’s most significant cause of morbidity and are
Ophthalmology, Kanuni Sultan Suleyman Education and preventable with early detection and timely treatment.
Research Hospital, Atakent Mahallesi, 4. Cadde. C 2-7 Blok. Kat: This review provides an overview of five main ocular
3 Daire: 13. Kücükcekmece, 34303 Istanbul, complications associated with DM, diabetic retinopathy
Turkey. [email protected] and papillopathy, cataract, glaucoma, and ocular
Telephone: +90-533-4383755 surface diseases.
Fax: +90-212-5714790
Received: July 9, 2014
Peer-review started: July 9, 2014 Sayin N, Kara N, Pekel G. Ocular complications of diabetes
First decision: September 23, 2014 mellitus. World J Diabetes 2015; 6(1): 92-108 Available from:
Revised: November 22, 2014
URL: http://www.wjgnet.com/1948-9358/full/v6/i1/92.htm DOI:
Accepted: December 3, 2014
Article in press: January 4, 2015 http://dx.doi.org/10.4239/wjd.v6.i1.92
Published online: February 16, 2015

INTRODUCTION
Abstract Complications of diabetes mellitus (DM) are progressive
Diabetes mellitus (DM) is a important health problem and almost resulting by chronic exposure to high blood
that induces ernestful complications and it causes levels of glucose caused by impairments in insulin
significant morbidity owing to specific microvascular metabolism and biological macromolecules such as
complications such as, retinopathy, nephropathy and carbohydrates, lipids, proteins and nucleic acids[1]. DM
neuropathy, and macrovascular complications such as, and its complications are rapidly becoming the world’s
ischaemic heart disease, and peripheral vasculopathy. most significant cause of morbidity and mortality[2,3]. The
It can affect children, young people and adults and DM pandemic has expanded speedily in the developed

WJD|www.wjgnet.com 92 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

and developing countries. It is expected that DM will The aldose reductase enzyme and nicotinamide adenine
reach epidemic proportions within the near future[4]. DM dinucleotide phosphate are involved in this biochemical
affects more than 240 million people worldwide, and reaction. Sorbitol is further metabolized to fructose
this number is expected to reach roughly 370 million by by sorbitol dehydrogenase. Since sorbitol movement
2030[5,6]. DM can lead to several ocular complications such is severly restricted by cellular membrane, excessive
as diabetic retinopathy, diabetic papillopathy, glaucoma, accumulation of sorbitol in the cell occurs[27,28]. The
cataract, and ocular surface diseases[7]. Diabetes related increased sorbitol has potential osmotic damage in retinal
ocular complications are general public health problem, cells[29] (Figure 1).
so we purpose of putting emphasis on the frequencies, Chronic hyperglycemia increases quantity of diacy-
pathogenesis, and management of these ocular com- lglycerol (DAG), which is leading to activate protein
plications. kinase C[30]. This activation leads to increase vascular
permeability and upregulation of VEGF in the retinal
structure. However, this abnormal patway may lead to
DIABETIC RETINOPATHY increase the activation of leukostasis[31-33] and significant
Diabetic retinopathy (DR), a microangiopathy affecting changes in extracellular matrix (ECM) protein synthesis
all of the small retinal vessels, such as arterioles, capillaries (Figure 2). Eventually, DAG and PKC pathway adversely
and venules, is characterized by increased vascular affect inflammation, neovascularization, and retinal
permeability, ocular haemorrhages, lipid exudate, by haemodynamics, which redounds to progression of
vascular closure mediated by the development of new DR[26].
vessels on the retina and the posterior vitreous surface[8]. VEGF is a crucial mediator in microvascular comp-
DR, the most common microvascular complication lications of DM. Normally, numerous retinal cells such as,
of DM, is predicted to be the principal reason of new retinal pigment epithelial (RPE) cells, Mueller cells, and
blindness among working population[9,10]. DR is the major pericytes, produce VEGF[31-33]. When a hypoxia occurs
reason of blindness in adults 20-74 years of age in the VEGF is secreted much more than normal production
United States of America[11]. In patients with type 1 and by hypoxic retinal tissues [31] . Clinical studies have
type 2 diabetics with disease duration of over twenty years, reported that there is a strong correlation between DR
the prevalences of DR are 95% and 60%, respectively[12]. and intraocular VEGF concentrations. Intravitreal and
Roughly 25% of type 1 diabetic patients have been intracameral VEGF levels were prominently increased in
reported to be influenced with DR, with the frequency patients with proliferative diabetic retinopathy (PDR)[34].
increasing to about 80% after 15 years of anguish[13]. Additionally, VEGF has a crucial role in the pathogenesis
The type 2 DM is responsible for a higher percentage of diabetic macular edema (DME) by increasing vascular
of patients with visual loss[13]. The incidence of DR is permeability[35,36].
related primarily to duration and control of diabetes and AGEs have been implicated in several diabetic
is related to hyperglycemia, hypertension, hyperlipidemia, complications, such as DR, and DME. Under chronic
pregnancy, nephropathy, and anemia[14-16]. According to hyperglycemic circumstances, proteins are nonenzymatically
reports published by Wisconsin epidemiologic study of glycated and the excessive amount of AGEs alter structures
diabetic retinopathy (WESDR)[17], the general 10-year and functions of ECM, basement membranes, and vessel
incidence of DR was 74%. Moreover in 64% of people wall.
with baseline DR developed more severe DR and 17% of Oxidative stress is also a serious condition that
those advanced to occur proliferative DR[18]. may result in microvascular complications[37,38]. Severe
production of reactive oxygen radicals may increase the
Pathogenesis oxidative stress and reduce antioxidant capacity[39].
There is a very strong relationship between chronic hyper- RAAS is the endocrine system that takes an essential
glycemia and the development of DR[19,20]. Hyperglycemia role to regulate vascular blood pressure, electrolyte, and
triggers a sequence of events causing vascular endothelial fluid balance and shows an aberration in patients with
dysfunction. Many interdependent metabolic pathways DM[40], although the accurate process of RAAS leads to
have been put forward as important connections between DR is not well clarified.
hyperglycemia and DR. These implicated metabolic Inflammation is a prominent part of the pathogenesis
pathways include increased polyol[21] and protein kinase of DR[41,42]. In response to hyperglycemic stress, AGE
C (PKC) pathway [22] activity, upregulation of growth formation, and hypertension, a sequence of inflammatory
factors of which vascular endothelial growth factor mediators are increased in DM. Retinal subclinical
(VEGF)[22], generation of advanced glycation endproducts inflammation contributes to elevated intraocular perfusion
(AGEs) [23,24], chronic oxidative damage [25], increased pressure by means of endothelial nitric oxide synthase
activation of the renin angiotensin system (RAS) [26], (eNOS), the development of neovascularization (NV)
chronic inflammation and abnormal clumping of due to hypoxia and VEGF. Although there are no
leukocytes (leukostasis)[26]. strong association between systemic inflammation and
When excessive amounts of glucose increase the development of DR [43,44], leukostasis is a likely to be
polyol way is activated to reduce glucose into sorbitol. a significant local factor in DR pathogeneis, causing

WJD|www.wjgnet.com 93 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

Aldose reductase Sorbitol dehydrogenase Hiperglycaemia

Increased Sorbitol Fructose
glucose
DAG
NADP NADP NAD NAD

Osmotic damage PKC

ECM protein synthesis leukostasis endothelial permeability

retinal haemodynamics expression of VEGF
Cell death

Figure 2 The protein kinase C pathway.

Figure 1 The polyol pathway.

capillary occlusion. Clinically significant macular edema

The Early Treatment Diabetic Retinopathy Study (ETDRS)
The classification of DR described the clinically significant macular edema (CSME)
Previously, DR was classified into three forms, such as, as the following conditions: (1) Retinal thickening within
background, pre-proliferative, and proliferative DR. The 500 microns of the center of the fovea; (2) Hard yellow
current classification is based on the location, extent, exudate within 500 microns of the center of the fovea
and degree of various clinically significant features, such with adjacent retinal thickening; and (3) Retinal thickening
as microaneurysms, intraretinal hemorrhages, venous 1 disc area or larger, any part of which is within 1 disc
abnormaities such as beading, intraretinal microvascular diameter of the center of the fovea.
abnormalities (IRMA), and NV. Recently, DR is classified The ETDRS indicated that the presence of CMSE guide
as either nonproliferative or proliferative. ophthalmologyst for the focal laser treatment.

Nonproliferative diabetic retinopathy: (1) Mild non- DME classification based on optical coherence
proliferative diabetic retinopathy (NPDR): There are a tomography
few microaneurysms; (2) Moderate NPDR: In this form, Optical coherence tomography (OCT) shows four
there are less than 20 microaneurysms. Hard yellow different types of DME: Sponge like retinal swelling,
exudates, cotton wool spots, and venous beading are cystoid macular edema (CME), macular edema with
present also in only one quadrant; (3) Severe NPDR: serous retinal detachment (SRD) and tractional macular
It is identified as any of following clinic features; edema (TDME)[46-48].
Microaneurysms in all 4 quadrants; Venous beading in 2
or more quadrants; IRMA in 1 or more quadrant; and (4) Sponge like retinal swelling: There is an increased
Very severe NPDR: This form includes 2 or more of the diffuse retinal thickness with reduced intraretinal
criteria for severe NPDR. reflectivity. This type of retinal swelling has a better visual
outcome than the CME, SRD and TRD types after laser
PDR: As a response to ischemia, NV grows at the optic treatment[49].
nerve (NVD) and elsewhere in the retina except the optic
disc (NVE). In general, NV grows at the border zone of CME: In this type, there is diffuse or focal retinal
perfused and non-perfused retina. These new vessels are thickening with intraretinal cystic spaces.
permeable, and the leakage of plasma contents probably
causes a structural change in the adjacent vitreous. SRD: There is an accumulation of subretinal fluid below
Also, NV may cause preretinal and subhyaloid vitreous reflective elevation. It is possible to confirm the presence
hemorrhages and can become membrane formations on of SRD only by OCT.
the posterior hyaloid surface.
TDME: TDME is identified by a hyperreflective
Diabetic macular edema membrane on OCT with loss of foveal depression and
Macular edema is defined as retinal thickening or the macular edema.
existence of hard exudates at 2 disk diameter of the
macula. Diabetic macular edema (DME) is the most First examination and follow-up
common cause of moderate or severe visual loss in The WESDR study represented that, for type 1 diabetic
diabetic patients. DME occurs apart from the stage of patients, the frequency of NPDR at less than 5 years
DR, so it should be evaluated independently. In diabetic was 17% and the frequency of PDR was nearly 0%[50].
eyes, central macular thickness does not correlate directly These frequencies were nearly 99%, and 50% after 20
with visual acuity, but there is a vigorous link between the years later, respectively. So, the first eye exam should be
unity of the photoreceptor inner/outer segment junction performed almost 4 years after diagnosis with annual
and visual acuity[45]. follow-up exams.

WJD|www.wjgnet.com 94 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

The same study indicated that, for type 2 diabetic fenofibrate reduced the need for focal laser treatment of
patients, the frequency of NPDR at 5 years was nearly CSME in type 2 diabetic patients[62].
30% and the frequency of PDR was nearly 2% [51].
These frequencies were nearly 80%, and 15% after 15 Laser treatment
years later, respectively. So, the first eye exam should be Laser treatment has been considered the evidence-
examined at diagnosis with annual follow-up exams. based treatment for DME and PDR for a long time.
Mild NPDR can be followed with dilated fundus Randomized studies have demonstrated the efficacy
exams every 12 mo. If DME that is not CSME is present, of laser photocoagulation to prevent vision loss from
follow-up every 3 mo is advised. If CSME is present, DME [63,64] . In eyes obser ved with CSME, prompt
treatment is advised promptly. Severe NPDR should be photocoagulation is highly recommended. Treatment is
followed up every 2 mo. If very severe NPDR is present, performed at areas of focal leaking microaneurysms by
patients should be followed more closely. After treatment using focal laser photocoagulation or at areas of diffuse
of PDR, they should be observed every 3 mo not to leakage by using grid laser photocoagulation. Laser spot
overlook complications, such as TRD and CSME. size should not be greater than 100 μm for focal laser
treatment. Grid laser treatment is characterized by mild
Current therapy RPE whitening spots as far as 2 optic disks diameters
The treatment of DR includes increased metabolic from the center of the fovea[65]. Combination treatment
control, laser treatment, intravitreal medication, and is applied in most patients, which involves focal and grid
surgery. laser treatment.
Patients are reevaluated for retreatment at 3 mo
Metabolic control intervals. For each retreatment, clinicians repeat the
Poor metabolic control is a good marker for development fluorescein angiogram to determine sites of persistent dye
and progression of DR. So, related risk factor such leakage. If patients have focal leakage with a circinate lipid
as, hyperglycemia, hypertension, and hyperlipidemia ring, it may not be necessary to repeat angiogram before
should be controlled. It reduces the risk of retinopathy the treatment because the leaking focal lesions are in the
occurrence and progression[52]. lipid ring.
Panretinal laser photocoagulation (PRP) treatment
Glysemic control became a standart of care for DR when the results of the
The trial research group [53] showed that, for type 1 Diabetic Retinopathy Study(DRS) were published[66,67].
diabetic patients, a 10% reduction in the hemoglobin A1c DRS showed that PRP enormously reduced the risk
(HbA1c) was associated with a 43% and 45% diminution of severe vision loss from 16% to 6.4% in patient with
in improvement of DR in the rigorous and traditional PDR. The goal of PRP is not to improve visual acuity. It
treatment group, respectively [53] . The another trial is applied to regress of the NVD or NVE and to prevent
group[54] found that, for type 2 diabetic patients, tighter the blinding complications of DRP. Generally, laser
blood glucose control had been found to correlate most treatment should be performed over a period of 4-6 wk
closely with a lower rate of DR[54]. However, very strict by applying 1.500-2.000 burns, with a size of 500 μm,
control of blood glucose may lead to cause worsening of spacing spots 0.5 burn widths from each other with a
DR due to up regulation of insulin-like growth factor-1 0.1-0.2 s duration[65].
(IGF-1)[52,55,56].
Intravitreal medication
Control of blood pressure The results of several investigations showed that these
Hypertension is more common in type 2 diabetic patients different intravitreal agents are effective not only in the
rather than patients with type 1 DM. Approximately prevention of visual loss, but also allowed a regain of
40%-60% of patients with hypertension are over the age visual acuity. The two main categories of intravitreal
range of 45 to 75[57]. Although the relationship between drugs recently used in the management of DME and
hypertension and progression of retinopathy is not PDR are steroids and anti-VEGF agents.
certain, good blood pressure control pulls down the risk The use of intravitreal steroids are preferred to
of DR. An another study[58] reported that strict control manage the DME. They have antiinflammatory and
of blood pressure reduces the risk of diabetic ocular antiangiogenic effects that stabilize of the inner blood-
complications[58]. retina barrier. Intraocular steroid injections have
benefical effects in PDR, by inhibiting production of the
Control of serum lipids VEGF[68,69]. Many various studies reported the benefits of
There is a positive correlations between the severity injections of triamcinolone acetonide (IVTA) to reduce
of DR and plasma lipid levels, particularly LDL-HDL DME and increase visual acuity[70-74].
cholesterol ratio[59]. Hard yellow exudates, which are lipid The effects of intravitreal steroids are temporary and
rich, have been found to correlate with plasma protein last for about 3 mo. In this cases, intravitreal steroids
levels. Dietary and medicine therapy may reduce hard may be repeated. But complications such as elevated
exudates [60,61]. Systemic lipid-lowering drugs such as, intraocular pressure and infection may occur. However,

