Corresponding Author: Ismail Shatriah, MD. Department of Ophthalmology and Visual Science, Hospital Universiti Sains Malaysia, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia. Type 1 diabetes mellitus (T1DM) is a chronic disease in which the pancreas is able to produce only a small amount of insulin or no insulin at all, resulting in hyperglycemia [1]. The disease typically has an early onset, from the age of 6 months to early adulthood [2]. The majority of T1DM cases present with classic T1DM symptoms, such as thirst, polyuria, polydipsia, recurrent infection, and weight loss [2]. The incidence of T1DM worldwide is estimated to be 15 per 100,000 people [3]. In Malaysia, it has been reported that 71.8% of children with DM have T1DM [2]. It has also been reported that the mean hemoglobin A1c (HbA1c) for children in Malaysia with T1DM is 10.8% [4].
The pathogenesis of T1DM revolves around the destruction of pancreatic islet β cells, leading to reduced or ceased insulin production. The innate and adaptive immunity of an individual is typically implicated in this process [5]. When the body perceives β-cell components as autoantigens, this leads to autoimmune attack of β cells. These autoantigens include insulin B-chain peptides, glutamate acid decarboxylase 65 (GAD65), insulinoma-associated antigen 2 (IA-2), and zinc transporter 8 (ZnT8) [6]. Managing T1DM requires multiple approaches, including medical therapy with insulin, nutritional therapy, physical activity, and psychosocial support [2]. Hyperglycemia is thought to cause cell injury via numerous mechanisms, such as the accumulation of sorbitol via the polyol pathway, the accumulation of advanced glycated end products, the production of radical oxygen species, and the activation of protein kinase C, which causes inflammation [7].
Studies on the relationship between cornea morphology and T2DM among adults in the Southeast Asia region have been published with respect to Malaysia [8] and Singapore [9]. Luo et al. [9] described that multiethnic Asian adults with T2DM have thicker cornea and thus, suggested a correct interpretation of intraocular pressure (IOP). However, there are no published data on the link between T1DM and cornea morphology among Southeast Asian children.
The aim of this study is to determine the mean central corneal thickness (CCT) and mean IOP in children with T1DM and to determine the relationship between CCT and IOP on the one hand and age, sex, HbA1c, retinopathy, and duration of diabetes on the other.
Materials and Methods
Ethics statement
The study was approved by the Human Research Ethics Committee of Universiti Sains Malaysia (No. 21070529), which is in accordance with the Declaration of Helsinki for human research. Consent was obtained from the parents of the participants, and assent was obtained from the cases and controls.
Study setting and subjects
This research is a case-control study conducted between January and November 2022 at Hospital Universiti Sains Malaysia (Kubang Kerian, Malaysia). We recruited 38 children with T1DM and 38 healthy children from the pediatric and ophthalmology departments for the study.
The cases enrolled in this study were diagnosed with T1DM based on the Malaysian Clinical Practice Guidelines and were between 7 and 17 years old with axial length between 23 to 24 mm and spherical equivalent ±2.0 diopters. The exclusion criteria included preexisting ocular or cornea surface diseases, glaucoma, ocular infection, and a history of ocular trauma or surgery. The individuals recruited to the control group were within the same age range as the cases and did not have any corneal, medical, or systemic diseases.
All cases and controls were subjected to the same examinations. Visual acuity measurements were performed using Snellen charts. Anterior segment examinations were performed using slit-lamp biomicroscopy, while posterior segment examinations were performed either using a slit-lamp with a 90-diopter lens or via binocular indirect ophthalmoscopy using a 20-diopter lens. IOP measurements were taken using an air puff tonometer. The CCT of the study participants was measured via anterior segment optical coherence tomography (AS-OCT) using a Cirrus 5000 HD OCT machine (Carl Zeiss Meditec Inc). For this study, only readings from the right eye were taken, and the measurements were repeated three times. The IOP data was recorded after adjustment for CCT.
All data collected were analyzed using the IBM SPSS ver. 26.0 (IBM Corp). The data were described as mean, standard deviation, and percentage. Independent sample t-tests were used to compare the mean CCT and mean IOP of the cases versus those of the controls. Simple and multiple linear regressions were used to further investigate the association between the CCT and IOP. A p-value equal to or less than 0.05 was considered significant in each analysis.
Results
Seventy-six children aged 7 to 17 years were recruited as participants for this study; 37 were male, and 39 were female. The number of cases and controls was equal. The visual acuity of all the children in both the case and control groups were 6/6 using the Snellen chart. No retinopathy or nephropathy was detected in the T1DM group. The demographics and clinical data are summarized in Table 1.
The age of onset of T1DM was 4 to 14 years, with a DM duration range of 1 to 9 years. Only two T1DM patients (5.3%) had good diabetic control, with HbA1c levels of less than 6.5%. The rest of the T1DM group had poor control, with 12 patients (31.6%) having an HbA1c level of between 6.6% and 10.0%, while 24 patients (63.2%) had HbA1c levels higher than 10.1%. The measured CCT range in the T1DM group was 492 to 568 μm, with a mean of 542.18 ± 20.40 μm; in the control group, it was 481 to 560 μm, with a mean of 529.52 ± 26.17 μm. The range of the IOP measured in the T1DM group was 10 to 18 mmHg, with a mean of 14.68 ± 1.98 mmHg; in the control group, it was 10 to 16 mmHg, with a mean of 13.52 ± 1.66 mmHg. The higher CCT and IOP values recorded for the T1DM group were statistically significant (all p = 0.02).
