Effect of carotenoids dietary supplementation on macular function in diabetic patients
Moschos et al. Eye and Vision
Effect of carotenoids dietary supplementation on macular function in diabetic patients
Marilita M. Moschos 0 1
Maria Dettoraki 0 1
Michael Tsatsos 3
George Kitsos 2
Christos Kalogeropoulos 2
0 Equal contributors
1 First Department of Ophthalmology, Medical School, National and Kapodistrian University of Athens , 6 Ikarias street, Ekali, 14578 Athens , Greece
2 Department of Ophthalmology, Medical School, University of Ioannina , Ioannina , Greece
3 Department of Ophthalmology, Medical School, Aristotle University of Thessaloniki , Thessaloniki , Greece
Background: Diabetic retinopathy is a major cause of visual impairment and blindness among working-age people worldwide. The aim of our study was to investigate the effects of a carotenoid supplementation on retinal thickness and macular function of patients with diabetes using optical coherence tomography (OCT) and multifocal electroretinography (mfERG). Methods: A retrospective study of one hundred and twenty eyes of sixty patients age between 40 and 60 years with non-insulin dependent type 2 diabetes mellitus without diabetic retinopathy who underwent OCT and mfERG and took vitamin supplements for a period of two years. Patients received a carotenoid supplement containing lutein (10 mg), zeaxanthin (2 mg) and meso-zeaxanthin (10 mg) once a day for two years. The thickness of the fovea was evaluated using OCT and the macular function was tested by mfERG. Results: OCT showed an increase in the central foveal thickness and mfERG revealed increased retinal response density within the central 13° surrounding the fovea (rings 1 to 3) at two years after the onset of carotenoids supplement intake. Conclusion: The use of carotenoid supplements may be of benefit for improving visual function of type 2 diabetes patients. However, further study is needed to assess the treatment's long-term efficacy.
Carotenoids; Diabetes mellitus; Visual function; Multifocal electroretinography; Optical coherence tomography
Diabetic retinopathy (DR) is a major cause of visual
impairment and blindness among working-age people worldwide.
Despite studies showing that timely treatment of DR can
significantly reduce the risk of visual complications and the
advances in clinical management of the disease, DR visual
impairment increased by an alarming 64% over the last two
decades globally [
]. Diabetic macular oedema (DME) is
one of the major complications of DR and the most
common form of sight-threatening retinopathy in diabetes
affecting more than 20 million people worldwide [
Poor glycaemic and blood pressure control are associated
with the presence and development of the disease. The
current treatment options of DME include laser
photocoagulation, intravitreal injections of anti-vascular
endothelial growth factor (anti-VEGF) agents and corticosteroids.
There have been few human studies evaluating the
effects of dietary supplements on the occurrence and
progression of DR. Although the positive influence of a
nutritional supplement on the progression of a
visionthreatening eye disease, age-related macular degeneration
(AMD), has been demonstrated by the Age-Related Eye
Disease Study (AREDS), the available evidence in support
of the use of carotenoids for retinal health in DR is scant
]. Daily consumption of a multi-component formula
containing xanthophyll pigments, antioxidants, and
selected botanical extracts had been shown to improve
contrast sensitivity, macular pigment optical density, colour
discrimination and perimetry in patients with diabetes,
both with and without retinopathy [
higher concentrations of the plasma carotenoids lutein,
zeaxanthin and lycopene, which are largely dependent on
dietary intake, are considered to have a protective role
against DR [
]. Lutein and zeaxanthin intake has been
reported to improve visual acuity, contrast sensitivity and
macular oedema in patients with non-proliferative DR [
The carotenoids lutein, zeaxanthin and meso-zeaxanthin
accumulate in the central retina, where they are
collectively known as macular pigment. Lutein is the dominant
carotenoid in the peripheral macula, zeaxanthin in the
mid-peripheral macula, and meso-zeaxanthin at the
epicentre of the macula [
]. In the last decade, the macular
pigment has generated increased interest due to its
possible protective role against AMD, which may be
attributed to its antioxidant effects and protection of the retina
against the phototoxic activity of blue light [
Humans cannot synthesize macular pigment but absorb
lutein and zeaxanthin from the diet, mainly the fruits,
vegetables and egg yolks.
Multifocal electroretinography (mfERG) has been
evaluated as an objective, non-invasive method to detect
subclinical DR and assess changes in the retinal function
of diabetic patients [
] Moreover, mfERG allows a
topographic mapping of retinal dysfunction in DR .
