The Relationship Between Obesity, Insulin Resistance, and Conjunctival Impression Cytology
Murat DAĞDEVIREN1, Mustafa ALTAY1, Zennure YILDIZ2, Gülçin ŞIMŞEK3, Mehmet ÇITIRIK4, İhsan ATEŞ5, Tanyel Sema DAĞDEVIREN6, Canan YILDIZ7, Tuğba ŞAHIN2
1Department of 1Endocrinology and Metabolism, niversity of Health Science, Keçiören Health Administration and Research Center, ANKARA, TURKEY
2Department of Ophthalmology, University of Health Science, Keçiören Health Administration and Research Center, ANKARA, TURKEY
3Department of Pathology, University of Health Science, Keçiören Health Administration and Research Center, ANKARA, TURKEY
4Department of Ophthalmology, University of Health Science, Ulucanlar Health Administration and Research Center, ANKARA, TURKEY
5Department of Internal Medicine, University of Health Science, Ankara Numune Health Administration and Research Center, ANKARA, TURKEY
6Department of Family Practice, University of Health Science, Keçiören Health Administration and Research Center, ANKARA, TURKEY
7Department of Internal Medicine, University of Health Science, Keçiören Health Administration and Research Center, ANKARA, TURKEY
Keywords: Conjunctiva, Impression cytology, Inflammation, Obesity
This study was designed to determine whether obesity causes the development of metaplasia in conjunctival epithelial cells.
Material and Method: A total of 61 volunteer participants who had no previous history of illness or drug use were involved in this study. Of
those, 20 were obese, and 41 were of normal weight. We measured the glucose and insulin values of all volunteers. We also measured the Body
Mass Index (BMI) and Homeostasis Model Assessment for Insulin Resistance (HOMA IR). The impression cytology method was used to analyze
the conjunctival epithelium cells, and to classify them between Grades 0 to 3 according to the Nelson criteria.
Results: There was a certain level of loss of goblet cells on the 90% level as well as squamous metaplasia (Grade 2-3) in 80% of the obese
participants and impression cytology was found to be normal in only two patients. The expected results were observed in 56.1% of the control
group where the squamous metaplasia rate was nearly 17% (p<0.001). 90.9% of the grade 3 patients were obese. The variables as independent
predictors were found to indicate the existence of abnormal cytology in the conjunctiva at various levels; BMI (OR: 1.24; p=0.002) and HOMA
IR (OR= 28.6; p= 0.001) in a Model I multivariable regression model, and the existence of obesity (OR: 11.91; p=0.002) and HOMA IR (OR=
15.08; p<0.001) in a Model II multivariable regression model.
Conclusion: Obesity was found to be a disorder that causes metaplasia in the conjunctival epithelium cells for the first time.
Obesity is a chronic disease that has rapidly increased in
terms of frequency, especially over the past three decades,
to the point that it is on the verge of becoming a global
health pandemic. According to global projections, it is
estimated that there are nearly 500 million obese adults
. The gradual increase in the obesity
incidence has also caused the escalation of some diseases
such as type 2 diabetes mellitus (DM), hepatosteatosis,
various cardiovascular diseases in addition to respiratory
tract, neurodegenerative, and biliary disorders, as well as
gonadal abnormalities, and certain forms of cancer 3
Furthermore, the systemic inflammation and immune
system activation observed in obesity impacts certain
organs as well 4-7,
one of which is the eye. Obesity and
secondary insulin resistance, as well as the related prediabetes
and diabetes, may cause retinal dysfunction 8
Furthermore, obesity may bring about complications such
as cataract, macular degeneration, increased intraocular
pressure, and dry eye due to Meibomian gland dysfunction
9-11. Additionally, it has been associated with the
increasing retinal nerve fiber thickness found in BMI,
as well as with central macular thickness and choroidal
thickness 12. Research indicates that obesity may have
certain effects on certain parts of the eye with different
mechanisms. When it comes to inflammation, it would
be expected that conjunctival cells may also be affected as
well due to such diseases. Nevertheless, there is no clear
evidence or data that shows how obesity affects either the
conjunctival surface or epithelium cells.
The principle objective of this study was to evaluate the
ocular surface cells in obese patients using impression
cytology, as well as to determine whether obesity had
caused metaplasia in these cells.
