Type 2 diabetes mellitus is one of the largest public health problems worldwide, especially in developing nations such as China [
However, according to a clinical study, up to 73.6% of type 2 diabetic patients suffer from corneal complications, such as punctate keratopathy, endothelial dystrophy, and recurrent erosions [
In contrast to aqueous-deficient dry eye, which is usually caused by a lack of tear production, evaporative dry eye is due to lid-related and ocular surface-related causes such as meibomian gland dysfunction (MGD) and is more frequent [
Corneal changes usually depend on the type, duration, and compensation of diabetes mellitus. In this study, we aimed to analyze the tear film stability and morphological changes in meibomian glands using keratography in diabetic patients compared with nondiabetic controls and to better understand the impact of disease duration on the ocular surface during the course of type 2 diabetes mellitus.
The study was approved by the Investigational Review Board of Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. All subjects enrolled were informed of the aims of this study.
One hundred twenty patients diagnosed with type 2 diabetes mellitus met the inclusion criteria and were enrolled in the study at the Shanghai Ninth People’s Hospital between April 2016 and January 2017. Data were obtained from the right eye of each subject unless this eye was excluded, in which case data were collected from the left eye. The inclusion criteria were as follows: at least 40 years of age and willingness to participate in the study. Patients were excluded if they used topical medications; wore contact lenses; had undergone ocular surgery in the past year or had evidence of other ocular surface diseases; had active ocular infection, inflammation, or systemic disease; or were taking medications that would alter the ocular surface. All diabetic patients had a blood glucose level within the normal range. Diabetic patients were divided into the following three groups according to duration of diabetes since the first diagnosis: less than 5 years, 5–10 years, or more than 10 years. Forty subjects were recruited as nondiabetic controls. The exclusion criteria were similar to those of the control group. Fasting blood glucose was measured to rule out diabetes even in those without a history of diabetes. All patients underwent noninvasive ocular surface examinations in the following order: tear meniscus height (TMH), noninvasive tear film breakup time, bulbar and limbal hyperemia, and grading of meibomian gland loss with the Oculus Keratograph 5M (Wetzlar, Germany). All patients were examined by the same physician (He FL).
All diabetic patients were from the Department of Endocrinology in our hospital. These patients had been followed up over a long period, and disease duration was confirmed by their professional endocrinologists. The data in this article are reliable and were obtained from medical files. The groups were matched by age.
Oculus Keratograph 5M can provide automated measurements of tear film dynamics and meibographic images using infrared light without topical anesthetic, fluorescein staining, cobalt blue light, or manual timing. Measurements of noninvasive breakup time (NIKBUT) obtained with the advanced corneal topographer provide a simple, noninvasive screening test for dry eyes with acceptable sensitivity, specificity, and repeatability [
TMH was measured twice in each eye using infrared images obtained from the keratograph. The lower tear film meniscus images were captured 5 s after blinking, and the values were graded perpendicular to the lower eyelid margin at the central point.
NIKBUT was measured twice in each eye using the Oculus noninvasive Keratograph tear breakup time (NIKBUT) tool. The participants were instructed to blink twice before screening and to keep their eyes open to the best of their ability when recording. The NIKBUT was then determined by Keratograph 5M, which automatically generated two measures for NIKBUT: NIKBUT first (NIKBUT-1st) and NIKBUT average (NIKBUT-avg). NIKBUT-1st represents the time point at which the tear film starts to break up. NIKBUT-avg represents the average time for the overall tear film to break up.
Increased conjunctival redness is often one of the first signs indicating abnormal strain or pathological changes in the eye. Patients were required to open their eyes as wide as possible and focus on a point inside the camera while a keratograph image was captured. The images were then analyzed by the R-SCAN tool following the evaluation protocol. The software analyzed the image automatically and assigned a red eye index (accurate to 0.1 unit).
