Early inner retinal thinning and cardiovascular autonomic dysfunction in type 2 diabetes
Early inner retinal thinning and cardiovascular autonomic dysfunction in type 2 diabetes
Jin A. Choi 1 2
Hyo Won Kim 1 2
Jin-Woo Kwon 1 2
Yun-sub Shim 1 2
Dong Hyun Jee 1 2
Jae- Seung Yun 2
Yu-Bae Ahn 2
Chan Kee Park 0 2
Seung-Hyun Ko 2
0 Department of Ophthalmology and Visual Science Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea , Seoul , Korea
1 Department of Ophthalmology and Visual Science St. Vincent's Hospital, College of Medicine, The Catholic University of Korea , Seoul , Korea , 2 Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea , Seoul , Korea
2 Editor: Patrice E. Fort, University of Michigan , UNITED STATES
Funding: The authors wish to acknowledge the
financial support of the St. Vincent's hospital,
research institute of medical science
(SVHR-201514) and the National Research Foundation of Korea
Grant funded by the Korean government (MSIP)
(No. NRF- 2016R1C1B1011287). The funders had
no role in the study design, data collection and
To investigate changes in the neural retina according to the presence of retinal nerve fiber
layer (RNFL) defects in type 2 diabetes, and to determine the association between inner
retina thickness and the severity of diabetic complications.
We studied non-glaucomatous patients with type 2 diabetes and control subjects
Circumpapillary RNFL and macula ganglion cell-inner plexiform layer (GCIPL) thicknesses were
measured by spectral-domain optical coherence tomography. In patients with type 2 diabetes, a
cardiovascular autonomic function test (AFT) was performed, which included the heart rate
parameter of beat-beat variationÐwith deep breathing, in response to the Valsalva
maneuver, and on postural change from lying to standing. The results of each test were scored as
0 for normal and 1 for abnormal. A total AFT score of 1 was defined as early cardiovascular
autonomic neuropathy (CAN), and an AFT score 2 as definite CAN.
We compared control eyes (n = 70), diabetic eyes with RNFL defects (n = 47), and eyes
without RNFL defects (n = 30). The average RNFL and GCIPL thicknesses were
significantly different among groups (all, P<0.05). On post-hoc testing, diabetic eyes with RNFL
defects had a significantly thinner average GCIPL thickness than those without RNFL
defects. On multivariate analyses, significantly thinner average GCIPL was seen in early
CAN staging (B = -4.32, P = 0.016) and in definite CAN staging (B = -10.33, P<0.001),
compared with no CAN involvement, after adjusting for confounding parameters.
Cardiovascular autonomic dysfunction was associated with early neurodegenerative changes in type 2 diabetes.
analysis, decision to publish, or preparation of the
It is widely recognized that the early neurodegenerative changes that characterize diabetes
involve dysfunction and degeneration of retinal neurons even before the manifestation of
] High blood glucose induces apoptosis in retinal neural cells.
Increased neurofilament phosphorylation,[
] glial cell reactivity during metabolic stress,[
microglial activation, and altered glutamate regulation  are also involved in
neurodegeneration in the diabetic retina. These early changes especially involve the inner retina, as shown by
the reduction in thickness of the retinal nerve fiber layer (RNFL)[
] and loss of ganglion cell
Optical coherence tomography (OCT) can quantitatively measure the thickness of the
retina. Recent advances in OCT technology enabled us to measure the inner layer of the macula,
consisting of the ganglion cell layer and inner plexiform layer (GCIPL) using a ganglion cell
analysis (GCA) algorithm. In diabetes, early thinning of the macular GCIPL thickness has
been reported even before visible vascular signs of diabetic retinopathy (DR).[
Neurodegeneration in the early stages of diabetes compromises the functions of neurons, resulting in subtle
but significant impairment of vision.[
] Despite its clinical importance, little is known about
the systemic risk factors associated with inner retina thinning in diabetes.