Approval was first requested from the hospitals ethics
committee (decision dated and numbered: 14.05.2014-
581) before initiating the study. The work was conducted
according to the principles of the Helsinki Declaration, and
a written consent concerning the study was obtained from
each of the participants.
A total of 61 volunteer participants were involved in this
study. Those who were under the age of 18 years, who
had active or chronic eye disease, who had an ongoing or
systemic disease outside of obesity, who had used systemic
drugs, local eye medicine, and/or contact lenses, and/or
who had previously undergone any form of eye surgery
were excluded from this study. Similarly, those who had
used topical cyclosporine, or who had used local or systemic
non-steroid anti-inflammatory medicine or steroids over
the last 6 months, alongside those who had used any
topical treatments for their eyes, and had a history of
herpes keratitis, blepharitis, ocular trauma, and/or non-eye
surgery were also not included in this study. Furthermore,
patients with the punctate epithelial erosion in the cornea
were disqualified from the study. Those who did qualify as
participants had neither Steven-Johnson syndrome, nor any
history of thermal, chemical, or radiation damage. None of
the subjects were consumers of tobacco products, alcohol,
diuretics, antihistamines, vitamins, antidepressants, or
The glucose and insulin levels were measured from the
peripheral venous blood, between 08:00 to 09:00 in the
morning following a 10 hour-minimum fasting period.
The Body Mass Index (BMI) was calculated as the body
weight (kg) divided by the square of the height (m2). Those
whose BMI was over 30 kg/m2 were accepted as obese.
The Homeostasis model assessment for insulin resistance
(HOMA IR) was calculated using the formula (insulin x
glucose) / 405.
Schirmers test was applied to both the patients and control
groups immediately following a routine eye examination. A
standard kit consisting of a 5x30 mm2 filter paper was placed
under the temporal part of the lower eyelid. Participants
with values of less than 5 mm in the measurements after a
5-minute period were assumed to be abnormal, and were
also disqualified. The stability of the tear-film layer was
evaluated by determining the tear break-up time (TBUT)
test. For the TBUT, a fluorescein-impregnated strip was
placed in the patients lower conjunctival sac after being
wetted with a non-preserved saline solution. The patient
was asked to blink three to five times, and then to keep
their eyes open. The time between the last blink and the appearance of the first dark dot was recorded as the TBUT.
The mean of three measurements was recorded. A value of
<10 s was accepted as abnormal.
The impression cytology technique was used to evaluate the
conjunctival ocular surface. This technique was conducted
after topical anesthesia was applied to the conjunctiva. The
4x5 mm cellulose acetate filter papers (MFS, Advantec MFS,
Pleasanton, USA, pore size 0.2 μm) were placed under the
superior temporal interpalpebral conjunctiva 5 mm away
from the limbus. They were lightly pressed for 5 seconds and
pulled away. The samples were fixed with the appropriate
solutions, and tinted with dye using Papanicolaus modified
version of Gills technique. The prepared samples were
evaluated under a light microscope with a pathologist. The
Nelson grade system was used in the classification of the
results. Nelson grades conjunctival impression cytology
specimens (grades 0-3) based on the appearance of the
epithelial cells and the numbers of goblet cells (13).
The Nelson Classification (Figure 1A-D)
Grade 0: The epithelium cells are small, oval, or rather
round, and firmly bonded to one another. Their
cytoplasms are eosinophilic colored. The nuclei are large
and basophilic. The nucleus-to-cytoplasm rate is 1/2. The
goblet cells are relatively prevalent or abundant, bulbous,
and densely colored PAS (+).
Click Here to Zoom
|Figure 1: Grading system of impression cytology. A) Grade 0: small, ground epithelial cells have a prominent nucleus (PAS stain; x400).
B) Grade 1: the epithelial cells are slightly larger. The nuclei are smaller. Goblet cells are decreased minimally (PAS stain; x200). C) Grade
2: larger and polygonal epithelial cells (N/C ratio 1:4-1:5). Goblet cells are smaller and markedly decreased (PAS stain; x200). D) Grade
3: goblet cells have disappeared (N/C ratio 1:6) (PAS stain; x400).