WJD|www.wjgnet.com 95 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

IVTA is more likely to be associated with cataract DME resolution. However, the removal of the vitreous
progression. Combination of IVTA and laser treatment gel might improve inner retina oxygenation and thus
has more benefical effects in pseudophakic eyes than promote the resolution of DME[98-101].
laser alone[74]. PPV was introduced in the early 1970 as a promising
Recently, a novel, biodegradable, slow-release de- treatment for the severe late complications of PDR,
xamethasone implant (DEX implant, Ozurdex) was including vitreous hemorrhage, TRD, and fibrovascular
developed to gradually release 0.7 mg of preservative- proliferation[102]. The proper timing for PPV in PDR
free dexamethasone in the vitreous cavity after a small was under discusion for a long time. The Diabetic
incision[75]. DEX implant have the advantage of a lower Retinopathy Vitrectomy Study (DRVS) considered
incidence of cataract and glaucoma than IVTA[76]. The the early PPV effects compared to deferral PPV in
maximum effects of the DEX implant occur at 3 mo and patients with severe vitreous hemorrhage (VH) [103].
gradually diminish from month 4 to 6[77]. The DRVS showed that at 2-year follow up, early PPV
Anti-VEGF agents (pegaptanib, bavacizumab, for nonclearing VH primarily increased the chance for
ranibizumab, aflibercept) have been investigated as a retaining vision ≥ 20/40. Today, PPV can be performed
treatment for DME and for PDR. Also, anti-VEGF as early as it is needed by the patients. The aim of PPV
injections might be useful adjuncts to facilitate effective in PDR includes removal of opacity from the vitreous
fibrovascular membrane dissection in eyes with active space, and the removal of tractional membrane from
vascularity components[78]. TRD occur or progress within the retinal surface. Anti-VEGF injections might be
1-4 wk of anti-VEGF injection, so, in general, these useful adjuncts to ease effective fibrovascular membrane
cases should be scheduled in a timely manner after the dissection in eyes with active vascularity components[78].
injection[79]. Finally, enzymatic vitrectomy performed by the
Nowadays, clinicians have the option of four anti intravitreal injection of autologous plasmin enzyme might
VEGF agents: Pegaptanib (Macugen), Bevacizumab be effective and could be considered as an alternative
(Avastin), Ranibizumab (Lucentis), Aflibercept (Eylea). for diabetic patients before performing other treatments,
Pegaptanib is a selective VEGF antagonist that binds such as intravitreal injections of anti-VEGF or steroids,
to the VEGF165 isoform. Intravitreal pegaptanib is surgical vitrectomy or laser. Several investigations on
currently an approved treatment in neovascular choroidal enzymatic vitreolysis, such as microplasmin, showed that
membrane, but several trials addressed the efficacy many agents might achieve vitreous dissolution, PVD, or
and safety of intravitreal pegaptanib injections in the VH clearance[104,105].
treatment of PDR and DME[80-82].
Bevacizumab[83] is a full-size humanized antibody that Indications for PPV in PDR: Severe nonclearing
binds to all VEGF-A isoform. Intravitreal bevacizumab vitreous hemorrhage; Nonclearing vitreous hemorrhage;
is currently used beneficially in the off-label treatment Premacular subhyaloid hemorrhage; TRD involving
of DR. There have been many studies with intravitreal the fovea; Tractional and rhegmatogenous retinal
bevacizumab injections and DME. The results of detachment; Macular edema due to vitreomacular
these retrospective or prospective trials showed an traction; Nontractional macular edema that is refractory
improvement in visual acuity and OCT outcomes. to pharmacotherapy and laser therapy.
However, bevacizumab injections were also associated
with short-term efficacy and a high recurrence rate[83-88].
Ranibizumab is a high affinity anti-VEGF Fab DIABETIC PAPILLOPATHY
specifically designed for ophthalmic use. It binds to all Definition and incidence
isoforms of VEGF-A and related degradation products Diabetic papillopathy (DP) is an uncommon ocular
and neutralizes their biological activity. Several studies manifestation of DM identified by unilateral or bilateral
confirmed its efficacy in treating DME[89-94]. disk swelling associated with minimal or no optic nerve
Aflibercept[95] is an intravitreally administered fusion dysfunction[106-108]. DP, which is self-limited disease, was
protein that is designed to bind both the VEGF-A repoted in 1971 in T1DM patients for the first time[109].
and the placental growth factor with higher affinity in So, it is very difficult to predict the exact incidence of
comparison to other anti- VEGF agents[95]. Aflibercept DP. The prevalence of DP in both types of DM is about
has a longer duration of action in the eye after intraocular 0.5%, regardless of glycemic control and seriousness
injection. This new agent has been recently investigated of DRP [106-108]. The percentage of patients with DP
in the treatment of DME[96,97]. presenting a NPDRP is higher than in the PDRP.

Surgery Pathogenesis
Pars plana vitrectomy (PPV) is considered an option for The pathophysiology is not fully understood and several
patients not responding to combined anti-VEGF- laser theories have been suggested. There are no links
and/or steroid-laser theraphy in DME[98]. PPV, including between DP and either DRP or metabolic control. Some
posterior hyaloid, internal limiting membrane (ILM) researchers suggest that DP is a subtype of non-arteritic
and epiretinal membrane (ERM) removal, might achieve anterior ischemic optic neuropathy (NAION), but there

WJD|www.wjgnet.com 96 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

are some differantial features between NAION and DP, would be more logical to investigate the association of
for insance, DP is an asymptomatic optic disc edema, glaucoma subtypes individually with DM.
whereas NAION is an acute optic disc infarction[110,111].
However, the most plausible mechanism responsible for OAG and DM
DP is a limited impairment to the peripapillary vascular OAG is one of the most common causes of vision loss
network, and superficial capillary network endothelial worldwide. In several studies, DM was reported as a risk
cells[111,112]. factor for OAG, along with other risk factors such as
elevated IOP, older age, family history of glaucoma and
Clinical evaluation black race[121-123]. It was found that as the duration of type
The other causes of disk swelling, and PDRP with NV 2 DM increases, risk of having OAG also increases[123].
on the disc have been ruled out to verify the diagnosis On the other hand, an association of having a history
of DP[113]. DP, which occurs generally in patients with of DM and risk of OAG was not found in several
uncontrolled diabetes, has following features: painless studies[124,125]. It is possible that diabetic patients are more
visual loss, macular edema, disk hyperfluorescence likely to have an ocular examination than the general
on fluorescein angiography, and significant visual population and are thus more likely to be diagnosed with
improvement after the treatment[106]. OAG[122]. Small vascular abnormalities including optic
However, several diseases can imitate DP, such nerve vessels and oxidative damage are some of the
as infection, inflammation, metastatic infil-tration, possible mechanisms by which DM might increase risk
hypertension, and papilledema [106,108,114]. Pseudopap- of OAG[122]. In the aspect of treatment, OAG patients
illoedema, that is seen in patients with disc drusen[113], with DM undergoing trabeculectomy do not have the
can be confused with DP. same long-term IOP control and surgical survival rate
In order to reach differential diagnosis, investigations when compared with patients without DM[126]. Medical
are required, such as fluorescein angiography, orbital treatment, laser trabeculoplasty, and surgery (filtering
magnetic resonance imaging, blood tests including serum surgery, aqueous drainage devices, etc.) are the treatment
angiotensin-converting enzyme, anti nuclear antibody, options.
vitamin B12, folate, erythrocyte sedimentation rate, C
reactive protein, and fluorescent treponemal antibody ACG and DM
test. The association between DM and ACG is not very clear.
But several studies showed that DM might be considered
Current therapy as a risk factor for ACG[127,128]. Saw and colleagues[127]
So far, definitive treatment has not been found to change reported that diabetic patients have shallower anterior
its native progression, as in most cases the disc edema chambers than individuals without DM, irrespective of
resolves within a few months with no visual impairment. age, gender, and socioeconomic factors. Senthil et al[128]
Intravitreal anti-VEGF injection increased visual acuity found that DM is associated with ACG, possibly because
and decreased disk edema in patients with DP[114-117]. At of the thicker lenses of diabetic patients. Weinreb et al[129]
the same time, it is unknown that how anti-VEGF agents reported that pseudophakic pupillary block with ACG
affect to the patients with DP. Another study showed might occur in patients with DM. Also, treatment of DR
that periocular corticosteroids stabilize the blood-ocular with argon laser panretinal photocoagulation could cause
barrier at the disc and the macula and causes resolution ACG soon after the laser[130]. Medical treatment (topical,
of the disc and macular edema[118]. Some degree of optic oral, and intravenous agents) and laser iridotomy are the
atrophy is seldom present after treatment. Tight control treatment options.
of blood pressure optimises the visual outcome.
NVG and DM
NVG is a severe and intractable glaucoma type. DR is
GLAUCOMA one of the most common etiologic factors for NVG.
Association of DM and glaucoma has been investigated NVG might occur in cases with no retinal or optic disc
much in the literature. DM is the major etiologic factor neovascularization, but it is more likely seen in PDR[131].
for neovascular glaucoma (NVG) [119]. However, the The association of iris and angle NV with DM mostly
association of DM with other types of glaucoma such as increase with the duration of the disease and blood sugar
open angle glaucoma (OAG) and angle closure glaucoma control[132]. Although iris and angle NVs are common
(ACG) is controversial. Since glaucoma is a type of in DM, they do not always progress to NVG; but NVs
optic neuropathy and DM alone could cause optic always develop prior to IOP increase[132]. This is due to
neuropathy, a complex relation may occur between DM a fibrovascular membrane that occurs on the anterior
and glaucomatous optic neuropathy. On the other hand, surface of the iris and iridocorneal angle. This membrane
central corneal thickness (CCT) is found to be thicker then causes anterior synechiae, angle closure, and rise of
in patients with DM that could cause higher intraocular IOP[131,132].
pressure (IOP) readings[120]. Since the mechanisms of NVG may develop in diabetic patients after cataract
glaucoma subtypes are different from each other; it surgery, laser posterior capsulotomy and pars plana