Thinning of the inner retina correlates with the distribution of RNFL visibility in fundus
] Reduction in RNFL visibility, described as an RNFL defect, does not
develop in normal eyes. Therefore, the presence of an RNFL defect indicates a pathological
change, and is a highly specific marker for optic nerve head abnormalities.[
presence of RNFL defects has been associated with several conditions such as arterial hypertension
, small vessel disease, [
] cerebrovascular infarction,[
] and glaucoma.[
] In type 2
diabetes patients, the RNFL defects that develop in the early stages of retinal changes have been
associated with increased urinary albumin excretion.[
] Also, the location of RNFL defects
during diabetes is associated with diabetic peripheral neuropathy and cardiovascular
autonomic neuropathy (CAN).[
Despite the clinical significance of RNFL defects as a diagnostic tool for optic nerve
abnormalities, the detection of RNFL defects using red-free fundus photography is sometimes
limited; it is a qualitative measurement, and the results are dependent on the operator.[
] It is
therefore important to determine the association of quantitative OCT parameters with the
severity of diabetic complications.
In this study, we examined the differences in the circumpapillary RNFL and macular
GCIPL thicknesses according to the presence of RNFL defects in patients with type 2 diabetes,
and then investigated the systemic potential risk factors affecting macular GCIPL thickness.
This study included consecutively enrolled patients with type 2 diabetes and age- and
sexmatched control subjects (40±80 years of age) who underwent ophthalmic examinations and
spectral domain OCT from July 2014 to June 2015 at St. Vincent's Hospital, Suwon, South
Korea. This retrospective chart review was approved by the Institutional Review and Ethics
Boards of the Catholic University, St. Vincent's Hospital (local Institutional Review Board
number: VC14RISI0153). The institutional review board waived the need for a written consent
from the participants, because of the retrospective design. Patient information was
anonymized and de-identified prior to analysis. The study design followed the tenets of the
Declaration of Helsinki for biomedical research.
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Subjects with type 2 diabetes were included if they had no signs of a glaucomatous optic
disc (focal or generalized narrowing, disappearance of the neuroretinal rim, disc hemorrhage,
or cup-to-disc asymmetry > 0.2). They were required to have normal visual field (VF) results
during the follow-up. A normal VF examination was defined as a glaucoma hemifield test
result within normal limits, and total and pattern standard deviation values associated with
probabilities of normality > 5%. Patients with type 1 diabetes, proliferative DR, neovascular
glaucoma, macular edema, or a known past history of macula edema were excluded from
the study. Patients who underwent interventions such as panretinal photocoagulation or
intravitreal injection, and those who were using anti-glaucoma eye drops, were also excluded.
Patients with acute complications of diabetes at present, or with arrhythmia, or with severe
illnesses such as heart failure, liver cirrhosis, alcoholism, severe infection, or malignancy, were
excluded. Patients with type 1 diabetes or gestational diabetes, chronic kidney disease stage 3
or higher, and end-stage renal disease were also excluded.
The control group included subjects with an intraocular pressure < 21 mmHg, a normal
optic disc appearance upon examination of color stereoscopic photographs (an intact
neuroretinal rim without peripapillary hemorrhage, thinning, or localized pallor), the absence of any
RNFL abnormality visible on red-free fundus photographs, normal VF test results, and no
systemic disease such as diabetes or hypertension. All subjects were required to have a
best-corrected visual acuity (BCVA) of 20/40 or better, a spherical equivalent within ± 5.0 diopters,
and open angles on gonioscopy.
All subjects underwent a comprehensive ophthalmic examination, including a review of
medical and ocular histories, measurement of BCVA, Goldmann applanation tonometry, slit-lamp
biomicroscopy, gonioscopic examination, dilated funduscopic examination, stereoscopic optic
disc photography, red-free RNFL photography (CF-60UD; Canon, Tokyo, Japan), standard
automated perimetry measurements using the 24±2 SITA program (Humphrey Visual Field
Analyzer; Carl Zeiss Meditec, Dublin, CA, USA), and OCT (Cirrus OCT; Carl Zeiss Meditec,
CA, USA). DR was graded by retinal specialists (DHJ and JWK), based on the International
Clinical Diabetic Retinopathy Severity Scale.[
To determine RNFL defects using fundus photography, two experienced ophthalmologists
(CJA and JWK), who were blinded to the subject's identity, evaluated the red-free photographs
to detect any RNFL defects. An RNFL defect was defined as described in definitions of
] Any cases involving disagreement of the presence of RNFL defects between
the two observers were excluded from the study.