MfERG reflects not only the electrophysiological
responses of the photoreceptors but also those of the
inner retinal layers, including bipolar cells and Muller
cells, which are mainly affected by DR [
The aim of our study was to investigate the effects of a
carotenoid supplement (Macushield), containing lutein,
zeaxanthin, and meso-zeaxanthin, on retinal thickness
and macular function of patients with type 2 diabetes,
using OCT and mfERG. To the best of our knowledge,
the use of mfERG to evaluate the effects of food
supplements on retinal function of diabetic patients has not
Sixty patients were included in this retrospective study
who received a soft gel capsule containing lutein (10 mg),
zeaxanthin (2 mg) and meso-zeaxanthin (10 mg) in a
sunflower oil suspension (commercially available as
Macushield). Patients were instructed to take one capsule daily
with a meal. The data collected include best corrected
visual acuity (BCVA), central foveal thickness (CFT) and
mfERG responses measured at baseline (pre-medication)
and after two years of carotenoid supplementation. BCVA
was measured with the use of a Snellen chart.
Inclusion criteria included BCVA ≥8/10 in each eye,
normal colour vision test and no signs of DR. All
patients were treated with oral antidiabetic therapy. No
previous lutein and/or other anti-oxidants
supplementation were taken. Patients with diabetes were excluded if
they exhibited any ocular disease such as cataract,
glaucoma, age-related macular degeneration, myopia of more
than 6 D or had previously undergone cataract
extraction or any treatment for DR or diabetic maculopathy.
The study was conducted at the 1st Department of
Ophthalmology, “G. Gennimatas” General Hospital,
University of Athens, Athens, Greece and adhered to the
principles laid out in the Declaration of Helsinki. The
study was approved by the institutional review board of
“G. Gennimatas” General Hospital, Athens, Greece.
SD-OCT scan acquisition and analysis
Sectional images of the macula of each patient were
scanned using SD-OCT (Spectralis OCT, Heidelberg
Engineering, Heidelberg, Germany) at baseline and 2 years
after carotenoid supplement intake. The patients were
asked to gaze at the fixation light within the instrument
and the foveolar fixation was confirmed by observing
the retinal image through the infrared monitoring
camera. A 9-mm line scan along the horizontal meridian
centered at the fovea was obtained using high-resolution
settings. The line scan was obtained as an average of 100
scans to give the highest signal-to-noise ratio (>25 dB).
The foveal line scans were examined for local
abnormalities such as macular oedema. The scans were then
analysed using a computer-aided, manual technique for
the measurement of central foveal thickness (CFT, the
distance between the innermost border of the retina
towards the vitreous to the ellipsoid zone) in all patients.
MfERG was performed according to the guidelines by
the International Society for Clinical Electrophysiology
of Vision using the VERIS III (Visual Evoked Response
Imaging System; Tomey, Nagoya, Japan) [
was recorded with an active fibre electrode positioned
on the bulbar conjunctiva directly beneath the cornea
and with a reference inactive electrode attached to the
skin, near to the orbital rim and lateral to the
corresponding eye. The ground electrode was attached to the
earlobe. The active, inactive and ground electrodes were
connected to a junctional box, from which the signals
were delivered to additional recording components for
amplification and display. The recording was performed
with eyes corrected for near vision. Pupils were fully
dilated with topical 0.5% tropicamide and 5%
phenylephrine eye drops. The fellow eye was closed and the
duration of the data acquisition was four minutes divided
into eight sessions of 30 s. Multiple retinal areas were
stimulated simultaneously using a stimulus array of 61
hexagons displayed on a cathode ray tube (CRT)
monitor (Sony, Tokyo). Each hexagon was independently
alternated between black and white at a rate of 75 Hz
and the stimulation technique allowed a retinal response
from each stimulus. A red fixation point of 2 mm
diameter was used. The stimulus luminance was 200 cd/m2
for the bright flashes and 1 cd/m2 for the dark flashes.
The radius of the stimulus array subtended
approximately 20° high and 25° wide. The bandwidth of the
amplifier was 10–300 Hz, and the amplification was
×10000. Topical anaesthesia with 0.5% proparacaine
hydrochloride eye drops was installed before the
recording. The recording procedure was repeated when
spurious potentials from eye blinks or ocular movements
The mfERG stimuli location and anatomical areas
corresponded roughly to five concentric rings as follows:
ring 1 to the fovea (0°-2°), ring 2 to the parafovea (2°-7°),
ring 3 to the perifovea (7°-13°), ring 4 to the near
periphery (13°-22°) and ring 5 to the central part of the middle
periphery (22°-30.5°). The retinal response density (RRD,
amplitude per unit retinal area, nV/deg2) and the
implicit time (P1 latency, ms) of the first positive peak of each
individual ring were measured in each patient at baseline
and 2 years after the carotenoid supplement intake.