WJD|www.wjgnet.com 97 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

vitrectomy[132]. NVG following these operations probably

CATARACT
results from a combination of surgical inflammation
and disruption of a barrier preventing diffusion of Definition and incidence
angiogenesis factors to the anterior segment[132]. Prompt Cataract, the commonest cause of curable blindness
diagnosis and treatment are very important to prevent worldwide, is the opacification of the crystalline
blindness due to NVG. Panretinal photocoagulation is the lens[143,144]. Diabetic cataract is considered a complication
key treatment method for prevention of NVG in DRP[131]. of DM, which can affect individuals at younger ages[145].
Panretinal photocoagulation laser therapy in the early Cataract formation in diabetics seems to be related to
stages may be efficacious in inhibiting and even reversing the hyperglicemia or to hastened senile lens opacity. A
new vessel proliferation in the anterior segment of the eye. snowflake like cataract is occured commonly in patients
Medical treatment, cyclophotocoagulation, cryotherapy, with insulin-dependent diabetes and more prones to
and surgery (trabeculectomy with antimetabolites and progress than others.
valve implantation) are the other therapeutic options. Diabetic patients are 2-5 times more at risk for cataract
formation and and are more likely to get it at an earlier
Other glaucoma types and DM age[146,147]. Although cataract frequency varies based on
Pseudoexfoliation (Psx) has been supposed to be a ethnic populations and geographic locations (ranges from
generalized or systemic disorder of the extracellular 35% to 48%), it is higher in diabetics when compared to
matrix[133]. Psx increases the risk of glaucoma develo- non-diabetics[148-152]. In a study by Raman et al[153], it has
pment[133]. It was reported that there is not a significant been indicated that the mixed cataract was more common
relationship between DM and psx [134]. Also, HbA1c than mono type cataract (42% vs 19%, respectively).
levels do not vary among patients with DM based on psx A combination of cortical, nuclear, and posterior
status[134]. Ellis et al[135] found that DM is not associated subcapsular cataract was the most common form of the
with ocular hypertension. On the other hand, it was mixed types (20%), followed by the combined posterior
revealed that DM is significantly associated with bilateral subcapsular cataract and cortical (16%). Among the
eye involvement in normotension glaucoma, maybe monotype cataracts, rate of cortical cataract was the
due to several impaired neurovascular autoregulation highest (15%), followed by nuclear cataract (5%) and
processes related to DM[136]. posterior subcapsular cataract (1%)[153]. On the other hand,
cataract frequency varies from 1% to 27% in patients with
Glaucomatous optic neuropathy and DM type 1 diabetes[154].
Retinal ganglion cell death is the major cause of blindness
in glaucoma. DM may increase susceptibility of retinal Pathogenesis
ganglion cells to apoptosis when there is a co-morbidity Several different pathogenetic mechanisms that may
with elevated IOP in glaucoma[137]. DM disrupts vascular precipitate formation of diabetic cataracts have been
tissues, compromises neuro-glial functions, and thus proposed: increased osmotic stress caused by activation
may take a role in the pathogenesis of optic neuropathy of the polyol pathway[155], non-enzymatic glycation of
related with glaucoma[138]. In the literature, it was shown lens proteins[156-159], and increased oxidative stress[160-164].
that DM may accelerate apoptosis of retinal inner
neurons, alter metabolism of astrocytes and Müller cells, The polyol pathway
and impair microglial function[138]. All of these factors In cases of high blood glucose levels in diabetic patients,
contribute to visual acuity, contrast sensitivity and color the crystalline lens is exposed to a hyperosmotic aqueous
vision loss in comorbidity of DM and glaucoma[138]. humour and its glucose concentration progressively
increases. During hyperglycemic conditions excess
Miscellaneous issues related to glaucoma and DM glucose to sorbitol. Sorbitol is further metabolized to
DM is associated with increased corneal stiffness, and fructose. In diabetic patients, the excessive accumulation
corneal hysteresis which have been shown to have an of sorbitol in the crystalline lens produces a high osmotic
effect on glaucoma risk [125,139]. IOP may increase in gradient that leads to a fluid infusion to equilibrate the
patients with DM due to aqueous outflow resistance osmotic gradient. The accumulation of sorbitol in lens
in trabecular meshwork, because of glycation and cell causes a collapse and liquefaction of lens fibers,
crosslinking of meshwork glycoproteins[140]. which eventually results in the cataract formation[165,166].
Since DM is frequently found with other systemic Moreover, increased osmotic stress in the crystalline lens
disorders, such as hypertension, this comorbid condition produced by excess accumulation of sorbitol initiates
may also affect glaucoma risk. Shoshani et al[141] reported apoptotic process in epithelial cells which contributes to
that DM may interfere with normal vascular regulation the cataractogenesis[155,167,168].
and contribute to glaucoma progression. Moise et al[142]
suggested that blindness due to glaucoma may be Non-enzymatic glycation
prevented by using a regular Mediterranean diet and Advanced glycation occurs during normal aging but to a
maintaining regular intake of vegetables in patients with greater degree in diabetic patients in which it contributes
DM. the formation of lens opacity[156]. Advanced glycation

WJD|www.wjgnet.com 98 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

produced by a nonenzymatically reaction beween the advisable to perform a large capsulorrhexis with a large
piece of the excess glucose and proteins, which may diameter IOLs, thus allowing better visualization of the
leads to production of superoxide radicals and AGE posterior segment for examination and further treatment
formation[169]. Excessive accumulation of AGEs in the of DR
crystalline lens of diabetic patients plays an essential role After cataract surgery, using topical anti-inflammatory
in cataractogenesis[157-161]. drugs such as steroids and nonsteroidal anti-inflammatory
drops may be useful to control inflammation and macular
Increased oxidative stress edema. Despite an uneventfully performed cataract
It is well known that chronic hyperglycemia may increase surgery, DR and macular edema can become exacerbated
the oxidant load[162] and facilitate the onset of senile after surgery, hence patients should be followed closely
cataract [163]. In diabetic eyes, antioxidant capacity is with fundus examinations and ancillary tests.
reduced free radical load is increased, which increases the
susceptibility of crystalline lens to oxidative damage. The
decrease in antioxidant capacity is facilitated by advanced
OCULAR SURFACE DISEASES
glycation and defects of antioxidant enzyme activity [164]. Ocular surface diseases, such as dry eye is frequently
present in diabetic patients. Ocular surface diseases
Clinical evaluation related with DM are developed in many mechanisms
DM can cause anterior segment changes as well including abnormal ocular surface sensitivity [178,179],
as posterior segment; therefore, a comprehensive decreased tear production[179-181], and delayed corneal re-
ophthalmologic examination including visual acuity epithelialization[181].
measurement, evaluation of relative afferent pupil
defect, slit-lamb biomicroscopy, gonioscopy, intraocular
DRY EYE SYNDROME
pressure measurement, and dilated fundus examination
are mandatory. In selected cases, ancillary tests such as Definition and incidence
fundus angiography and OCT may also be useful. Dry eye is a condition which is a complex disease
T he level of cataract should cor respond to of tear film and anterior surface of the cornea. The
patient’s visual complaints including decreased visual resulting changes in the ocular surface may lead to ocular
acuity, decreased contrast sensitivity, and glare. If the discomfort, and visual disturbance. Tear osmolarity,
biomicroscopic examination shows mild cataract but and ocular surface inflammation[182] are also increased
the patient reports severe visual dysfunction, other in diabetic patients causing dry eye disease. Burning,
ocular diabetic complications such as DR should be foreign body sensation, photophobia, blurred vision[183],
investigated. Recently, there has been a shift in emphasis and blurred vision are present in patients with dry eye.
towards early cataract removal in diabetics to enable Both dry eye disease and DM increase the risk of corneal
adequate identification for examination of posterior infections and scarring, in advanced disease, corneal
segment, and facilitate panretinal photocoagulation perforation and irreversible tissue damages[184] may occur.
and treatment of underlying macular edema [170]. Pre- Patients with dry eye have serious corneal complications
existing PDR and macular edema may exacerbate after such as, superficial punctuate keratitis, neurotrophic
cataract surgery[171] which contributes to the poor visual keratopathy, and persistent epithelial defect[185]. Dry eye
outcomes[172]. Therefore if posterior segment is visualized, syndrome (DES) is more like to occur in the industrial
diabetic patients with pre-existing retinopathy should be country. Studies showed that approximately 1.68 million
preoperatively treated. men and 3.2 million women[186] aged 50 and older are
affected with DES in the United States[187]. DES, one of
Current therapy the most common diagnosis for diabetic patients[188], is
First of all, good blood glucose control is main goal to a condition in which abnormal tear film and an changed
prevention of diabetic cataract. It has however been anterior surface of the cornea is present. Studies show
suggested that cataractogenesis can be prevented through at least 50% of DM patients have either symptomatic
nutrition and supplementation, including high content of or asymptomatic DES. 92 patients with diabetes types
nutritional antioxidants[173], lower dietary carbohydrate[174] I and II have been evaluated by Seifart[189]. The patients
and linolenic acid intake [175] , and aldose reductase were aged from 7 to 69 years old as well as normal
inhibitors[144,176]. healthy controls comparable in number, age and sex.
Currently, the main treatment for the diabetic cataract The study demonstrated that 52.8 of all diabetic patients
is surgery. Phacoemulsification results in better visual complained about eye dry symptoms, whereas 9.3% of
results, less intraocular inflammation and less capsular the healthy controls complained about dry eye symptoms.
opacification as compared to extracapsular surgery[177].
Femtosecond assisted cataract surgery may be a better Pathogenesis
option for diabetics; however, there has been no DM can lead to DES through a variety of mech-
comparative study comparing the results of femtosecond anisms[190-192], but the association between DM and DES
assisted to conventional cataract surgery in diabetics. It is is unclear[193]. The most possible mechanism responsible

WJD|www.wjgnet.com 99 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

for dry eye in DM is extensive hyperglycemia bring about widely used for the treatment of DES. The most widely
corneal neuropathy. Corneal neuropathy leads to tear film used anti-inflammatory agents are topical corticosteroids,
instability and lower tear break up time (TBUT) values NSAID, and cyclosporine A[203-205].
due to conjunctival goblet cell loss. Mucin, which covers Corticosteroids can reduce the symptoms and signs
the villus surface of the corneal epithelium and reduce of dry eye [206] to control inflammatory process. On
evaporative tear loss[181] is produced by conjunctival goblet the other hand, after long-term use, steroids produce
cells. severe side effects such as bacterial, viral, and fungal
The other suggested mechanisms for disruption of infection, elevated IOP, and cataract formation. NSAIDs
corneal integrity include AGE accumulation[194,195] and are increasingly used as dry eye treatment instead of
polyol pathway[196,197] bi-product accumulation within steroids because of their non-severe side effects. Topical
the corneal layers. It is believed that DM affects tear cyclosporine A are used to increase tear production[207]
production and quality by compromising the functional and the number of goblet cells decreased by chronic
integrity of the lacrimal gland. Corneal sensitivity is also inflammation due to dry eye disease[207].
reduced in DM, which affects the stimulation of basal
tear production. Both lacrimal gland integrity[180] and
corneal sensitivity are shown to be affected by diabetic DIABETIC KERATOPATHY
neuropathy[180,198]. These proposed mechanisms imply that Definition and incidence
DM affects both tear production and corneal integrity, DM can trigger acceleration of ocular surface abnor-
suggesting disruption to one or both may cause and lead malities which have been termed diabetic keratopathy[208].
to the exacerbation of DES. In contrast to healthy persons, patients with diabetes
have corneal epithelial erosions that may recur and
Clinical evaluation be associated with unresponsiveness to conventional
During rutine eye examination clinicians should be aware treatment regimens [209-211]. This clinical condition is
of dry eye in diabetic patients[199]. Dry eye index scores can known as diabetic keratopathy[212-214]. Diabetic keratopathy
be used for uncovering the presence of dry eye and for includes various symptomatic corneal conditions, such
evaluating the response to therapeutic treatment. Several as, punctate keratopathy and persistent corneal epithelial
questionnaires are available, with the most common being defect[208].
the Ocular Surface Disease Index (OSDI)[200]. However, Diabetic keratopathy is a common complication of
there is still no standardized dry eye disease questionnaire patients with evidence of DR. A study reported that
that is universally accepted. several symptomatic corneal epithelial lesions have been
The most common test for determining tear film occured in diabetic patients at the rate of 47% to 64%[208].
quality in use today is the TBUT which shows the tear In another study, authors showed that the incidence of
film stability. The TBUT value is the time from the diabetic keratopathy in diabetic patients with DR was 2
last complete blink to the appearance of dry spot. The times greater than that of patients without DR[215]. Several
Schirmer test is used for measuring the aqueous tear studies reported that the incidence of diabetic keratopathy
manufacture. Normally, the Schirmer filter paper gets wet increased following pars plana vitrectomy [216,217] ,
10mm for 5 min. A result yielding less than 5 mm shows penetrating keratoplasty [218], laser iridectomy [219], and
aqueous tear deficiency. Fluorescein is useful in assessing refractive surgery[220] in diabetic patients.
dry eye where its application can detect the epithelial
defects due to dry eye disease Pathogenesis
Risk factors for DES include duration of DM and Several pathophysiological abnormalities have been
higher HbA1c levels[188,201]. So, strict blood glucose control shown in diabetic keratopathy, including, an abnormally
and close follow-up reduce the risk of DES[188]. thickened and discontinuous basement membrane,
abnormal adhesion between the stroma and basement
Current therapy membrane [219-223] , increased epithelial fragility [206] ,
DES may cause loss of vision, scarring, perforation, and decreased epithelial healing rates, increased sorbitol
corneal infection. If patients with dry eye are treated in concentrations[224], decreased oxygen consumption and
time, there will be no complications of DES[185]. The uptake[225], increase in the polyol metabolism[196], decreased
patients should be treated with tear supplements called or alter epithelial hemidesmosomes, and increased
“artificial tears” which contains surfactans, different glycosyltransferas activity[214,226].
viscosity agents, and electrolytes[202]. Recently, studies have demonstrated [194,195,227] that
Dry eye disease is the outcome of many factors there is a relationship between AGE and development
resulting in inflammation of the cornea and conjunctiva. of diabetic keratopathy. Increased AGE in the laminin
Artificial tears can reduce blurred vision, and the of the corneal epithelial basement membrane causes
symptoms of dry eye, temporarily. These agents do abnormal weak attachment between the basal cells and
not contain the cytokines and growth factors which are basement membrane of the cornea in diabetics[194]. Also,
comprised in normal tears and do not have direct anti- the loss of the corneal sensation and neural stimulus
inflammatory effect[203,204]. Anti-inflammatory drugs are have been regarded as the reason of the development of