Diabetes was diagnosed in subjects with a fasting plasma glucose 126 mg/dL or symptoms of
diabetes and a casual plasma glucose concentration of 200 mg/dL using an automated
] Glycated hemoglobin (HbA1c) levels were measured using
high-performance liquid chromatography (Bio-Rad, Montreal, Quebec, Canada) every 3 months. The
average HbA1c level during the most recent 12 months (the mean HbA1c) was used in this
study. The treatment of diabetes was categorized according to use an oral agent, insulin, or
lifestyle modifications alone. Hypertension was defined as systolic blood pressure 140 mmHg,
diastolic blood pressure 90 mmHg, or the use of hypertensive medications. Serum lipid
concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density
lipoprotein (LDL) cholesterol, and triglycerides were measured enzymatically using an automatic
analyzer (Model 736±40; Hitachi, Tokyo, Japan). Smoking status was defined as either current
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or past smoker. The estimated glomerular filtration rate was calculated using the Modification
of Diet in Renal Disease Study equation.[
] From the first-voided spot urine samples, the
albumin-to-creatinine ratio (ACR) was calculated.
The cardiovascular autonomic function test (AFT) was performed using Ewing's method. This
includes a test for heart rate variability, such as the beat-beat variation with deep breathing,
on postural change (from lying to standing), and in response to the Valsalva maneuver, as
] Each of the three ratios described above was scored as 0 (normal)
or 1 (abnormal), for a total maximum score of 3. The CAN stage was defined as follows: 0,
normal autonomic function; 1, early CAN; and 2, definite diagnosis of CAN.
All participants were imaged by spectral-domain OCT, which comprised an optic-disc scan
(optic disc cube, 200 × 200 protocol) and a macular scan (macular cube, 514 × 128 protocol).
The circumpapillary scan allowed measurement of RNFL thickness, whereas the macular scan
determined the macular GCIPL thickness using the GCA algorithm.[
] The average
RNFL thickness and RNFL thickness for each quadrant sector were determined for all
participants. The GCA provides the average GCIPL thickness and that for each of the six individual
sectors [superior (S), superonasal (SN), inferonasal (IN), inferior (I), inferotemporal (IT), and
superotemporal (ST)], in addition to the deviation map, on which areas appear as yellow or
red to represent GCIPL thickness less than the lower 5% or 1% of normative data, respectively.
In this study, the average and by-sector GCIPL thicknesses were recorded. The average values
of S, SN, and ST were designated as superior hemifield GCIPL thicknesses, and the average
values of I, IN, and IT were the inferior hemifield GCIPL thicknesses. A sector map with one or
more yellow/red colored sectors was considered abnormal. The abnormal deviation map was
defined as the presence of yellow/red pixels in the map, as previously described. Only
wellfocused signal strengths 7/10 were used.
The reproducibility of interobserver measurements (by CJA and JWK) for the detection of
photographic RNFL defects was assessed by calculation of intraclass correlation coefficients
(ICCs). Student's t-test and the chi-squared test were used to compare between group means
and percentages derived from independent samples. Differences between three groups were
determined by analysis of variance (ANOVA) followed by Bonferroni post-hoc testing. For
factors that were markedly skewed, log-transformed values were used in the analyses. Crude
associations between potential systemic risk factors and macula GCIPL thickness parameters
were determined using univariate linear regression analyses. A dummy variable linear
regression model was used to investigate the effect of the three CAN gradings on the average GCIPL
thickness. To determine the association between the severity of CAN and the average GCIPL
thickness, multiple linear regression analyses were used. The dependent variable was average
GCIPL thickness. For multiple linear regression analyses, variables with P < 0.15 (age, CAN
stage, spherical equivalent, total cholesterol, triglyceride level, and the duration of diabetes) in
univariate analyses were included in Model 1. In Model 2, potential confounders that could
affect the association between CAN stage and the average GCIPL thickness (presence of DR,
average HbA1c, smoking, use of statins, antiplatelet activity, and angiotensin-converting
enzyme inhibitors or angiotensin receptor blockers) were additionally included. A backward
elimination process was used to develop the final multivariate model. Statistical analyses were
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performed using SPSS for Windows software (ver. 18.0; SPSS Inc., Chicago, IL, USA). A value
of P < 0.05 was considered statistically significant.