The Gaussian distribution assumption was tested using
the method of Kolmogorov and Smirnov. All variables
succeeded in passing the normality test. For statistical
analysis, the paired comparison t-test was used to test
the significance of the mean values before and after the
supplement intake in diabetic patients. The data were
expressed as the mean ± standard deviation (SD). A p
value of less than 0.05 was considered to indicate
The study included 120 eyes of 60 patients with type 2
diabetes. The mean age of patients at baseline was
50 years with a range from 40 to 60 years. Of the 60
patients, 31 (52%) were males and 29 (48%) were females.
Two years after the carotenoid supplementation,
BCVA remained normal (≥ 9/10) in each eye. The mean
CFT in the right eye increased from 157.4 ± 13.7 μm at
baseline to 162.8 ± 13.1 μm following carotenoid intake
(p < 0.001). Similarly, in the left eye, the mean CFT
increased from 157.1 ± 14 μm to163.4 ± 13.2 μm after
carotenoid intake (p < 0.001) (Table 1). No intraretinal
fluid or cystic changes in the retina were detected on
morphological analysis of the OCT cross-sectional scans
in any of the eyes examined.
The RRD of mfERG significantly increased in all
central 3 rings in both eyes of the patients two years
after supplement intake compared to baseline, as shown
in Table 1. No differences in P1 latency were observed
in any of the 3 central rings in both eyes after
supplement intake compared to baseline (Fig. 1).
CFT=central foveal thickness; OD=oculus dexter; OS=oculus sinister
Data are expressed as mean ± SD
No adverse reactions due to the supplement intake
were recorded during the entire period of treatment.
This study demonstrated that carotenoid supplements
increased the CFT on OCT and significantly improved
the RRD on mfERG at the central rings in patients with
type 2 diabetes without DR, suggesting that carotenoids
may have a beneficial effect on the macular function of
Several studies have shown that serum lutein and
zeaxanthin concentrations are significantly lower in patients
with non-proliferative DR than those in normal subjects
]. Possible reasons include an unhealthy diet poor in
fruits and vegetables since the diabetic patients’ body
mass index is generally higher than the normal standard,
decreased absorption of lutein and zeaxanthin because
of hyperglycaemia and limited accumulation in the
retina due to destructing local microcirculation
characteristic in DR . Following dietary supplementation of
lutein and zeaxanthin in diabetic patients, their serum
concentrations are higher than those in normal subjects
]. Specifically, serum lutein can reach maximum
concentration 16 h after 10 mg of lutein intake .
Furthermore, several studies have demonstrated that
following serum lutein and zeaxanthin elevation, the
lutein, and zeaxanthin density in the retina also increases
6, 21, 23, 24
]. Therefore, a positive relationship exists
between the higher consumption of these carotenoids,
the higher serum carotenoid levels, and the higher
macular pigment density.
Brazionis et al. assessed the relationship between the
major carotenoids, lutein, zeaxanthin and lycopene, and
DR in a cross-sectional study of 111 individuals with
type 2 diabetes [
]. The authors reported that a higher
combined lutein, zeaxanthin and lycopene concentration
in plasma was associated with significantly lower odds of
DR, after adjusting for potential confounding
retinopathy risk factors. Hu et al. reported a decrease in the
average foveal thickness of 30 diabetic patients with
non-proliferative DR and macular oedema three months
after lutein and zeaxanthin supplementation compared
to pre-medication status [
]. The authors proposed that
the carotenoids may play a role in diabetic macular
oedema since lutein and zeaxanthin can reduce vascular
permeability, inhibit vascular leakage and protect the
integrity of blood vessels.
Loss of retinal capillaries leading to progressive retinal
hypoxia, increased retinal vascular permeability, and
new retinal vessel growth are characteristic of DR [
Moreover, DR is considered a multifactorial disease with
various abnormalities contributing to its development.
Oxidative stress is increased in the retina of diabetic
patients and is implicated in the development of DR. DR is
also known to have an inflammatory component in that
leukostasis occurs and increased levels of the adhesion
molecule ICAM-1 have been found in the retina of
]. VEGF, an angiogenic factor that induces
vascular endothelial cell proliferation, migration, and
vasopermeability in many tissues, is also elevated in the
retina and vitreous of diabetic patients and is implicated
in the pathogenesis of DR [
]. Studies have shown that
lutein can attenuate oxidative stress in experimental
models of early DR and zeaxanthin significantly inhibits
diabetes-induced retinal oxidative damage and elevations
in VEGF and adhesion molecule ICAM-1 in diabetic rats
]. Hence, animal studies have demonstrated that
carotenoids have a protective role against the
abnormalities associated with the pathogenesis of DR.