WJD|www.wjgnet.com 100 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

diabetic keratopathy[228]. Axonal degeneration of corneal 17641741 DOI: 10.1155/2007/43603]

unmyelinated nerves occurs under chronic hyperglycemic 2 Forbes JM, Soldatos G, Thomas MC. Below the radar:
advanced glycation end products that detour “around the
conditions. side”. Is HbA1c not an accurate enough predictor of long
term progression and glycaemic control in diabetes? Clin
Clinical evaluation Biochem Rev 2005; 26: 123-134 [PMID: 16648883]
Diabetic keratopathy is a condition that can result 3 Jang C, Lim JH, Park CW, Cho YJ. Regulator of Calcineurin
1 Isoform 4 (RCAN1.4) Is Overexpressed in the Glomeruli
in blindness and should be closely monitored. Early of Diabetic Mice. Korean J Physiol Pharmacol 2011; 15: 299-305
diagnosis and treatment of diabetic keratopathy, [PMID: 22128263 DOI: 10.4196/kjpp.2011.15.5.299]
particularly, before corneal complications occur, is very 4 Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes
crucial. If the diagnosis is late, patients will become atlas: global estimates of the prevalence of diabetes for 2011
resistance to the routine treatment of corneal defects. and 2030. Diabetes Res Clin Pract 2011; 94: 311-321 [PMID:
22079683 DOI: 10.1016/j.diabres.2011.10.029]
Nonhealing corneal epithelial erosion may also occur 5 International Diabetes Federation. The Diabetes Atlas 2006.
after pars plana vitrectomy for advanced PDR[208,211]. If 3rd ed. [accessed 2013 May 17]. Available from: URL: http:
corneal epithelium is removed manually for clarity by //www.idf.org/sites/default/files/Diabetes-Atlas-3rd-
surgeons, this conditions may accelerate dramatically. So, edition.pdf
when diabetic patients are examined after vitrectomy their 6 International Diabetes Federation. The Diabetes Atlas 2011.
5th ed. [accessed on 2013 May 17]. Available from: URL: http:
corneas should be examined carefully. //www.drsharma.ca/world-diabetes-atlas-5th-edition.html
7 Threatt J, Williamson JF, Huynh K, Davis RM. Ocular
Current therapy disease, knowledge and technology applications in patients
Keratopathy is generally treated with artificial tears, with diabetes. Am J Med Sci 2013; 345: 266-270 [PMID:
and antibiotics. Additionally, bandage contact lens, and 23531956 DOI: 10.1097/MAJ.0b013e31828aa6fb]
8 Singh PP, Mahadi F, Roy A, Sharma P. Reactive oxygen
tarsorrhaphy can be used for re-epithelialization. In species, reactive nitrogen species and antioxidants in
selected cases new treatments modalities will be used such etiopathogenesis of diabetes mellitus type-2. Indian J Clin
as, topical administration of naltrexone, nicergoline[229], Biochem 2009; 24: 324-342 [PMID: 23105858 DOI: 10.1007/
aldose reductase inhibitor [194,214,230], and some growth s12291-009-0062-6]
hormones[231] to accelerate re-epithelialization. All of 9 Moss SE, Klein R, Klein BE. The 14-year incidence of visual
loss in a diabetic population. Ophthalmology 1998; 105: 998-1003
these drugs were associated with a high corneal epithelial [PMID: 9627648 DOI: 10.1016/S0161-6420(98)96025-0]
wound healing rate. 10 Aiello LM. Perspectives on diabetic retinopathy. Am J
Recently, new topical drugs such as substance P and Ophthalmol 2003; 136: 122-135 [PMID: 12834680 DOI: 10.1016/
IGF-1 were tested on diabetic animals to accelerate re- S0002-9394(03)00219-8]
epithelialization. Successful outcomes were obtained with 11 Klein R, Klein B. National Diabetes Data Group. Diabetes in
America. 2. National Institutes of Health, National Institute
these new drugs[231]. Corneal epithelial barrier function of Diabetes and Digestive and Kidney Diseases. Vision
was improved by topical aldose reductase inhibitors, but disorders in diabetes. Bethesda, MD, 1995: 293-337
superficial punctate keratopathy could not be prevented 12 Garg S, Davis RM. Diabetic Retinopathy Screening
by these topical drugs. Aminoguanidine had benefical Update. Clinical Diabetes Fall 2009; 4: 140-145 [DOI: 10.2337/
effects in corneal epithelial defecets, by improving diaclin.27.4.140]
13 Kumari S, Panda S, Mangaraj M, Mandal MK, Mahapatra
attachment between the epithelial cells and basement PC. Plasma MDA and antioxidant vitamins in diabetic
membrane of the cornea[185,194]. The in vivo benefical effect retinopathy. Indian J Clin Biochem 2008; 23: 158-162 [PMID:
of aminoguanidine were unknown[194]. In additional to 23105743 DOI: 10.1007/s12291-008-0035-1]
these new drugs, amniotic membrane transplantation is 14 Retinopathy and nephropathy in patients with type 1
used to treat persistant corneal epithelial defects[232]. diabetes four years after a trial of intensive therapy. The
Diabetes Control and Complications Trial/Epidemiology of
Diabetes Interventions and Complications Research Group. N
Engl J Med 2000; 342: 381-389 [PMID: 10666428 DOI: 10.1056/
CONCLUSION NEJM200002103420603]
DM and its ocular complications remain a major cause of 15 Stratton IM, Kohner EM, Aldington SJ, Turner RC, Holman
blindness despite increased understanding of these ocular RR, Manley SE, Matthews DR. UKPDS 50: risk factors for
incidence and progression of retinopathy in Type II diabetes
conditions and identification of successful treatments. over 6 years from diagnosis. Diabetologia 2001; 44: 156-163
All of diabetic ocular complications can be prevented [PMID: 11270671 DOI: 10.1007/s001250051594]
by early diagnosis and theraphy. Therefore, periodic eye 16 Kaštelan S, Tomić M, Pavan J, Orešković S. Maternal immune
examinations are required for the reduction of diabetes- system adaptation to pregnancy--a potential influence on the
related vision loss. Good blood glucose control and course of diabetic retinopathy. Reprod Biol Endocrinol 2010; 8:
124 [PMID: 20964838 DOI: 10.1186/1477-7827-8-124]
other systemic risk factors such as hypertension, and 17 Varma R. From a population to patients: the Wisconsin
hyperlipidemia are main goal to prevention of ocular epidemiologic study of diabetic retinopathy. Ophthalmology
complications of DM. 2008; 115: 1857-1858 [PMID: 19068373 DOI: 10.1016/
j.ophtha.2008.09.023]
18 Klein R. Epidemiology of Diabetic Retinopathy. In: Duh E,
REFERENCES ed. Diabetic Retinopathy. Totowa: Humana Press, 2008
19 Matthews DR, Stratton IM, Aldington SJ, Holman RR,
1 Kowluru RA, Chan PS. Oxidative stress and diabetic
Kohner EM. Risks of progression of retinopathy and vision
retinopathy. Exp Diabetes Res 2007; 2007: 43603 [PMID: loss related to tight blood pressure control in type 2 diabetes

WJD|www.wjgnet.com 101 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

mellitus: UKPDS 69. Arch Ophthalmol 2004; 122: 1631-1640 Inomata H. Vascular endothelial growth factor plays a role in
[PMID: 15534123 DOI: 10.1001/archopht] hyperpermeability of diabetic retinal vessels. Ophthalmic Res
20 White NH, Cleary PA, Dahms W, Goldstein D, Malone J, 1995; 27: 48-52 [PMID: 7596559 DOI: 10.1159/000267567]
Tamborlane WV. Beneficial effects of intensive therapy of 37 Zong H, Ward M, Stitt AW. AGEs, RAGE, and diabetic
diabetes during adolescence: outcomes after the conclusion retinopathy. Curr Diab Rep 2011; 11: 244-252 [PMID: 21590515
of the Diabetes Control and Complications Trial (DCCT). J DOI: 10.1007/s11892-011-0198-7]
Pediatr 2001; 139: 804-812 [PMID: 11743505 DOI: 10.1067/ 38 Cui Y, Xu X, Bi H, Zhu Q, Wu J, Xia X, Qiushi Ren PC.
mpd.2001.118887] Expression modification of uncoupling proteins and MnSOD
21 Naruse K, Nakamura J, Hamada Y, Nakayama M, Chaya in retinal endothelial cells and pericytes induced by high
S, Komori T, Kato K, Kasuya Y, Miwa K, Hotta N. Aldose glucose: the role of reactive oxygen species in diabetic
reductase inhibition prevents glucose-induced apoptosis retinopathy. Exp Eye Res 2006; 83: 807-816 [PMID: 16750827
in cultured bovine retinal microvascular pericytes. Exp DOI: 10.1016/j.Exer.2006.0]
Eye Res 2000; 71: 309-315 [PMID: 10973739 DOI: 10.1006/ 39 Baynes JW. Role of oxidative stress in development of
exer.2000.0882] complications in diabetes. Diabetes 1991; 40: 405-412 [PMID:
22 Kowluru RA. Diabetic retinopathy: mitochondrial 2010041 DOI: 10.2337/diab.40.4.405]
dysfunction and retinal capillary cell death. Antioxid Redox 40 Wilkinson-Berka JL. Angiotensin and diabetic retinopathy.
Signal 2005; 7: 1581-1587 [PMID: 16356121] Int J Biochem Cell Biol 2006; 38: 752-765 [PMID: 16165393 DOI:
23 Stitt AW. The role of advanced glycation in the pathogenesis 10.1016/j.biocel.2005.08.002]
of diabetic retinopathy. Exp Mol Pathol 2003; 75: 95-108 [PMID: 41 Antonetti DA, Barber AJ, Bronson SK, Freeman WM,
12834631 DOI: 10.1016/S0014-4800(03)00035-2] Gardner TW, Jefferson LS, Kester M, Kimball SR, Krady JK,
24 Chu J, Ali Y. Diabetic Retinopathy: A Review. Drug Dev Res LaNoue KF, Norbury CC, Quinn PG, Sandirasegarane L,
2008; 69: 1-14 [DOI: 10.1002/ddr.20222] Simpson IA. Diabetic retinopathy: seeing beyond glucose-
25 Kowluru RA, Tang J, Kern TS. Abnormalities of retinal induced microvascular disease. Diabetes 2006; 55: 2401-2411
metabolism in diabetes and experimental galactosemia. VII. [PMID: 16936187 DOI: 10.2337/db05-1635]
Effect of long-term administration of antioxidants on the 42 Xu H, Chen M, Forrester JV. Para-inflammation in the aging
development of retinopathy. Diabetes 2001; 50: 1938-1942 retina. Prog Retin Eye Res 2009; 28: 348-368 [PMID: 19560552
[PMID: 11473058 DOI: 10.2337/diabetes.50.8.1938] DOI: 10.1016/j.preteyeres.2009.06.001]
26 Tarr JM, Kaul K, Chopra M, Kohner EM, Chibber R. 43 Klein BE, Knudtson MD, Tsai MY, Klein R. The relation
Pathophysiology of diabetic retinopathy. ISRN Ophthalmol 2013; of markers of inflammation and endothelial dysfunction
2013: 343560 [PMID: 24563789 DOI: 10.1155/2013/343560] to the prevalence and progression of diabetic retinopathy:
27 Gabbay KH. Hyperglycemia, polyol metabolism, and Wisconsin epidemiologic study of diabetic retinopathy. Arch
complications of diabetes mellitus. Annu Rev Med 1975; 26: Ophthalmol 2009; 127: 1175-1182 [PMID: 19752427]
521-536 [PMID: 238458] 44 Nguyen TT, Alibrahim E, Islam FM, Klein R, Klein BE, Cotch
28 Kinoshita JH. A thirty year journey in the polyol pathway. MF, Shea S, Wong TY. Inflammatory, hemostatic, and other
Exp Eye Res 1990; 50: 567-573 [PMID: 2115448] novel biomarkers for diabetic retinopathy: the multi-ethnic
29 Gabbay KH. The sorbitol pathway and the complications study of atherosclerosis. Diabetes Care 2009; 32: 1704-1709
of diabetes. N Engl J Med 1973; 288: 831-836 [PMID: 4266466 [PMID: 19549733 DOI: 10.2337/dc09-0102]
DOI: 10.1056/NEJM197304192881609] 45 Maheshwary AS, Oster SF, Yuson RM, Cheng L, Mojana F,
30 Wang QJ. PKD at the crossroads of DAG and PKC signaling. Freeman WR. The association between percent disruption of
Trends Pharmacol Sci 2006; 27: 317-323 [PMID: 16678913 DOI: the photoreceptor inner segment-outer segment junction and
10.1016/j.tips.2006.04.003] visual acuity in diabetic macular edema. Am J Ophthalmol 2010;
31 Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA. 150: 63-67.e1 [PMID: 20451897 DOI: 10.1016/j.ajo.2010.01.039]
Hypoxic regulation of vascular endothelial growth factor 46 Otani T, Kishi S, Maruyama Y. Patterns of diabetic
in retinal cells. Arch Ophthalmol 1995; 113: 1538-1544 [PMID: macular edema with optical coherence tomography. Am J
7487623 DOI: 10.1001/archopht.1995.01100120068012] Ophthalmol 1999; 127: 688-693 [PMID: 10372879 DOI: 10.1016/
32 Simorre-Pinatel V, Guerrin M, Chollet P, Penary M, Clamens S0002-9394(99)00033-1]
S, Malecaze F, Plouet J. Vasculotropin-VEGF stimulates 47 Kim NR, Kim YJ, Chin HS, Moon YS. Optical coherence
retinal capillary endothelial cells through an autocrine tomographic patterns in diabetic macular oedema: prediction
pathway. Invest Ophthalmol Vis Sci 1994; 35: 3393-3400 [PMID: of visual outcome after focal laser photocoagulation. Br J
8056513] Ophthalmol 2009; 93: 901-905 [PMID: 19254904 DOI: 10.1136/
33 Adamis AP, Shima DT, Yeo KT, Yeo TK, Brown LF, Berse B, bjo.2008.152553]
D’Amore PA, Folkman J. Synthesis and secretion of vascular 48 Yamamoto S, Yamamoto T, Hayashi M, Takeuchi S.
permeability factor/vascular endothelial growth factor by Morphological and functional analyses of diabetic macular
human retinal pigment epithelial cells. Biochem Biophys Res edema by optical coherence tomography and multifocal
Commun 1993; 193: 631-638 [PMID: 8512562 DOI: 10.1006/ electroretinograms. Graefes Arch Clin Exp Ophthalmol 2001;
bbrc.1993.1671] 239: 96-101 [PMID: 11372551 DOI: 10.1007/s004170000238]
34 Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah 49 Otani T, Kishi S. Tomographic assessment of vitreous surgery
ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE. Vascular for diabetic macular edema. Am J Ophthalmol 2000; 129: 487-494
endothelial growth factor in ocular fluid of patients with [PMID: 10764858 DOI: 10.1016/S0002-9394(99)00409-2]
diabetic retinopathy and other retinal disorders. N Engl J 50 Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The
Med 1994; 331: 1480-1487 [PMID: 7526212 DOI: 10.1056/ Wisconsin epidemiologic study of diabetic retinopathy. II.
NEJM199412013312203] Prevalence and risk of diabetic retinopathy when age at
35 Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, Takagi diagnosis is less than 30 years. Arch Ophthalmol 1984; 102: 520-526
C, Mori F, Ciulla TA, Ways K, Jirousek M, Smith LE, King [PMID: 6367724 DOI: 10.1001/archopht.1984.01040030398010]
GL. Vascular endothelial growth factor-induced retinal 51 Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The
permeability is mediated by protein kinase C in vivo and Wisconsin epidemiologic study of diabetic retinopathy. III.
suppressed by an orally effective beta-isoform-selective Prevalence and risk of diabetic retinopathy when age at
inhibitor. Diabetes 1997; 46: 1473-1480 [PMID: 9287049 DOI: diagnosis is 30 or more years. Arch Ophthalmol 1984; 102: 527-532
10.2337/diab.46.9.1473] [PMID: 6367725 DOI: 10.1001/archopht.1984.01040030405011]
36 Murata T, Ishibashi T, Khalil A, Hata Y, Yoshikawa H, 52 Early worsening of diabetic retinopathy in the Diabetes