A total of 333 patients with diabetes underwent ophthalmic examinations between July 2014
and July 2015. Of these, 199 with glaucomatous optic discs or glaucomatous VF losses were
excluded, and 14 were excluded because of ambiguous RNFL defects. Six eyes about which
the two observers were in disagreement in terms of RNFL defect measurements were also
excluded. Also, 37 eyes were excluded because AFT results were lacking. Finally, 77 patients
with type 2 diabetes and 70 control subjects were included. The interobserver ICC (95%
confidence interval) for the detection of photographic RNFL defects was 0.918 (0.874±0.947).
The mean patient age and diabetes duration were 55.7 ± 10.7 years and 9.3 ± 6.8 years,
respectively; 47 subjects (61.0%) had RNFL defects and 30 subjects (39.0%) did not. In total, 51
patients (66.2%) had no DR, 17 patients (22.1%) had mild non-proliferative diabetic
retinopathy (NPDR), 8 patients (10.4%) had moderate NPDR, and 1 patient (1.3%) had severe NPDR.
The mean age, sex, and spherical equivalent were not significantly different among controls,
diabetic patients with RNFL defects, and those without RNFL defects (Table 1). When
comparing patients with RNFL defects with those without RNFL defects, abnormal CAN staging was
significantly more frequent in patients with RNFL defects (P = 0.037), and the log-transformed
ACR was higher in subjects with RNFL defects (P = 0.045).
Regarding comparison of circumpapillary RNFL parameters, the average RNFL thickness
and superior quadrant and inferior quadrant RNFL thicknesses were significantly different
among groups (P = 0.027, 0.020, and < 0.001, respectively; Table 2) Post-hoc analyses showed
no significant difference in the circumpapillary RNFL thicknesses between diabetic patients
without RNFL defects and those with RNFL defects. Regarding comparison of the macula
GCIPL thickness, the average GCIPL thickness and the superior and inferior hemifield GCIPL
thicknesses were significantly different among groups (P = 0.001, < 0.001, and 0.016,
respectively). Post-hoc analyses showed that diabetic patients with RNFL defects had significantly
thinner average GCIPL and superior hemifield GCIPL thicknesses, compared with diabetic
patients without RNFL defects. Disc areas were 1.94 ± 0.27 mm2 for the control group,
2.02 ± 0.32 mm2 for diabetic patients without RNFL defects, and 1.90 ± 0.28 mm2 for diabetic
patients with RNFL defects (P = 0.148). Fig 1 shows the differences in sectorial GCIPL
thicknesses according to the presence of RNFL defects in diabetic patients. The ST, S, SN, and IN
sectors were significantly thinner in patients with RNFL defects compared with those without
RNFL defects (P = 0.032, 0.011, 0.011, and 0.046, respectively).
Table 3 shows the difference in circumpapillary RNFL and macular GCIPL thicknesses in
diabetic patients according to CAN stage. The average circumpapillary RNFL thickness, and
the values for the four individual quadrants did not differ significantly among the groups.
However, the average, superior hemifield, and inferior hemifield GCIPL thicknesses were
significantly thinner with increasing CAN stage (P = 0.003, 0.006, and 0.007, respectively).
Dummy variable regression analyses showed a significantly thinner average GCIPL in early
CAN (B = -4.38, P = 0.021) and definite CAN (B = -7.33, P = 0.006) compared with the absence
of CAN involvement (Table 4). Using crude univariate linear regression analyses, other
systemic risk factors associated with the average GCIPL thickness were age, total cholesterol, and
triglyceride level (P = 0.040, 0.044, and < 0.001, respectively; Table 3).
In multivariate Model 1, the presence of early CAN (B = -2.32, P = 0.075) and definite CAN
(B = -8.65, P = 0.001; Table 5) contributed significantly more to the decreased average GCIPL
thickness relative to the absence of CAN involvement. Serum triglyceride was also significantly
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RNFL retinal nerve ®ber layer, DM diabetes mellitus, DR diabetic retinopathy, CAN cardiovascular autonomic neuropathy, eGFR estimated glomerular
®ltration rate, ACR urinary albumin-to-creatinine ratio, HDL high-density lipoprotein, LDL low-density lipoprotein.
associated with higher average GCIPL thickness (B = 0.027, P = 0.001). In multivariate Model
2, the presence of early CAN (B = -4.32, P = 0.016) and definite CAN (B = -10.33, P < 0.001)
also contributed significantly more to the decreased average GCIPL thickness. Serum
triglyceride and use of statins were significantly associated with a higher average GCIPL thickness
(B = 0.028, P = 0.001 and B = 4.36, P = 0.008, respectively).