Studies in patients with AMD and healthy subjects
have evaluated the impact of the same carotenoid
formulation as in our study on macular function. Macular
pigment optical density and contrast sensitivity have
been found to increase after the carotenoid
supplementation, whereas no significant changes in BCVA or
progression to advanced AMD were observed in healthy
subjects and patients with early AMD [
12, 13, 29
recent report demonstrated that the daily oral
supplementation with Macushield for six months in patients with
retinal pathology (including those with DR) increased
the mean macular pigment optical density and
significantly increased the contrast sensitivity at low and
medium spatial frequencies [
]. Furthermore, a
significant improvement in the vision-related quality of life
was reported. Recently, the Central Retinal Enrichment
Supplementation Trial (CREST) study reported a
significant increase in contrast sensitivity of subjects free of
retinal disease after the daily consumption of the same
formulation used in the previous studies compared to
]. In our study, two years after the daily
supplementation with Macushield in patients with
type 2 diabetes, mfERG macular responses
significantly improved and foveal thickness increased
compared to baseline findings, indicating an improvement
of visual function. Visual acuity did not change over
the study period, which is consistent with the CREST
study as well as with the studies concerning patients
with early AMD [
Changes in retinal function can be depicted in detail
by means of mfERG recording, which is essential mainly
for the investigation of macular lesions. It has been
shown that in all types of maculopathy there is a
decrease or loss of central electrical response, which is
related to the degree and extent of the lesion. MfERG is a
valuable method particularly in cases where the patient
is visually asymptomatic, visual acuity is normal and
macular lesions are not clearly visible
]. MfERG reflects the electrophysiological
responses mainly from the inner retinal layers. DR is
characterized by the pathology of the microvasculature
in the inner nuclear layer, where the primary generators
of mfERG, the bodies of bipolar cells, are located.
Moreover, changes in the retinal vasculature of diabetic
subjects have been reported to take place before retinopathy
becomes clinically apparent [
]. Thus, mfERG is a
suitable method for the study of DR. Several investigators
have used mfERG recordings to assess retinal
dysfunction both in patients with DR [
14, 15, 17, 18
] and in
diabetic subjects without signs of retinopathy [
15, 16, 18,
]. A delay in the implicit time of the first order
component of mfERG has been demonstrated in diabetics
without retinopathy compared to normal subjects,
whereas in patients with DR both a decrease in
amplitude and a delay in peak implicit time of mfERG has
been reported. Harrison et al. have shown that the
implicit time measure of mfERG is a good predictor for the
development of retinopathy in adult patients with
diabetes in a 1-year follow-up period [
]. Patients with
type 1 diabetes display a greater risk for the onset of
retinopathy with smaller comparative delays in implicit
time than the type 2 group.
In our study, the central foveal thickness of patients
with diabetes and no retinopathy measured with the use
of OCT increased at two years after the carotenoid
supplementation compared with the baseline values. It
should be mentioned, however, that several studies have
suggested that patients with diabetes and no retinopathy
have retinal thickness values that are similar to values
from populations without diabetes and normal retinas
]. Further studies are needed to assess the
significance of the anatomical change demonstrated by OCT
in our study. Nevertheless, until now, no previous study
evaluating the effects of nutritional supplements on
diabetes has utilized mfERG as a visual function evaluation
tool. Limitations of our study include its retrospective
nature, the absence of a placebo group and the
nonassessment of serum carotenoids and macular pigment
optical density in diabetic patients.
Our study confirms the effectiveness of carotenoid
intake on visual function of type 2 diabetic patients.
Furthermore, the present study gives strength to the
recommendation of increasing consumption of lutein
and zeaxanthin-rich foods. Further prospective studies
are needed to determine whether both over time and in
more severe stages of DR a high concentration of
carotenoids can delay the onset or reduce the risk of
progression in DR.
AMD: Age-related macular degeneration; anti-VEGF: Anti-vascular endothelial
growth factor; AREDS: Age-Related Eye Disease Study; BCVA: Best corrected
visual acuity; CFT: Central foveal thickness,; CREST: Central Retinal Enrichment
Supplementation Trial; DME: Diabetic macular oedema; DR: Diabetic
retinopathy; mfERG: Multifocal electroretinography; RRD: Retinal response
density; SD-OCT: Spectral domain optical coherence tomography
Availability of data and materials
The datasets used and analysed during the current study are available from
the corresponding author on reasonable request.
MMM: designed the study, collected data, supervised the study, MD:
analysed data and wrote the manuscript, MT, GK, CK: contributed to data
acquisition. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Approved by the institutional review board of “G. Gennimatas” General
Hospital, Athens, Greece (ID 30726/83).
Consent for publication
The authors declare that they have no competing interests.
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