WJD|www.wjgnet.com 102 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

Control and Complications Trial. Arch Ophthalmol 1998; 116: D, Segal MS, Harrison JK, Scott EW, Grant MB. Vitreous
874-886 [PMID: 9682700 DOI: 10.1001/archopht.116.7.874] levels of vascular endothelial growth factor and stromal-
53 The relationship of glycemic exposure (HbA1c) to the risk of derived factor 1 in patients with diabetic retinopathy and
development and progression of retinopathy in the diabetes cystoid macular edema before and after intraocular injection
control and complications trial. Diabetes 1995; 44: 968-983 of triamcinolone. Arch Ophthalmol 2004; 122: 1801-1807 [PMID:
[PMID: 7622004 DOI: 10.2337/diab.44.8.968] 15596583 DOI: 10.1001/archopht.122.12.1801]
54 Intensive blood-glucose control with sulphonylureas or 70 Audren F, Erginay A, Haouchine B, Benosman R, Conrath J,
insulin compared with conventional treatment and risk Bergmann JF, Gaudric A, Massin P. Intravitreal triamcinolone
of complications in patients with type 2 diabetes (UKPDS acetonide for diffuse diabetic macular oedema: 6-month
33). UK Prospective Diabetes Study (UKPDS) Group. results of a prospective controlled trial. Acta Ophthalmol
Lancet 1998; 352: 837-853 [PMID: 9742976 DOI: 10.1016/ Scand 2006; 84: 624-630 [PMID: 16965492 DOI: 10.1111/
S0140-6736(98)07019-6] j.1600-0420.2006.00700.x]
55 Chantelau E. Evidence that upregulation of serum IGF-1 71 Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu
concentration can trigger acceleration of diabetic retinopathy. M. Intravitreal triamcinolone for refractory diabetic macular
Br J Ophthalmol 1998; 82: 725-730 [PMID: 9924360 DOI: edema: two-year results of a double-masked, placebo-
10.1136/bjo.82.7.725] controlled, randomized clinical trial. Ophthalmology 2006; 113:
56 Chantelau E, Meyer-Schwickerath R. Reversion of ‘early 1533-1538 [PMID: 16828501 DOI: 10.1016/j.ophtha.2006.02.065]
worsening’ of diabetic retinopathy by deliberate restoration 72 Massin P, Audren F, Haouchine B, Erginay A, Bergmann JF,
of poor metabolic control. Ophthalmologica 2003; 217: 373-377 Benosman R, Caulin C, Gaudric A. Intravitreal triamcinolone
[PMID: 12913330 DOI: 10.1159/000071355] acetonide for diabetic diffuse macular edema: preliminary
57 RR Associates. Blood pressure and diabetes: everyone’s results of a prospective controlled trial. Ophthalmology 2004;
concern. London: British Diabetic Association; 1994 111: 218-24; discussion 224-5 [PMID: 15019365 DOI: 10.1016/
58 Prospective Diabetes Study Group. Tight blood pressure j.ophtha.2003.05.037]
control and risk of macrovascular and microvascular 73 Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA,
complications in type 2 diabetes: UKPDS 38. UK Prospective Reichel E, Baumal C. Intravitreal triamcinolone for refractory
Diabetes Study Group. BMJ 1998; 317: 703-713 [PMID: diabetic macular edema. Ophthalmology 2002; 109: 920-927
9732337 DOI: 10.1136/bmj.317.7160.703] [PMID: 11986098 DOI: 10.1016/S0161-6420(02)00975-2]
59 Kissebah AH, Kohner EM, Lewis B, Siddiq YK, Lowy C, 74 Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB,
Fraser TR. Plasma-lipids and glucose/insulin relationship Edwards AR, Ferris FL, Friedman SM, Glassman AR, Miller
in non-insulin-requiring diabetics with and without KM, Scott IU, Stockdale CR, Sun JK. Randomized trial
retinopathy. Lancet 1975; 1: 1104-1108 [PMID: 49469 DOI: evaluating ranibizumab plus prompt or deferred laser or
10.1016/S0140-6736(75)92497-6] triamcinolone plus prompt laser for diabetic macular edema.
60 Duncan LJ, Cullen JF, Ireland JT, Nolan J, Clarke BF, Oliver Ophthalmology 2010; 117: 1064-1077.e35 [PMID: 20427088 DOI:
MF. A three-year trial of atromid therapy in exudative 10.1016/j.Ophtha.2010.02.031]
diabetic retinopathy. Diabetes 1968; 17: 458-467 [PMID: 75 Haller JA, Dugel P, Weinberg DV, Chou C, Whitcup SM.
4875170 DOI: 10.2337/diab.17.7.458] Evaluation of the safety and performance of an applicator for
61 Houtsmuller AJ, Zahn KJ, Henkes HE. Unsaturated fats and a novel intravitreal dexamethasone drug delivery system for
progression of diabetic retinopathy. Doc Ophthalmol 1980; 48: the treatment of macular edema. Retina 2009; 29: 46-51 [PMID:
363-371 [PMID: 6995054] 18827732 DOI: 10.1097/IAE.0b013e318188c814]
62 Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TM, 76 Haller JA, Kuppermann BD, Blumenkranz MS, Williams
Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E, GA, Weinberg DV, Chou C, Whitcup SM. Randomized
Merrifield A, Laatikainen LT, d’Emden MC, Crimet DC, O’ controlled trial of an intravitreous dexamethasone drug
Connell RL, Colman PG. Effect of fenofibrate on the need delivery system in patients with diabetic macular edema.
for laser treatment for diabetic retinopathy (FIELD study): Arch Ophthalmol 2010; 128: 289-296 [PMID: 20212197 DOI:
a randomised controlled trial. Lancet 2007; 370: 1687-1697 10.1001/archophthalmol.2010.21]
[PMID: 17988728 DOI: 10.1016/S0140-6736(07)61607-9] 77 Zucchiatti I, Lattanzio R, Querques G, Querques L, Del Turco
63 Photocoagulation for diabetic macular edema. Early C, Cascavilla ML, Bandello F. Intravitreal dexamethasone
Treatment Diabetic Retinopathy Study report number 1. implant in patients with persistent diabetic macular edema.
Early Treatment Diabetic Retinopathy Study research group. Ophthalmologica 2012; 228: 117-122 [PMID: 22310491 DOI:
Arch Ophthalmol 1985; 103: 1796-1806 [PMID: 2866759 DOI: 10.1159/000336225]
10.1001/archopht.1985.01050120030015] 78 Avery RL, Pearlman J, Pieramici DJ, Rabena MD, Castellarin
64 Olk RJ. Modified grid argon (blue-green) laser photocoagulation AA, Nasir MA, Giust MJ, Wendel R, Patel A. Intravitreal
for diffuse diabetic macular edema. Ophthalmology 1986; 93: bevacizumab (Avastin) in the treatment of proliferative
938-950 [PMID: 3763140] diabetic retinopathy. Ophthalmology 2006; 113: 1695.e1-1695.15
65 Treatment techniques and clinical guidelines for photoco- [PMID: 17011951 DOI: 10.1016/j.Ophtha.2006.05.064]
agulation of diabetic macular edema. Early Treatment Diabetic 79 Arevalo JF, Maia M, Flynn HW, Saravia M, Avery RL,
Retinopathy Study Report Number 2. Early Treatment Diabetic Wu L, Eid Farah M, Pieramici DJ, Berrocal MH, Sanchez
Retinopathy Study Research Group. Ophthalmology 1987; 94: JG. Tractional retinal detachment following intravitreal
761-774 [PMID: 3658348] bevacizumab (Avastin) in patients with severe proliferative
66 Preliminary report on effects of photocoagulation therapy. diabetic retinopathy. Br J Ophthalmol 2008; 92: 213-216 [PMID:
The Diabetic Retinopathy Study Research Group. Am J 17965108]
Ophthalmol 1976; 81: 383-396 [PMID: 944535] 80 Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M,
67 Photocoagulation treatment of proliferative diabetic Guyer DR. Pegaptanib for neovascular age-related macular
retinopathy: the second report of diabetic retinopathy study degeneration. N Engl J Med 2004; 351: 2805-2816 [PMID:
findings. Ophthalmology 1978; 85: 82-106 [PMID: 345173] 15625332 DOI: 10.1056/NEJMoa042760]
68 Edelman JL, Lutz D, Castro MR. Corticosteroids inhibit VEGF- 81 Cunningham ET, Adamis AP, Altaweel M, Aiello LP,
induced vascular leakage in a rabbit model of blood-retinal Bressler NM, D’Amico DJ, Goldbaum M, Guyer DR, Katz B,
and blood-aqueous barrier breakdown. Exp Eye Res 2005; 80: Patel M, Schwartz SD. A phase II randomized double-masked
249-258 [PMID: 15670803 DOI: 10.1016/j.exer.2004.09.013] trial of pegaptanib, an anti-vascular endothelial growth factor
69 Brooks HL, Caballero S, Newell CK, Steinmetz RL, Watson aptamer, for diabetic macular edema. Ophthalmology 2005;

WJD|www.wjgnet.com 103 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

112: 1747-1757 [PMID: 16154196] G, Gerstner O, Weichselberger A. The RESTORE study:

82 Loftus JV, Sultan MB, Pleil AM. Changes in vision- and ranibizumab monotherapy or combined with laser versus
health-related quality of life in patients with diabetic macular laser monotherapy for diabetic macular edema. Ophthalmology
edema treated with pegaptanib sodium or sham. Invest 2011; 118: 615-625 [PMID: 21459215 DOI: 10.1016/
Ophthalmol Vis Sci 2011; 52: 7498-7505 [PMID: 21896838 DOI: j.ophtha.2011.01.031]
10.1167/iovs.11-7613] 94 Filho JA, Messias A, Almeida FP, Ribeiro JA, Costa RA,
83 Scott IU, Edwards AR, Beck RW, Bressler NM, Chan CK, Scott IU, Jorge R. Panretinal photocoagulation (PRP) versus
Elman MJ, Friedman SM, Greven CM, Maturi RK, Pieramici PRP plus intravitreal ranibizumab for high-risk proliferative
DJ, Shami M, Singerman LJ, Stockdale CR. A phase II diabetic retinopathy. Acta Ophthalmol 2011; 89: e567-e572
randomized clinical trial of intravitreal bevacizumab for [PMID: 21726427 DOI: 10.1111/j.1755-3768.2011.02184.x]
diabetic macular edema. Ophthalmology 2007; 114: 1860-1867 95 Economides AN, Carpenter LR, Rudge JS, Wong V, Koehler-
[PMID: 17698196 DOI: 10.1016/j.ophtha.2007.05.062] Stec EM, Hartnett C, Pyles EA, Xu X, Daly TJ, Young MR,
84 Lam DS, Lai TY, Lee VY, Chan CK, Liu DT, Mohamed Fandl JP, Lee F, Carver S, McNay J, Bailey K, Ramakanth S,
S, Li CL. Efficacy of 1.25 MG versus 2.5 MG intravitreal Hutabarat R, Huang TT, Radziejewski C, Yancopoulos GD,
bevacizumab for diabetic macular edema: six-month results Stahl N. Cytokine traps: multi-component, high-affinity
of a randomized controlled trial. Retina 2009; 29: 292-299 blockers of cytokine action. Nat Med 2003; 9: 47-52 [PMID:
[PMID: 19287286 DOI: 10.1097/IAE.0b013e31819a2d61] 12483208 DOI: 10.1038/nm811]
85 Arevalo JF, Sanchez JG, Wu L, Maia M, Alezzandrini AA, 96 Do DV, Schmidt-Erfurth U, Gonzalez VH, Gordon CM,
Brito M, Bonafonte S, Lujan S, Diaz-Llopis M, Restrepo Tolentino M, Berliner AJ, Vitti R, Rückert R, Sandbrink R, Stein
N, Rodríguez FJ, Udaondo-Mirete P. Primary intravitreal D, Yang K, Beckmann K, Heier JS. The DA VINCI Study:
bevacizumab for diffuse diabetic macular edema: the Pan- phase 2 primary results of VEGF Trap-Eye in patients with
American Collaborative Retina Study Group at 24 months. diabetic macular edema. Ophthalmology 2011; 118: 1819-1826
Ophthalmology 2009; 116: 1488-197, 1497.e1 [PMID: 19545900 [PMID: 21546089 DOI: 10.1016/j.ophtha.2011.02.018]
DOI: 10.1016/j.ophtha.2009.03.016] 97 Do DV, Nguyen QD, Boyer D, Schmidt-Erfurth U, Brown
86 Kook D, Wolf A, Kreutzer T, Neubauer A, Strauss R, Ulbig DM, Vitti R, Berliner AJ, Gao B, Zeitz O, Ruckert R, Schmelter
M, Kampik A, Haritoglou C. Long-term effect of intravitreal T, Sandbrink R, Heier JS. One-year outcomes of the da Vinci
bevacizumab (avastin) in patients with chronic diffuse Study of VEGF Trap-Eye in eyes with diabetic macular
diabetic macular edema. Retina 2008; 28: 1053-1060 [PMID: edema. Ophthalmology 2012; 119: 1658-1665 [PMID: 22537617
18779710 DOI: 10.1097/IAE.0b013e318176de48] DOI: 10.1016/j.ophtha.2012.02.010]
87 Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, 98 Stefánsson E. Ocular oxygenation and the treatment of
Rajendram R, Quhill F, Boos CJ, Xing W, Egan C, Peto T, diabetic retinopathy. Surv Ophthalmol 2006; 51: 364-380 [PMID:
Bunce C, Leslie RD, Hykin PG. A prospective randomized 16818083 DOI: 10.1016/j.survophthal.2006.04.005]
trial of intravitreal bevacizumab or laser therapy in the 99 Stefánsson E, Hatchell DL, Fisher BL, Sutherland FS,
management of diabetic macular edema (BOLT study) Machemer R. Panretinal photocoagulation and retinal
12-month data: report 2. Ophthalmology 2010; 117: 1078-1086. oxygenation in normal and diabetic cats. Am J Ophthalmol
e2 [PMID: 20416952 DOI: 10.1016/j.ophtha.2010.03.045] 1986; 101: 657-664 [PMID: 3717248]
88 Rajendram R, Fraser-Bell S, Kaines A, Michaelides M, 100 Stefansson E, Landers MB, Wolbarsht ML. Increased retinal
Hamilton RD, Esposti SD, Peto T, Egan C, Bunce C, Leslie oxygen supply following pan-retinal photocoagulation and
RD, Hykin PG. A 2-year prospective randomized controlled vitrectomy and lensectomy. Trans Am Ophthalmol Soc 1981;
trial of intravitreal bevacizumab or laser therapy (BOLT) in 79: 307-334 [PMID: 7200671]
the management of diabetic macular edema: 24-month data: 101 Yamamoto T, Akabane N, Takeuchi S. Vitrectomy for diabetic
report 3. Arch Ophthalmol 2012; 130: 972-979 [PMID: 22491395 macular edema: the role of posterior vitreous detachment and
DOI: 10.1001/archophthalmol.2012.393] epimacular membrane. Am J Ophthalmol 2001; 132: 369-377
89 Massin P, Bandello F, Garweg JG, Hansen LL, Harding [PMID: 11530050 DOI: 10.1016/S0002-9394(01)01050-9]
SP, Larsen M, Mitchell P, Sharp D, Wolf-Schnurrbusch UE, 102 Machemer R, Buettner H, Norton EW, Parel JM. Vitrectomy:
Gekkieva M, Weichselberger A, Wolf S. Safety and efficacy a pars plana approach. Trans Am Acad Ophthalmol Otolaryngol
of ranibizumab in diabetic macular edema (RESOLVE 1971; 75: 813-820 [PMID: 5566980]
Study): a 12-month, randomized, controlled, double-masked, 103 Diabetic Retinopathy Vitrectomy Study Group. Early
multicenter phase II study. Diabetes Care 2010; 33: 2399-2405 vitrectomy for severe vitreous hemorrhage in diabetic
[PMID: 20980427 DOI: 10.2337/dc10-0493] retinopathy. Four-year results of a randomized trial:
90 Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Diabetic Retinopathy Vitrectomy Study Report 5. Arch
Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio Ophthalmol 1990; 108: 958-964 [PMID: 2196036 DOI: 10.1001/
RG, Ehrlich JS. Ranibizumab for diabetic macular edema: archopht.1990.01070090060040]
results from 2 phase III randomized trials: RISE and RIDE. 104 Lopez-Lopez F, Rodriguez-Blanco M, Gómez-Ulla F,
Ophthalmology 2012; 119: 789-801 [PMID: 22330964 DOI: Marticorena J. Enzymatic vitreolysis. Curr Diabetes Rev 2009; 5:
10.1016/j.ophtha.2011.12.039] 57-62 [PMID: 19199900]
91 Nguyen QD, Shah SM, Heier JS, Do DV, Lim J, Boyer D, 105 Benz MS, Packo KH, Gonzalez V, Pakola S, Bezner D, Haller
Abraham P, Campochiaro PA. Primary End Point (Six JA, Schwartz SD. A placebo-controlled trial of microplasmin
Months) Results of the Ranibizumab for Edema of the mAcula intravitreous injection to facilitate posterior vitreous
in diabetes (READ-2) study. Ophthalmology 2009; 116: 2175-81. detachment before vitrectomy. Ophthalmology 2010; 117:
e1 [PMID: 19700194 DOI: 10.1016/j.ophtha.2009.04.023] 791-797 [PMID: 20138368 DOI: 10.1016/j.ophtha.2009.11.005]
92 Nguyen QD, Shah SM, Khwaja AA, Channa R, Hatef E, Do 106 Regillo CD, Brown GC, Savino PJ, Byrnes GA, Benson WE,
DV, Boyer D, Heier JS, Abraham P, Thach AB, Lit ES, Foster Tasman WS, Sergott RC. Diabetic papillopathy. Patient
BS, Kruger E, Dugel P, Chang T, Das A, Ciulla TA, Pollack JS, characteristics and fundus findings. Arch Ophthalmol 1995;
Lim JI, Eliott D, Campochiaro PA. Two-year outcomes of the 113: 889-895 [PMID: 7605280]
ranibizumab for edema of the mAcula in diabetes (READ-2) 107 Friedrich Y, Feiner M, Gawi H, Friedman Z. Diabetic
study. Ophthalmology 2010; 117: 2146-2151 [PMID: 20855114 papillopathy with macular star mimicking clinically
DOI: 10.1016/j.ophtha.2010.08.016] significant diabetic macular edema. Retina 2001; 21: 80-82
93 Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, [PMID: 11217941]
Massin P, Schlingemann RO, Sutter F, Simader C, Burian 108 Bayraktar Z, Alacali N, Bayraktar S. Diabetic papillopathy

WJD|www.wjgnet.com 104 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

in type II diabetic patients. Retina 2002; 22: 752-758 [PMID: DOI: 10.1136/bjophthalmol-2012-302227]
12476102] 127 Saw SM, Wong TY, Ting S, Foong AW, Foster PJ. The
109 Lubow M, Makley TA. Pseudopapilledema of juvenile relationship between anterior chamber depth and the presence
diabetes mellitus. Arch Ophthalmol 1971; 85: 417-422 [PMID: of diabetes in the Tanjong Pagar Survey. Am J Ophthalmol 2007;
5554869 DOI: 10.1001/archopht.1971.009900] 144: 325-326 [PMID: 17659975 DOI: 10.1016/j.ajo.2007.03.038]
110 Hayreh SS, Zimmerman MB. Nonarteritic anterior ischemic 128 Senthil S, Garudadri C, Khanna RC, Sannapaneni K.
optic neuropathy: clinical characteristics in diabetic patients Angle closure in the Andhra Pradesh Eye Disease Study.
versus nondiabetic patients. Ophthalmology 2008; 115: Ophthalmology 2010; 117: 1729-1735 [PMID: 20466426 DOI:
1818-1825 [PMID: 18502511] 10.1016/j.ophtha.2010.01.021]
111 Slagle WS, Musick AN, Eckermann DR. Diabetic 129 Weinreb RN, Wasserstrom JP, Forman JS, Ritch R. Pseudo-
papillopathy and its relation to optic nerve ischemia. Optom phakic pupillary block with angle-closure glaucoma in
Vis Sci 2009; 86: e395-e403 [PMID: 19225435 DOI: 10.1097/ diabetic patients. Am J Ophthalmol 1986; 102: 325-328 [PMID:
OPX.0b013e318198927c] 3752197 DOI: 10.1016/0002-9394(86)90006-1]
112 Wise GN, Dollery CT, Henkind P. The Retinal Circulation. 130 Blondeau P, Pavan PR, Phelps CD. Acute pressure elevation
New York: Harper & Row, 1971 following panretinal photocoagulation. Arch Ophthalmol
113 Zachariah S, Sharfi O, Burton B, Nussey SS, Bano G. 1981; 99: 1239-1241 [PMID: 7196215 DOI: 10.1001/
Diabetic papillopathy diagnosed on retinal screening in an archopht.1981.03930020113011]
asymptomatic patient. BJDVD 2007; 7: 140 [DOI: 10.1177/147 131 Hayreh SS. Neovascular glaucoma. Prog Retin Eye Res 2007;
46514070070030701] 26: 470-485 [PMID: 17690002 DOI: 10.1016/j.preteyeres.2007.0
114 Kim M, Lee JH, Lee SJ. Diabetic papillopathy with macular 6.001]
edema treated with intravitreal ranibizumab. Clin Ophthalmol 132 Morrison JC, Pollack IP. Neovascular glaucoma (Chapter
2013; 7: 2257-2260 [PMID: 24348012 DOI: 10.2147/OPTH. 21). Glaucoma Science and Practice, 1st edition. New York:
S55076] Thieme Medical Publishers, 2003: 226-236
115 Al-Hinai AS, Al-Abri MS, Al-Hajri RH. Diabetic papillopathy 133 Miyazaki M, Kubota T, Kubo M, Kiyohara Y, Iida M, Nose Y,
with macular edema treated with intravitreal bevacizumab. Ishibashi T. The prevalence of pseudoexfoliation syndrome in
Oman J Ophthalmol 2011; 4: 135-138 [PMID: 22279402 DOI: a Japanese population: the Hisayama study. J Glaucoma 2005;
10.4103/0974-620X.91270] 14: 482-484 [PMID: 16276281 DOI: 10.109701.ijg.0000185436.1]
116 Al-Dhibi H, Khan AO. Response of diabetic papillopathy to 134 Wood SD, Asefzadeh B, Fisch B, Jiwani A, Lee RK, Conlin
intravitreal bevacizumab. Middle East Afr J Ophthalmol 2011; PR, Pasquale LR. The relationship between diabetes mellitus
18: 243-245 [PMID: 21887082 DOI: 10.4103/0974-9233.84056] and exfoliation syndrome in a United States Veterans Affairs
117 Willerslev A, Munch IC, Larsen M. Resolution of diabetic population: a case-control study. J Glaucoma 2011; 20: 278-281
papillopathy after a single intravitreal injection of [PMID: 20577098 DOI: 10.1097/IJG.0b013e3181e3d483]
ranibizumab. Acta Ophthalmol 2012; 90: e407-e409 [PMID: 135 Ellis JD, Evans JM, Ruta DA, Baines PS, Leese G, MacDonald
22268957 DOI: 10.1111/j.1755-3768.2011.02282.x] TM, Morris AD. Glaucoma incidence in an unselected cohort
118 Mansour AM, El-Dairi MA, Shehab MA, Shahin HK, of diabetic patients: is diabetes mellitus a risk factor for
Shaaban JA, Antonios SR. Periocular corticosteroids in glaucoma? DARTS/MEMO collaboration. Diabetes Audit
diabetic papillopathy. Eye (Lond) 2005; 19: 45-51 [PMID: and Research in Tayside Study. Medicines Monitoring Unit.
15094720 DOI: 10.1038/sj.eye.6701418] Br J Ophthalmol 2000; 84: 1218-1224 [PMID: 11049943 DOI:
119 Al-Shamsi HN, Dueker DK, Nowilaty SR, Al-Shahwan SA. 10.1136/bjo.84.11.1218]
Neovascular glaucoma at king khaled eye specialist hospital - 136 Kim C, Kim TW. Comparison of risk factors for bilateral
etiologic considerations. Middle East Afr J Ophthalmol 2009; 16: and unilateral eye involvement in normal-tension glaucoma.
15-19 [PMID: 20142954 DOI: 10.4103/0974-9233.48860] Invest Ophthalmol Vis Sci 2009; 50: 1215-1220 [PMID: 18836170
120 Ozdamar Y, Cankaya B, Ozalp S, Acaroglu G, Karakaya J, DOI: 10.1167/iovs.08-1886]
Ozkan SS. Is there a correlation between diabetes mellitus 137 Kanamori A, Nakamura M, Mukuno H, Maeda H, Negi
and central corneal thickness? J Glaucoma 2010; 19: 613-616 A. Diabetes has an additive effect on neural apoptosis in
[PMID: 20051882 DOI: 10.1097/IJG.0b013e3181ca7c62] rat retina with chronically elevated intraocular pressure.
121 Bonovas S, Peponis V, Filioussi K. Diabetes mellitus as a risk Curr Eye Res 2004; 28: 47-54 [PMID: 14704913 DOI: 10.1076/
factor for primary open-angle glaucoma: a meta-analysis. ceyr.28.1.47.23487]
Diabet Med 2004; 21: 609-614 [PMID: 15154948 DOI: 10.1111/ 138 Nakamura M, Kanamori A, Negi A. Diabetes mellitus as a
j.1464-5491.2004.01173.x] risk factor for glaucomatous optic neuropathy. Ophthalmologica
122 Newman-Casey PA, Talwar N, Nan B, Musch DC, Stein JD. 2005; 219: 1-10 [PMID: 15627820 DOI: 10.1159/000081775]
The relationship between components of metabolic syndrome 139 Congdon NG, Broman AT, Bandeen-Roche K, Grover D,
and open-angle glaucoma. Ophthalmology 2011; 118: 1318-1326 Quigley HA. Central corneal thickness and corneal hysteresis
[PMID: 21481477 DOI: 10.1016j.Ophhtha] associated with glaucoma damage. Am J Ophthalmol 2006;
123 Chopra V, Varma R, Francis BA, Wu J, Torres M, Azen SP. 141: 868-875 [PMID: 16527231 DOI: 10.1016/j.ajo.2005.12.007]
Type 2 diabetes mellitus and the risk of open-angle glaucoma 140 Chihara E. Myopia and diabetes mellitus as modificatory factors
the Los Angeles Latino Eye Study. Ophthalmology 2008; 115: of glaucomatous optic neuropathy. Jpn J Ophthalmol 2014; 58:
227-232.e1 [PMID: 17716734] 16-25 [PMID: 23942995 DOI: 10.1007/s10384-013-0267-3]
124 de Voogd S, Ikram MK, Wolfs RC, Jansonius NM, Witteman 141 Shoshani Y, Harris A, Shoja MM, Arieli Y, Ehrlich R, Primus
JC, Hofman A, de Jong PT. Is diabetes mellitus a risk S, Ciulla T, Cantor A, Wirostko B, Siesky BA. Impaired ocular
factor for open-angle glaucoma? The Rotterdam Study. blood flow regulation in patients with open-angle glaucoma
Ophthalmology 2006; 113: 1827-1831 [PMID: 16884777] and diabetes. Clin Experiment Ophthalmol 2012; 40: 697-705
125 Tan GS, Wong TY, Fong CW, Aung T. Diabetes, meta- [PMID: 22394354 DOI: 10.1111/j.1442-9071.2012.02778.x]
bolic abnormalities, and glaucoma. Arch Ophthalmol 142 Moïse MM, Benjamin LM, Doris TM, Dalida KN, Augustin
2009; 127: 1354-1361 [PMID: 19822853 DOI: 10.1001/ NO. Role of Mediterranean diet, tropical vegetables rich in
archophthalmol.2009.268] antioxidants, and sunlight exposure in blindness, cataract and
126 Law SK, Hosseini H, Saidi E, Nassiri N, Neelakanta G, glaucoma among African type 2 diabetics. Int J Ophthalmol
Giaconi JA, Caprioli J. Long-term outcomes of primary 2012; 5: 231-237 [PMID: 22762057 DOI: 10.3980/j.issn.2222-39
trabeculectomy in diabetic patients with primary open angle 59.2012.02.23]
glaucoma. Br J Ophthalmol 2013; 97: 561-566 [PMID: 23355527 143 Kothadia AD, Shenoy AM, Shabaraya AR, Rajan MS, Viradia