Grade 1: The cytoplasm-portion of the epithelium cells is
eosinophilic-colored, slightly large, and polygonal. They
are about to separate from each other. The nuclei are rather
small, and the nucleus-to-cytoplasm rate is 1/3. The goblet
cells colored with PAS (+) are less prevalent but they are
quite similar in terms of both size and shape (early loss of
Grade 2: The coloring of the cytoplasm varies. The
epithelium cells are rather large and polygonal. They
are sometimes multiple in number, and their nuclei are
small. The nucleus-to-cytoplasm ratio is between 1/4
and 1/5. The prevalence of goblet cells is clearly reduced
(marked decrease of goblet cells), the volume is small, cell
boundaries are barely identifiable, and the PAS (+) coloring
Grade 3: The cytoplasm portion of the epithelium cells
are eosinophilic-colored, rather large, and polygonal in
shape. The nucleus is lost in most of the cells. Those cells
containing nucleolus are small, and have an apyknotic
structure. The nucleus-to-cytoplasm ratio is 1/6, and
cells that are keratinized in appearance are present. The
prevalence of goblet cells is low to non-existent (total loss
of goblet cells, large epithelial cells).
All specimens that were grade 1, 2 or 3 were abnormal (loss
of goblet cells = abnormal cytology). In essence, grade 2 and
3 inflammations have been dubbed as squamous metaplasia
due to their changing of the non-keratinized secretory
epithelia into the keratinized non-secretory phase.
The Statistical Package for Social Sciences (SPSS) for
Windows 20 (IBM SPSS Inc., Chicago, USA), alongside
the Med Calc 11.4.2 (MedCalc Software, Mariakerke,
Belgium) software programs were used for statistical
analysis. The normal distribution of the data was
evaluated with using the Shapiro-Wilk test. Values with
normal distribution were presented as a mean ± standard
deviation. Categorical variables were presented in terms of numbers and percentages. Numerical values in two groups
were compared using the Student T test. The Chi-square
and Fishers exact Chi-square tests were used to compare
the categorical data. Numerical values in the grade groups
were compared using the ANOVA test. Invariable analysis
was utilized in order to determine the effects of potential
prognostic factors on a loss of goblet cells. Significant
factors were included in the stepwise multivariate logistic
regression model, and independent predictors were
identified. The diagnostic discrimination of independent
predictors in the loss of goblet cells were examined using
ROC Curve analysis, or the area beneath the curve. In the
statistical analysis, the p<0.05 significance level with a 95%
confidence interval alongside a 5% margin of error was
considered to be statistically significant.
A total of 61 volunteer participants, including 9 men
(14.8%) and 52 women (85.2%) were involved in this study.
The participants were divided into two groups for analysis:
an obesity group (n=20, 32.8%) and a control group (n=41,
67.2%). There was no significant difference between
the two groups in terms of age or sex. Table I
demographic and clinical characteristics of both the obesity
and control groups.
Click Here to Zoom
|Table I: The distribution of clinical and demographic results by
There was a certain level loss of goblet cells in 90% and
squamous metaplasia (Nelson grade 2-3) in 80% of obese
participants and the impression cytology was found to be
normal in only two patients (10%). The rate of participants
without abnormal cytology was 56.1% in the control
group, and the squamous metaplasia rate was nearly
17% (p<0.001). Furthermore, the average BMI, insulin,
glucose and HOMA IR levels were significantly higher in
the obesity group (p<0.001). When the participants were
grouped according to grade level, a gradual increase in the
average BMI, insulin, glucose, and HOMA IR levels was
observed in association with the increase in grade levels
(Table II). 90.9% (n=10) of those with grade 3 were obese.
Grade 1 was found in only one of the patients belonging to
the control group. Table II indicates both the demographic
and clinical data associated with these grade levels.
Click Here to Zoom
|Table II: The distribution of clinical and demographic results by grade level.
Importantly, there was a certain level of goblet cell loss found
in 59% (n=36) of all of population involved in this study. Of
these, 36.1% (n=13) had grade 1, 33.3% (n=12) had grade
2, and 30.6% (n=11) had grade 3 cytology. For those with abnormal cytology, the average BMI was 32.1 ± 8.3, insulin
was 23.2 ± 7.7, glucose was 100.8 ± 14.7, and HOMA IR was
5.9 ± 1.7. These values were significantly higher (p<0.001)
compared to those with the normal impression cytology.