In the GCA deviation map, 70.0% of patients with definite CAN showed abnormal findings,
whereas 54.2% of patients with early CAN±and 26.7% patients without CAN±were abnormal
(chi-squared test, P = 0.025). In the GCA sector map, 30.0% of patients with definite CAN had
abnormal findings, whereas no patients with early CAN, and 16.7% of patients with normal
CAN, were abnormal (chi-squared test, P = 0.016).
In the present study, diabetic patients with RNFL defects showed a lower macular GCIPL
thickness compared with those without RNFL defects. The average macular GCIPL thickness
was significantly decreased with the severity of CAN after adjusting for potential confounding
factors. Collectively, our results suggest that diabetic cardiovascular autonomic neuropathy is
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associated with the early neurodegenerative changes of type 2 diabetes, as shown in
representative case (Table 5; Fig 2).
Diabetic cardiovascular autonomic neuropathy is one of the most common and serious
complications of diabetes.[
26, 32, 33
] Damage to the autonomic nerve fibers that innervate the
heart and blood vessels causes abnormalities in heart rate control and vascular dynamics. [
In patients with diabetes, the extent of CAN is inversely related to survival and quality-of-life,
Fig 1. Comparisons of sectorial GCIPL thickness according to the presence of RNFL defect in diabetes.
GCIPL ganglion cell-inner plexiform layer, RNFLD retinal nerve fiber layer defect, SN superonasal, S superior, ST
superotemporal, IN inferonasal, I inferior, IT inferoteporal. *independent t-test.
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] and is associated with cardiovascular events, stroke, and other diabetic complications
such as severe hypoglycemia and chronic kidney disease.[
27, 28, 35
] CAN may be detected at
the time of diabetes diagnosis; poor glycemic control plays a central role in the development
and progression of CAN.  In the present study, we used Ewing's method to determine the
extent of CAN. [
] In contrast to other diabetic, autonomic neuropathic complications,
which are usually diagnosed by exclusion because of the absence of confirmatory diagnostic
tools, CAN can be evaluated both easily and noninvasively on an outpatient basis.
In this study, patients with an RNFL defect showed thinner macula GCIPLs, compared
with those without RNFL defects. To the best of our knowledge, this is the first study to report
the characteristics of OCT parameters on photographs of RNFL defects in type 2 diabetes.
Notably, the RNFL defects originating from the optic nerve head accompanied significant
changes in the macula area. RNFL defects are one of the early signs of neurodegenerative
changes in diabetes.[
] However, RNFL defects also reflect systemic conditions such as
arterial hypertension, stroke,[
] and small vessel disease. [
]. In patients with normal
tension glaucoma, those with central VF defects on initial presentation have higher levels of
systemic vascular risk factors and disc hemorrhage.[
] Based on our present results, the
early neurodegenerative changes represented by RNFL defects may accompany generalized
changes in the ganglion cells of the macula.
Although RNFL defects on red-free fundus photographs provide useful clinical
information, detection of RNFL defects using these photographs represents a qualitative measurement,
so the results could be subjective and dependent on the operator.[
] The macular GCIPL
topography is less variable among normal individuals compared with that of other
diagnostically important structures, such as the optic disc and RNFL. In our study, subjects with
definite CAN showed significantly more abnormal findings in the GCA deviation and sector
maps (chi-squared test, P = 0.025 and 0.016, respectively). Corneal neurodegenerative changes
detected by corneal confocal microscopy have also been considered as early biomarkers of
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Age, per 1 yr
per 1 diopter
SBP, per 1 mmHg
DBP, per 1 mmHg
eGFR per 1 mml/min per
ACR, per1 ug/mg
Total cholesterol, per 1
HDL cholesterol, per 1
LDL cholesterol, per 1
Triglycerides, per 1 mg/
Duration of diabetes, per
Mean hemoglobin A1c,
Use of statin medication,
yes vs. no
DR, yes vs. no
Average GCIPL thickness
GCIPL ganglion cell-inner plexiform layer, SBP systolic blood pressure, DBP diastolic blood pressure, eGFR estimated glomerular ®ltrationrate, ACR
urinary albumin-to-creatinine ratio, CAN cardiovascular autonomic neuropathy, HDL high-density lipoprotein, LDL low-density lipoprotein, RNFL retinal
nerve ®ber layer, DR diabetic retinopathy.