WJD|www.wjgnet.com 105 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

UM, Patel NH. Evaluation of cataract preventive action of and pigmentation implicates ascorbate oxidation in human
phycocyanin. Int J Pharm Sci Drug Res 2011; 3: 42-44 [DOI: lens senescence and cataractogenesis. Proc Natl Acad Sci U S
10.2337/diaclin.27.4.140] A 1991; 88: 10257-10261 [PMID: 1946446]
144 Kato A, Yasuko H, Goto H, Hollinshead J, Nash RJ, Adachi I. 161 Shamsi FA, Sharkey E, Creighton D, Nagaraj RH. Maillard
Inhibitory effect of rhetsinine isolated from Evodia rutaecarpa reactions in lens proteins: methylglyoxal-mediated
on aldose reductase activity. Phytomedicine 2009; 16: 258-261 modifications in the rat lens. Exp Eye Res 2000; 70: 369-380
[PMID: 17498942 DOI: 10.1016/j.phymed.2007.04.008] [PMID: 10712823 DOI: 10.1006/exer.1999.0800]
145 Falck A, Laatikainen L. Diabetic cataract in children. Acta 162 Agte VV, Tarwadi KV. Combination of diabetes and cataract
Ophthalmol Scand 1998; 76: 238-240 [PMID: 9591961 DOI: worsens the oxidative stress and micronutrient status in
10.1034/j.1600-0420.1998.760223.x] Indians. Nutrition 2008; 24: 617-624 [PMID: 18472398 DOI:
146 Klein BE, Klein R, Moss SE. Incidence of cataract surgery in 10.1016/j.nut.2008.03.005]
the Wisconsin Epidemiologic Study of Diabetic Retinopathy. 163 Jeganathan VS, Wang JJ, Wong TY. Ocular associations of
Am J Ophthalmol 1995; 119: 295-300 [PMID: 7872389] diabetes other than diabetic retinopathy. Diabetes Care 2008;
147 Klein BE, Klein R, Wang Q, Moss SE. Older-onset diabetes 31: 1905-1912 [PMID: 18753669 DOI: 10.2337/dc08-0342]
and lens opacities. The Beaver Dam Eye Study. Ophthalmic 164 Ookawara T, Kawamura N, Kitagawa Y, Taniguchi N. Site-
Epidemiol 1995; 2: 49-55 [PMID: 7585233] specific and random fragmentation of Cu,Zn-superoxide
148 Foster PJ, Wong TY, Machin D, Johnson GJ, Seah SK. Risk dismutase by glycation reaction. Implication of reactive
factors for nuclear, cortical and posterior subcapsular oxygen species. J Biol Chem 1992; 267: 18505-18510 [PMID:
cataracts in the Chinese population of Singapore: the Tanjong 1326527]
Pagar Survey. Br J Ophthalmol 2003; 87: 1112-1120 [PMID: 165 Kinoshita JH. Mechanisms initiating cataract formation.
12928278 DOI: 10.1136/bjo.87.9.1112] Proctor Lecture. Invest Ophthalmol 1974; 13: 713-724 [PMID:
149 Nirmalan PK, Robin AL, Katz J, Tielsch JM, Thulasiraj RD, 4278188]
Krishnadas R, Ramakrishnan R. Risk factors for age related 166 Kinoshita JH. Cataracts in galactosemia. The Jonas S.
cataract in a rural population of southern India: the Aravind Friedenwald Memorial Lecture. Invest Ophthalmol 1965; 4:
Comprehensive Eye Study. Br J Ophthalmol 2004; 88: 989-994 786-799 [PMID: 5831988]
[PMID: 15258010 DOI: 10.1136/bjo.2003.038380] 167 Takamura Y, Sugimoto Y, Kubo E, Takahashi Y, Akagi Y.
150 Husain R, Tong L, Fong A, Cheng JF, How A, Chua WH, Lee Immunohistochemical study of apoptosis of lens epithelial
L, Gazzard G, Tan DT, Koh D, Saw SM. Prevalence of cataract cells in human and diabetic rat cataracts. Jpn J Ophthalmol
in rural Indonesia. Ophthalmology 2005; 112: 1255-1262 [PMID: 2001; 45: 559-563 [PMID: 11754895 DOI: 10.1016/S0021-
15993241 DOI: 10.1016/j.ophtha.2005.02.015] 5155(01)00418-X]
151 Dandona L, Dandona R, Naduvilath TJ, McCarty CA, 168 Li WC, Kuszak JR, Dunn K, Wang RR, Ma W, Wang GM,
Mandal P, Srinivas M, Nanda A, Rao GN. Population- Spector A, Leib M, Cotliar AM, Weiss M. Lens epithelial cell
based assessment of the outcome of cataract surgery in apoptosis appears to be a common cellular basis for non-
an urban population in southern India. Am J Ophthalmol congenital cataract development in humans and animals. J
1999; 127: 650-658 [PMID: 10372874 DOI: 10.1016/ Cell Biol 1995; 130: 169-181 [PMID: 7790371]
S0002-9394(99)00044-6] 169 Stitt AW. The maillard reaction in eye diseases. Ann N Y
152 Chen SJ, Liu JH, Shih HC, Chou P, Tsai CY, Tung TH. Acad Sci 2005; 1043: 582-597 [PMID: 16037281 DOI: 10.1196/
Prevalence and associated factors of lens opacities among annals.1338.066]
Chinese type 2 diabetics in Kinmen, Taiwan. Acta Diabetol 170 Chew EY, Benson WE, Remaley NA, Lindley AA, Burton TC,
2008; 45: 7-13 [PMID: 17828461] Csaky K, Williams GA, Ferris FL. Results after lens extraction
153 Raman R, Pal SS, Adams JS, Rani PK, Vaitheeswaran K, in patients with diabetic retinopathy: early treatment diabetic
Sharma T. Prevalence and risk factors for cataract in diabetes: retinopathy study report number 25. Arch Ophthalmol
Sankara Nethralaya Diabetic Retinopathy Epidemiology and 1999; 117: 1600-1606 [PMID: 10604663 DOI: 10.1001/
Molecular Genetics Study, report no. 17. Invest Ophthalmol archopht.117.12.1600]
Vis Sci 2010; 51: 6253-6261 [PMID: 20610838 DOI: 10.1167/ 171 Pollack A, Dotan S, Oliver M. Course of diabetic retinopathy
iovs.10-5414] following cataract surgery. Br J Ophthalmol 1991; 75: 2-8
154 Bron AJ, Cheng H. Cataract and retinopathy: screening for [PMID: 1991081]
treatable retinopathy. Clin Endocrinol Metab 1986; 15: 971-999 172 Squirrell D, Bhola R, Bush J, Winder S, Talbot JF. A
[PMID: 3096617] prospective, case controlled study of the natural history of
155 Srivastava SK, Ramana KV, Bhatnagar A. Role of aldose diabetic retinopathy and maculopathy after uncomplicated
reductase and oxidative damage in diabetes and the phacoemulsification cataract surgery in patients with type 2
consequent potential for therapeutic options. Endocr Rev 2005; diabetes. Br J Ophthalmol 2002; 86: 565-571 [PMID: 11973256
26: 380-392 [PMID: 15814847 DOI: 10.1210/er.2004-0028] DOI: 10.1136/bjo.86.5.565]
156 Ahmed N. Advanced glycation endproducts--role in pathology 173 Pollreisz A, Schmidt-Erfurth U. Diabetic cataract-
of diabetic complications. Diabetes Res Clin Pract 2005; 67: 3-21 pathogenesis, epidemiology and treatment. J Ophthalmol 2010;
[PMID: 15620429 DOI: 10.1016/j.diabres.2004.09.004] 2010: 608751 [PMID: 20634936 DOI: 10.1155/2010/608751]
157 Araki N, Ueno N, Chakrabarti B, Morino Y, Horiuchi S. 174 Chiu CJ, Morris MS, Rogers G, Jacques PF, Chylack LT, Tung
Immunochemical evidence for the presence of advanced W, Hankinson SE, Willett WC, Taylor A. Carbohydrate intake
glycation end products in human lens proteins and its and glycemic index in relation to the odds of early cortical
positive correlation with aging. J Biol Chem 1992; 267: and nuclear lens opacities. Am J Clin Nutr 2005; 81: 1411-1416
10211-10214 [PMID: 1587810] [PMID: 15941895]
158 Duhaiman AS. Glycation of human lens proteins from 175 Lu M, Taylor A, Chylack LT, Rogers G, Hankinson SE, Willett
diabetic and (nondiabetic) senile cataract patients. Glycoconj J WC, Jacques PF. Dietary linolenic acid intake is positively
1995; 12: 618-621 [PMID: 8595250] associated with five-year change in eye lens nuclear density. J
159 Lyons TJ, Silvestri G, Dunn JA, Dyer DG, Baynes JW. Role Am Coll Nutr 2007; 26: 133-140 [PMID: 17536124]
of glycation in modification of lens crystallins in diabetic 176 Drel VR, Pacher P, Ali TK, Shin J, Julius U, El-Remessy
and nondiabetic senile cataracts. Diabetes 1991; 40: 1010-1015 AB, Obrosova IG. Aldose reductase inhibitor fidarestat
[PMID: 1907246 DOI: 10.2337/diab.40.8.1010] counteracts diabetes-associated cataract formation, retinal
160 Nagaraj RH, Sell DR, Prabhakaram M, Ortwerth BJ, Monnier oxidative-nitrosative stress, glial activation, and apoptosis. Int
VM. High correlation between pentosidine protein crosslinks J Mol Med 2008; 21: 667-676 [PMID: 18506358 DOI: 10.3892/