The upper and lower eyelids were ectropionized, and their respective infrared images were captured. Meibomian gland loss was graded as described by Arita et al. [
Pearson’s chi-squared test was applied to analyze sex and age differences between the groups. The Shapiro–Wilk test or Kruskal–Wallis test was performed accordingly. Normally distributed continuous parameters were analyzed between the groups by one-way ANOVA and Welch ANOVA tests. The Spearman correlation test was used to calculate correlations. All analyses were performed using the statistical software package GraphPad Prism (version 6.00 for Mac). All
From April 2016 to January 2017, 120 eyes of 120 type 2 diabetic patients and 40 eyes of 40 nondiabetic patients (22 women and 18 men; aged 64.88 ± 7.04 years) were included in this study. In the diabetic group, the duration of diabetes ranged from 1 to 25 years: in 44 eyes of 44 patients (24 women and 20 men; aged 64.75 ± 8.20 years), the duration was less than 5 years; in 40 eyes of 40 patients (23 women and 17 men; aged 65.03 ± 7.141 years), the duration was 5–10 years; and the duration was more than10 years in 36 eyes of 36 patients (20 women and 16 men; aged 66.11 + 7.44 years). Table
Clinical parameters of the four study groups.
Parameter | Control | <5 years | 5–10 years | >10 years |
---|---|---|---|---|
Age (yr) | 64.88 ± 7.04 | 64.75 ± 8.20 | 65.03 ± 7.14 | 66.11 ± 7.44 |
Sex ratio (male/female) | 18/22 | 20/24 | 17/23 | 16/20 |
TMH (mm) | 0.23 ± 0.06 | 0.23 ± 0.05 | 0.21 ± 0.07 | 0.18 ± 0.06 |
NIKBUT-1st (s) | 6.86 ± 2.20 | 6.76 ± 2.24 | 6.25 ± 2.53 | 5.13 ± 1.77 |
NIKBUT-avg (s) | 9.33 ± 3.68 | 8.32 ± 2.63 | 8.21 ± 2.60 | 7.30 ± 1.63 |
Bulbar hyperemia | 1.53 ± 0.69 | 1.57 ± 0.69 | 1.56 ± 0.57 | 1.92 ± 0.66 |
Limbal hyperemia | 1.52 ± 0.67 | 1.57 ± 0.64 | 1.56 ± 0.55 | 1.93 ± 0.64 |
Meibography score | 3.15 ± 1.09 | 3.13 ± 1.08 | 3.53 ± 1.05 | 4.25 ± 1.14 |
Medians and ranges of clinical parameters in the control group and diabetic groups are shown in Figures
(a) Tear meniscus height (mm) in each group (
Noninvasive meibographic images of the upper and lower eyelids, respectively. (a) No morphologic changes of meibomian glands in either eyelid were apparent (meiboscore of 0). (b) Minor morphologic changes of meibomian glands in both upper and lower eyelids were apparent (meiboscore of 1). The arrow in the upper eyelid shows the partial absence of meibomian glands, and the arrow in the lower eyelid shows a minor distortion of meibomian glands. (c) Less than 1/3 of the meibomian gland loss and minor morphologic changes in both upper and lower eyelids were apparent (meiboscore of 2). The arrow in the upper eyelid shows partial distortion of meibomian glands, and the arrow in the lower eyelid shows an obvious meibomian gland loss. (d) More than 2/3 of shortening, distortion, and dilation of meibomian glands were observed in both eyelids (meiboscore of 5). The arrow in the upper eyelid shows a large area of meibomian gland loss, and the arrow in the lower eyelid shows a significant distortion and dilatation of meibomian glands.