CAN cardiovascular autonomic neuropathy, GCIPL ganglion cell-inner plexiform layer. For multiple linear regression models between CAN staging and the
average GCIPL thickness, parameters were included as follows: model1, age, spherical equivalent, total cholesterol, triglyceride, duration of diabetes
(parameters showing P < 0.150 in univariate associations), model 2, model 1 plus presence of diabetic retinopathy, mean hemoglobin A1c, smoking, use of
statin, antiplatelet, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers. A backward elimination process was used to develop the
®nal multivariate model.
] In this regard, it is therefore possible that the macular GCIPL
thickness represents a useful parameter for the early detection of neurodegenerative changes
in diabetic patients.
Fig 2. Representative case showing the association between photographic RNFL defect and macular GCIPL thickness. A 57-year old
female with a 17-year history of type 2 diabetes exhibited a definite involvement of cardiac autonomic neuropathy. In the red-free photograph,
retinal nerve fiber layer (RNFL) defects are observed (A, white arrow). In the quadrant and clock-hour based map, the circumpapillary RNFL
thickness is within normal limit (B). However, in the GCA deviation map and sector map exhibit abnormal finding (C)
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In regional analyses, the GCIPLs, especially at the superior sectors (ST, S, and SN), were
significantly thinner in patients with RNFL defects (Fig 1). As previously reported, RNFL loss in
diabetic patients usually occurs in the superior hemisphere. Our observation that the superior
GCIPL thickness was thinner in diabetic patients with RNFL defects is consistent with these
Crude univariate associations of systemic factors with macula GCIPL thickness, and higher
serum triglycerides were also significantly associated with higher average GCIPL, and superior
and inferior hemifield GCIPL, thicknesses (P <0.001, <0.001, and 0.003, respectively).
Consistent with our data, Sasaki et al. [
] reported that a higher LDL cholesterol level was associated
with increased macular thickness in diabetic patients without macula edema. Lipid-lowering
agents such as statins decrease vascular disease and may increase the lifespan.[
the use of statin medication was not significantly associated with the average GCIPL thickness
on univariate analyses in our study. Further prospective studies are therefore needed to
investigate possible associations of the overall serum lipid status with the retinal structures.
This study had some limitations. First, we did not include patients who did not receive
complete ophthalmic examinations, spectral domain OCT, and systemic evaluations, which
may have affected the interpretation of the results, including due to selection bias). Second, we
excluded eyes with proliferative DR and macular edema. Furthermore, most patients (64.9%)
had no DR. However, the presence of DR may result in potential errors in OCT
measurements, such as misidentification of the outer layer and off-center artifacts.[
] Finally, causal
relationships cannot be inferred, such that the results of our cross-sectional study should be
interpreted with caution.
In summary, the results of our study emphasize the potential utility of macula GCIPL
parameters as markers of early neurodegenerative changes during diabetes. Careful clinical
attention to diabetic patients with abnormal thinning in macular GCIPL is recommended,
when considering that the macular GCIPL thickness significantly decreases with the severity
of CAN. Further prospective studies are needed to confirm the longitudinal changes in
macular OCT parameters associated with the severity of systemic complications during diabetes.
The authors alone are responsible for the content and writing of the paper.
Conceptualization: JAC CKP SHK.
Data curation: HYK JWK YSS DHJ JSY YBA.
Formal analysis: JAC JSY.
Funding acquisition: JAC.
Investigation: SHK YSS.
Methodology: JAC HWK.
Project administration: YBA SHK.
Resources: JWK YSS DHJ JSY YBA SHK.
Supervision: CKP SHK.
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Visualization: JAC JSY.
Writing ± original draft: JAC.
Writing ± review & editing: SHK.
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