Table III indicates both the demographic and clinical data
associated with abnormal cytology.
Click Here to Zoom
|Table III: The distribution of clinical and demographic results
by abnormal cytology presence.
There was a positive correlation between BMI and the age,
alongside insulin, glucose, and HOMA IR levels within
the given population. The positive correlation between
the BMI level and insulin level, glucose level and HOMA
IR levels remained stable in those patients with abnormal
cytology; however, a significant relationship with age was
lost. A correlation between the BMI versus the insulin,
glucose, and HOMA IR levels was not observed in patients
without abnormal cytology or obesity (Table IV).
Click Here to Zoom
|Table IV: The distribution of clinical and demographic results
by BMI level.
The likely risk factors associated with abnormal cytology
were plugged into the multiple regression model. The
BMI (OR=1.24; p=0.002) and HOMA IR (OR=28.6;
p=0.001) were estimated as being independent predictors
that indicated the presence of abnormal cytology in
Model I, as observed with the multivariable regression
model encompassing BMI, insulin, glucose, and HOMA
IR variables. Hence, while an increase of one kg/m2 in
BMI level causes the risk of goblet cell loss to increase in
the conjunctiva by a factor of 1.24, a similar one unit of
increase in HOMA IR level causes the risk of goblet cell loss
to increase by a factor of 28.6.
The BMI (OR=11.91; p=0.002) and HOMA IR (OR=15.08;
p<0.001) were estimated as being independent predictors
that indicated the presence of obesity in the Model II
developed with the multivariable regression model
employing BMI, insulin, glucose, and HOMA IR variables.
Therefore, the goblet cell loss risk was 11.91 times higher
in obese patients compared to non-obese patients. It was
found that a one unit of increase in HOMA IR level had
caused the goblet cell loss risk to increase by a factor of 15.08
(Table V). Additionally, the diagnostic potential of the
BMI, insulin, glucose, and HOMA IR levels in predicting
the goblet cell loss risk was evaluated using ROC Curve
analysis. Thus, the HOMA IR level had a higher diagnostic
ability compared to BMI and obesity. BMI and obesity also
had similar diagnostic capability (Figure 2).
Click Here to Zoom
|Table V: The independent predictors/variables indicating the
existence of abnormal cytology.
Click Here to Zoom
|Figure 2: The diagnostic ability of the BMI and the insulin and
HOMA IR levels to predict abnormal cytology.
BMI: Body Mass Index, HOMA IR: Homeostasis model assessment for
insulin resistance, AUC: Area Under the Curve, SE: Standard error.
In our study, we have observed that obesity causes abnormal
cytology and squamous metaplasia in conjunctival surface
epithelial cells. We thought that this may be due to systemic
inflammation. The presence of obesity, BMI, and HOMA
IR levels were found to be independent risk factors, thus
advancing the impression cytology grade in conjunctiva.
While obesity is known to be a systemic disease that affects
many organs, its effects on the eyes has not yet been clearly
identified. However, a handful of recent studies indicate
that there is a relationship between obesity and certain types
of eye diseases such as cataract, glaucoma, retinopathy,
maculopathy, and dry eye disease 12-14. A handful of
different theories have been put forth that explain the
mechanisms behind such complications. For example,
hormonal changes such as an increase in leptin and a decrease
in ghrelin, vascular changes (a decrease in vasodilator levels
such as nitric oxide, a increase in vasoconstrictor levels
such as Endothelin 1 and Angiotensin 2), mechanic factors
(i.e. an increase in intraorbital fat tissue), and oxidative
stress are likely factors that may cause the development
of ocular complications in obese patients 12,15-17.