WJD|www.wjgnet.com 106 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

ijmm.21.6.667] 10.2337/diacare.24.3.479]
177 Dowler JG, Hykin PG, Hamilton AM. Phacoemulsification 196 Kinoshita JH, Fukushi S, Kador P, Merola LO. Aldose
versus extracapsular cataract extraction in patients with reductase in diabetic complications of the eye. Metabolism
diabetes. Ophthalmology 2000; 107: 457-462 [PMID: 10711881 1979; 28: 462-469 [PMID: 45423]
DOI: 10.1016/S0161-6420(99)00136-0] 197 Kador PF, Kinoshita JH. Role of aldose reductase in the
178 Arthur SN, Peng Q, Apple DJ, Escobar-Gomez M, Bianchi R, development of diabetes-associated complications. Am J Med
Pandey SK, Werner L. Effect of heparin surface modification 1985; 79: 8-12 [PMID: 3934965]
in reducing silicone oil adherence to various intraocular 198 Inoue K, Kato S, Ohara C, Numaga J, Amano S, Oshika
lenses. J Cataract Refract Surg 2001; 27: 1662-1669 [PMID: T. Ocular and systemic factors relevant to diabetic
11687368 DOI: 10.1016/S0886-3350(01)00891-4] keratoepitheliopathy. Cornea 2001; 20: 798-801 [PMID: 11685054]
179 Rosenberg ME, Tervo TM, Immonen IJ, Müller LJ, 199 Jin J, Chen LH, Liu XL, Jin GS, Lou SX, Fang FN. [Tear film
Grönhagen-Riska C, Vesaluoma MH. Corneal structure and function in non-insulin dependent diabetics]. Zhonghua Yan
sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Ke Za Zhi 2003; 39: 10-13 [PMID: 12760806]
Sci 2000; 41: 2915-2921 [PMID: 10967045] 200 Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD,
180 Cousen P, Cackett P, Bennett H, Swa K, Dhillon B. Tear Reis BL. Reliability and validity of the Ocular Surface Disease
production and corneal sensitivity in diabetes. J Diabetes Index. Arch Ophthalmol 2000; 118: 615-621 [PMID: 10815152
Complications 2007; 21: 371-373 [PMID: 17967709 DOI: DOI: 10.1001/archopht.118.5.615]
10.1016/j.jdiacomp.2006.05.008] 201 Akinci A, Cetinkaya E, Aycan Z. Dry eye syndrome in
181 Dogru M, Katakami C, Inoue M. Tear function and ocular diabetic children. Eur J Ophthalmol 2007; 17: 873-878 [PMID:
surface changes in noninsulin-dependent diabetes mellitus. 18050110]
Ophthalmology 2001; 108: 586-592 [PMID: 11237914 DOI: 202 Albietz JM, Bruce AS. The conjunctival epithelium in dry
10.1016/S0161-6420(00)00599-6] eye subtypes: effect of preserved and non-preserved topical
182 The definition and classification of dry eye disease: report treatments. Curr Eye Res 2001; 22: 8-18 [PMID: 11402374 DOI:
of the Definition and Classification Subcommittee of the 10.1076/ceyr.22.1.8.6977]
International Dry Eye WorkShop (2007). Ocul Surf 2007; 5: 203 Management and therapy of dry eye disease: report of the
75-92 [PMID: 17508116] Management and Therapy Subcommittee of the International
183 Lemp MA. Report of the National Eye Institute/Industry Dry Eye WorkShop (2007). Ocul Surf 2007; 5: 163-178 [PMID:
workshop on Clinical Trials in Dry Eyes. CLAO J 1995; 21: 17508120]
221-232 [PMID: 8565190] 204 Jackson WB. Management of dysfunctional tear syndrome:
184 Lubniewski AJ, Houchin KW, Holland EJ, Weeks DA, a Canadian consensus. Can J Ophthalmol 2009; 44: 385-394
Wessels IF, McNeill JI, Cameron JD. Posterior infectious [PMID: 19606158 DOI: 10.3129/i09-015]
crystalline keratopathy with Staphylococcus epidermidis. 205 Pflugfelder SC. Anti-inflammatory therapy of dry eye.
Ophthalmology 1990; 97: 1454-1459 [PMID: 2255518] Ocul Surf 2003; 1: 31-36 [PMID: 17075627 DOI: 10.1016/
185 Riordan-Eva, Asbury T, Whitcher JP. Vaughan and Asbury’ S1542-0124(12)70005-8]
s General Ophthalmology. USA, McGraw-Hill Medical 2003; 206 Yang CQ, Sun W, Gu YS. A clinical study of the efficacy of
16: 308–310 topical corticosteroids on dry eye. J Zhejiang Univ Sci B 2006; 7:
186 Schaumberg DA, Sullivan DA, Buring JE, Dana MR. 675-678 [PMID: 16845723 DOI: 10.1631/jzus.2006.B0675]
Prevalence of dry eye syndrome among US women. Am J 207 Zhou XQ, Wei RL. Topical cyclosporine A in the treatment of
Ophthalmol 2003; 136: 318-326 [PMID: 12888056 DOI: 10.1016/ dry eye: a systematic review and meta-analysis. Cornea 2014;
S0002-9394(03)00218-6] 33: 760-767 [PMID: 24815112]
187 Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence 208 Schultz RO, Van Horn DL, Peters MA, Klewin KM, Schutten
of dry eye disease among US men: estimates from the WH. Diabetic keratopathy. Trans Am Ophthalmol Soc 1981; 79:
Physicians’ Health Studies. Arch Ophthalmol 2009; 127: 763-768 180-199 [PMID: 7342400]
[PMID: 19506195 DOI: 10.1001/archophthalmol.2009.103] 209 Friend J, Thoft RA. The diabetic cornea. Int Ophthalmol Clin
188 Seifart U, Strempel I. [The dry eye and diabetes mellitus]. 1984; 24: 111-123 [PMID: 6500867]
Ophthalmologe 1994; 91: 235-239 [PMID: 8012143] 210 Datiles MB, Kador PF, Fukui HN, Hu TS, Kinoshita JH.
189 Kaiserman I, Kaiserman N, Nakar S, Vinker S. Dry eye in Corneal re-epithelialization in galactosemic rats. Invest
diabetic patients. Am J Ophthalmol 2005; 139: 498-503 [PMID: Ophthalmol Vis Sci 1983; 24: 563-569 [PMID: 6841002]
15767060 DOI: 10.1016/j.ajo.2004.10.022] 211 Perry HD, Foulks GN, Thoft RA, Tolentino FI. Corneal
190 Alves Mde C, Carvalheira JB, Módulo CM, Rocha EM. Tear complications after closed vitrectomy through the pars plana.
film and ocular surface changes in diabetes mellitus. Arq Bras Arch Ophthalmol 1978; 96: 1401-1403 [PMID: 678179 DOI:
Oftalmol 2005; 71: 96-103 [PMID: 19274419] 10.1001/archopht.1978.03910060155011]
191 Goebbels M. Tear secretion and tear film function in insulin 212 Cisarik-Fredenburg P. Discoveries in research on diabetic
dependent diabetics. Br J Ophthalmol 2000; 84: 19-21 [PMID: keratopathy. Optometry 2001; 72: 691-704 [PMID: 12363257]
10611093 DOI: 10.1136/bjo.84.1.19] 213 Kaji Y. Prevention of diabetic keratopathy. Br J Ophthalmol 2005;
192 Figueroa-Ortiz LC, Jiménez Rodríguez E, García-Ben A, 89: 254-255 [PMID: 15722297 DOI: 10.1136/bjo.2004.055541]
García-Campos J. [Study of tear function and the conjunctival 214 Sánchez-Thorin JC. The cornea in diabetes mellitus. Int
surface in diabetic patients]. Arch Soc Esp Oftalmol 2011; 86: Ophthalmol Clin 1998; 38: 19-36 [PMID: 9604736]
107-112 [PMID: 21569919 DOI: 10.1016/j.oftal.2010.12.010] 215 Saini JS, Khandalavla B. Corneal epithelial fragility in
193 Hom M, De Land P. Self-reported dry eyes and diabetic diabetes mellitus. Can J Ophthalmol 1995; 30: 142-146 [PMID:
history. Optometry 2006; 77: 554-558 [PMID: 17145567 DOI: 7627899]
10.1016/j.optm.2006.08.002] 216 Chung H, Tolentino FI, Cajita VN, Acosta J, Refojo MF.
194 Kaji Y, Usui T, Oshika T, Matsubara M, Yamashita H, Araie Reevaluation of corneal complications after closed vitrectomy.
M, Murata T, Ishibashi T, Nagai R, Horiuchi S, Amano S. Arch Ophthalmol 1988; 106: 916-919 [PMID: 3390054 DOI:
Advanced glycation end products in diabetic corneas. Invest 10.1001/archopht.1988.01060140062025]
Ophthalmol Vis Sci 2000; 41: 362-368 [PMID: 10670463] 217 Foulks GN, Thoft RA, Perry HD, Tolentino FI. Factors related
195 Sato E, Mori F, Igarashi S, Abiko T, Takeda M, Ishiko S, to corneal epithelial complications after closed vitrectomy in
Yoshida A. Corneal advanced glycation end products diabetics. Arch Ophthalmol 1979; 97: 1076-1078 [PMID: 444136
increase in patients with proliferative diabetic retinopathy. DOI: 10.1001/archopht.1979.01020010530002]
Diabetes Care 2001; 24: 479-482 [PMID: 11289471 DOI: 218 Chou L, Cohen EJ, Laibson PR, Rapuano CJ. Factors associated

WJD|www.wjgnet.com 107 February 15, 2015|Volume 6|Issue 1|

 Sayin N et al . Ocular complications of diabetes mellitus

with epithelial defects after penetrating keratoplasty. Goto-Kakizaki rats. Invest Ophthalmol Vis Sci 2003; 44:
Ophthalmic Surg 1994; 25: 700-703 [PMID: 7898864] 3802-3809 [PMID: 12939295 DOI: 10.1167/iovs.03-0227]
219 Jeng S, Lee JS, Huang SC. Corneal decompensation after 227 Kaji Y, Amano S, Usui T, Oshika T, Yamashiro K, Ishida
argon laser iridectomy--a delayed complication. Ophthalmic S, Suzuki K, Tanaka S, Adamis AP, Nagai R, Horiuchi S.
Surg 1991; 22: 565-569 [PMID: 1961612] Expression and function of receptors for advanced glycation
220 Simpson RG, Moshirfar M, Edmonds JN, Christiansen SM. end products in bovine corneal endothelial cells. Invest
Laser in-situ keratomileusis in patients with diabetes mellitus: Ophthalmol Vis Sci 2003; 44: 521-528 [PMID: 12556378 DOI:
a review of the literature. Clin Ophthalmol 2012; 6: 1665-1674 10.1167/iovs.02-0268]
[PMID: 23109803 DOI: 10.2147/OPTH.S36382/OPTH] 228 Saito J, Enoki M, Hara M, Morishige N, Chikama T, Nishida T.
221 Gipson IK, Grill SM, Spurr SJ, Brennan SJ. Hemidesmosome Correlation of corneal sensation, but not of basal or reflex tear
formation in vitro. J Cell Biol 1983; 97: 849-857 [PMID: secretion, with the stage of diabetic retinopathy. Cornea 2003;
6885921] 22: 15-18 [PMID: 12502941]
222 Gipson IK, Spurr-Michaud SJ, Tisdale AS. Anchoring fibrils 229 Awata T, Sogo S, Yamagami Y, Yamamoto Y. Effect of an
form a complex network in human and rabbit cornea. Invest aldose reductase inhibitor, CT-112, on healing of the corneal
Ophthalmol Vis Sci 1987; 28: 212-220 [PMID: 8591898] epithelium in galactose-fed rats. J Ocul Pharmacol 1988; 4:
223 McDermott AM, Xiao TL, Kern TS, Murphy CJ. Non- 195-201 [PMID: 3143793]
enzymatic glycation in corneas from normal and diabetic 230 Nakamura M, Kawahara M, Morishige N, Chikama T,
donors and its effects on epithelial cell attachment in vitro. Nakata K, Nishida T. Promotion of corneal epithelial wound
Optometry 2003; 74: 443-452 [PMID: 12877277] healing in diabetic rats by the combination of a substance
224 Yue DK, Hanwell MA, Satchell PM, Turtle JR. The effect P-derived peptide (FGLM-NH2) and insulin-like growth
of aldose reductase inhibition on motor nerve conduction factor-1. Diabetologia 2003; 46: 839-842 [PMID: 12764579]
velocity in diabetic rats. Diabetes 1982; 31: 789-794 [PMID: 231 Abdelkader H, Patel DV, McGhee CNj, Alany RG. New
6819173 DOI: 10.2337/diab.31.9.789] therapeutic approaches in the treatment of diabetic keratopathy:
225 Graham CR, Richard RD, Varma SD. Oxygen consumption a review. Clin Experiment Ophthalmol 2011; 39: 259-270 [PMID:
by normal and diabetic rat and human corneas. Ophthalmol 20973888 DOI: 10.1111/j.1442-9071.2010.02435.x]
Res 1981; 13: 65–71 [DOI: 10.1159/000265134] 232 Kheirkhah A, Casas V, Raju VK, Tseng SC. Sutureless
226 Akimoto Y, Kawakami H, Yamamoto K, Munetomo E, Hida amniotic membrane transplantation for partial limbal stem
T, Hirano H. Elevated expression of O-GlcNAc-modified cell deficiency. Am J Ophthalmol 2008; 145: 787-794 [PMID:
proteins and O-GlcNAc transferase in corneas of diabetic 18329626 DOI: 10.1016/j.ajo.2008.01.009]

P- Reviewer: Hong YJ, Irons BK S- Editor: Ji FF L- Editor: A

E- Editor: Lu YJ

WJD|www.wjgnet.com 108 February 15, 2015|Volume 6|Issue 1|

View publication stats