The results of clinical parameters in each group and
Statistical comparison (
Parameter | Control versus <5 years | Control versus 5–10 years | Control versus >10 years | <5 years versus 5–10 years | <5 years versus >10 years | >10 years versus 5–10 years |
---|---|---|---|---|---|---|
TMH (mm) | 0.9617 | 0.3517 | 0.0016 | 0.6246 | 0.0061 | 0.1561 |
NIKBUT-1st (s) | 0.9977 | 0.6299 | 0.0056 | 0.7274 | 0.0079 | 0.1327 |
NIKBUT-avg (s) | 0.5321 | 0.4151 | 0.0100 | 0.9958 | 0.2234 | 0.3468 |
Bulbar hyperemia | 0.9839 | 0.9937 | 0.0490 | 0.9997 | 0.0996 | 0.0912 |
Limbal hyperemia | 0.9726 | 0.9888 | 0.0262 | 0.9995 | 0.0672 | 0.0595 |
Meibography score | >0.9999 | 0.4259 | 0.0001 | 0.3725 | <0.0001 | 0.0241 |
The NIKBUT-1st was significantly shorter in the over 10 years diabetic group compared with the control group (5.13 ± 1.77 versus 6.86 ± 2.20,
Scatterplot graph showing a slight negative Spearman correlation (
Scatterplot graph showing a slight negative Spearman correlation (
The bulbar and limbal redness scan found that more patients in the over 10 years diabetic group showed bulbar and limbal hyperemia compared with the control group (bulbar hyperemia: 1.92 ± 0.66 versus 1.53 ± 0.69,
The over 10 years diabetic group showed more meibomian gland changes including dropouts, shortening, distortion, and dilation. The meiboscore in this group was significantly higher compared with the other three groups (the control group versus the over 10 years group,
In addition to the significant difference in tear film parameters observed between the over 10 years diabetic group and the control group, we also observed a tendency for ocular surface damage in the three diabetic groups as disease duration increased.
In addition to higher bulbar hyperemia and shorter NIKBUT-1st in the over 10 years diabetic group compared with the nondiabetic group, we also found that bulbar hyperemia had a significant negative correlation with NIKBUT-1st in the over 10 years diabetic group (
Scatterplot graph showing a negative correlation between bulbar hyperemia and NIKBUT-1st (
Diabetic eye disease is well known due to its retinal microvascular disorder, diabetic retinopathy. However, diabetes also has an impact on tear film dynamics and can lead to dry eye. The loss of tear film homeostasis in diabetes may be involved and induce dry eye disease [
Our study found that NIKBUT-1st and NIKBUT-avg in the over 10 years diabetic group decreased significantly compared with the normal control group, reflecting instability of the tear film in these patients. These results correlated with previous studies [
The bulbar conjunctiva and anterior episclera are nourished by vessels from the anterior and long posterior ciliary arteries [
We compared meibographic findings in the 4 groups, and a significant difference in the meiboscore was found between the control patients and the over 10 years diabetic patients. This was consistent with previous findings [
The meibomian gland synthesizes and produces lipids and proteins which form the outermost layer of the tear film. These lipids decrease evaporation and promote stability of the tear film. The International Workshop on Meibomian Gland Dysfunction suggested that MGD is the most prevalent cause of evaporative dry eye and may play a role in aqueous-deficient dry eye [
In addition, Oculus Keratograph 5M is a corneal topographer with additional noninvasive imaging tools for the assessment of tear film kinetics and meibography. It includes the ability to capture clear images of the meibomian gland architecture using infrared light, eliminating the need for instillation of sodium fluorescein into the tear film or the use of white light that exacerbates photophobia in patients with ocular surface disturbance. However, there is no consistent method for meibographic analysis in clinical practice. Our results provide an objective grading method to illustrate complementary data of glandular density.
In summary, our data suggest that long-term type 2 diabetes predisposes to various changes on the ocular surface, which should be noted at an early stage and treated appropriately in order to prevent more severe eye complications. Therefore, close attention should be paid to the ocular surface, especially in long-term diabetics. Further studies are needed to expand the sample size and include fluctuations in blood sugar as a key factor in studying the ocular surface.
The data used to support the findings of this study are available from the corresponding author upon request.
The authors report no conflicts of interest.
This study was supported by the National Natural Science Foundation of China (nos. 81370992, 81570812, and 81500765), the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (Grant no. 20161421), the Science and Technology Commission of Shanghai (17DZ2260100), and the Fundamental Research Program Funding of Ninth People’s Hospital affiliated to the Shanghai Jiao Tong University School of Medicine (JYZZ001).