Furthermore, Baser et al., have indicated that there is a
relationship between the increase of BMI and Meibomian
gland dysfunction, thus causing the development of dry eye
disease 9. Another essential mechanism is the activation
of systematic chronic inflammation and immune system
4-7. For the first time, Hotamisligil et al., has shown
an increase of TNF-alpha expression in the fat tissue of
obese patients, which has a direct influence on insulin
resistance 18. A number of other studies indicated that
increased adipose tissue was shown to cause up-regulation in genes encoding inflammatory factors, activation in c-Jun
N-terminal kinase (JNK) and nuclear factor-kappa B (NF-
κB) pathways, and also increase in production of some
cytokines and chemokines 4-7. Although the main source
of inflammation is adipose tissue, it was shown that the
liver, pancreas, brain, and muscle tissue also contribute
to the inflammatory response 19. The primary markers
influencing the inflammation include coagulative factors
such as white blood cells, fibrinogen, and plasminogen
activator inhibitors (PAI-1); acute phase proteins such
as serum Amyloids A (SAA); and pro-inflammatory
cytokines and chemokines such as TNF-alpha, IL-1β and
IL-6 20-25. The inflammatory response moderately
and frequently endures as long as it is not induced with a
stimulant such as trauma or acute immune response 19.
The two pathologic processes causing loss of goblet cells in
squamous metaplasia include the loss of vascularization and
intense inflammation 26. A number of matrix protease
inhibitors resemble anti-inflammatory factors such as
the T lymphocytes, IL-1 receptor antagonists, TGF-β2,
and tissue inhibitors of metalloproteinase-1 (TIMP-1) and all play important roles in the immune balance of
the ocular surface 27. When all of the aforementioned
mechanisms are considered together, it can be thought
that the inflammatory response developing in obesity may
destroy the immune system balance and thus cause the
development of inflammation on conjunctival epithelium
cells. This may be attributed to the results of earlier
research regarding obesity causing inflammation on the
ocular surface cells of patients with certain autoimmune
and inflammatory diseases such as autoimmune thyroid
disease, diabetes mellitus, inflammatory colon disease, and
chronic kidney disease 28-31. The development of dry eye
disease was found to be responsible for the inflammation
caused by some of these diseases. In our study, however,
dry eye disease was either excluded or disqualified as based
on Schirmers test. Although the primary reason for the
development of squamous metaplasia is thought to be
systemic inflammation, the hormonal and vascular changes
may have either caused or contributed to the development
of this situation.
Obesity is the main reason behind the lessening in insulin
vulnerability, thus resulting in insulin resistance (IR)
occurring in most of the patients 32-34. It is thought that
insulin resistance plays an important role in inflammation
35,36. The existence of the relationship between IR and
the immune system was demonstrated for the first time
through studies showing the increase of insulin resistance
based on infections 37,38. These studies have also shown
that there is a positive correlation between insulin resistance
and pro-inflammatory cytokine levels 20,21,39. We have
found a strong relationship between the worsening of the
grade in conjunctiva and IR (insulin level and HOMA IR
index). In other words, the existence as well as strength of
insulin resistance appears to be an independent risk factor
for squamous metaplasia.
Glucose metabolism disorders are also frequently
associated with obesity 40. DM is a disease that develops
due to systemic inflammation 40. Little in the way of
research exists that shows the increase of the frequency of
conjunctival squamous metaplasia in diabetes, and what
exists only shows that this is related to the poor control
of diabetes 41-43. There was no diabetes in our study;
however, we did determine that there is a relationship
between glucose levels and the development of squamous
The formation or origination mechanism of the
conjunctival squamous metaplasia developed in most
systemic diseases such as obesity, DM and IR has not yet
been clearly understood. However, numerous studies have claimed that the most important mechanism is dry eye
disease, which is caused by the effect of the tear gland. In
addition, there are also other important studies showing
that other factors such as inflammation (which directly
affect the epithelium cells) may play an important role in
the development of the disease 43. Our study is crucial
in that not only does it indicate directly the relationship
between obesity and conjunctival squamous metaplasia for
the first time, but it also supports the idea that other factors
such as primary systemic inflammation alongside dry eye
disease may also play an important role in its development
There are, however, some limitations to our study.
The number of patients participating in the study was
insufficient. Furthermore, we did not examine data such as
systemic inflammation markers or leptin and ghrelin levels,
which are more objectively able to indicate the relationships
of squamous metaplasia with systemic inflammation and
In conclusion, our study is the first to indicate that the ocular
surface cells can be affected by obesity. Such situations
may lead to certain vision problems in conjunction with
other obesity-related ocular complications. Routine eye
examinations therefore need to be conducted, whereby
ocular surface cells are evaluated carefully during the
follow up of obese patients, this in turn requiring a
multidisciplinary approach. More comprehensive future
research into this subject seems to be necessary.
CONFLICT of INTEREST
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the
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