Multiple linear regressions were performed to investigate the relationship between age, sex, HbA1c, retinopathy, and duration of DM on the one hand, and CCT and IOP on the other (Tables 2, 3). Age and the duration of DM were found to have a significant association with CCT in children with T1DM. The duration of DM was also found to have a significant relationship with IOP. Sex and HbA1c levels were found to have no significant relationship with either CCT or IOP. The relationship between retinopathy and CCT and IOP could not be established, as none of the cases had retinopathy.
Discussion
T1DM is a disease that can lead to many ocular complications, including complications involving the anterior segment of the eye. Several previous studies conducted in Europe, North Africa, Central Asia, and South Asia investigate the links between CCT and IOP in children with T1DM. These studies are summarized in Table 4 [10-15]. Based on PubMed search engine, there is no such study focuses on Southeast Asia populations on this topic. This study provides new data that can serve as locally representative statistics on the CCT and IOP of children with T1DM in Southeast Asia.
In this study, we found that the mean CCT of the T1DM group was significantly higher than that of the control group. This finding is consistent with the results of most previous studies on this subject [10-12]. This can be attributed to several mechanisms, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which are involved in the synthesis and degradation of the extracellular matrix of the cornea stroma. It has been reported that this balance is disrupted in DM patients with MMP-3 and MMP-10 upregulation and TIMP-4 downregulation, thereby increasing the synthesis of the extracellular matrix in the stroma [16]. In addition, it is thought that the accumulation of reactive oxygen species, advanced glycated end products, and growth factors induce the activation and proliferation of corneal stromal keratocytes [16]. In contrast, studies by Dereci et al. [13] and Wang et al. [14] report lower mean CCT values in children with T1DM than the control group in their study. Wang et al. [14] argue that low CCT values were due to apoptosis and cell death resulting from hyperglycemia.
The mean IOP was also higher in the T1DM group than in the control group. Dereci et al. [13] and Akil et al. [15] reported similar findings in their studies. This can potentially be attributed to persistent hyperglycemia, which is thought to cause excessive extracellular matrix synthesis in the trabecular meshwork, sequentially causing outflow obstruction of the aqueous humor in the anterior segment of the eye and elevating intraocular pressure [17]. Furthermore, thick corneas have been found to have higher measured IOP values than thin corneas [18].
We also analyzed the probable factors impacting CCT and IOP values in children with T1DM. In this study, we found a significant relationship between the duration of DM and the CCT and IOP values. This finding is congruent with a study on CCT conducted by Urban et al. [10] and a study on IOP conducted by Akil et al. [15]. It has been postulated that the effect of T1DM on ocular tissues is time dependent [13]. Dujic and Ignjatovic [19] reported risk of severe eye complications with T1DM 10 years after developing the disease.
Our study also shows that age is linked to CCT in children with T1DM. However, other studies on children with T1DM have reported no significant association between age and CCT [10-12,14-15]. Nonetheless, a study conducted on a large population by the Pediatric Eye Disease Investigator Group [20] found a general but modest increase in CCT with age among children. We postulate that our findings may be attributable to the synergistic effect brought about by the physiological changes accompanying age and pathological corneal changes due to DM.
We found that the current HbA1c levels of the children in our T1DM group has no association with their CCT and IOP. This is consistent with other studies performed by Fernandes and Nagpal [12], Anbar et al. [11], Akil et al. [15], and Urban et al. [10]. We surmise that this might be due to HbA1c levels at a single point and may not reflect overall DM control over the years. An analysis of serial HbA1c levels over many years may provide a better estimate. We also noted that the mean HbA1c level in our study is almost equal to the national mean HbA1c in Malaysia, which was 10.8% [5]. This is comparable to the mean HbA1c level in India of 10.9% [12]. In contrast, other developed countries have better DM control than Malaysia. The mean HbA1c in Poland was 8.0% [10], and in the United States, it was 8.5% [21]. Ethnicity, psychosocial challenges, and poor compliance have been identified as contributors to poor DM control in Malaysia [22].
None of our patients had diabetic retinopathy. Therefore, we were unable to proceed with further analysis investigating its relationship with CCT and IOP. However, a study by Urban et al. [10] reports that there is no relationship between retinopathy and CCT. We were unable to find any published data on the relationship between retinopathy and IOP in children with T1DM. However, a study by Matsuoka et al. [23] on adult Japanese with T2DM reports a significant correlation between retinopathy and IOP.
The limitations of this study include we did not include cornea endothelial cell analysis that will give more value to the data interpretation. Secondly, Goldman tonometer was not used for IOP measurement in this study. However, we observed that the pediatric patients tolerated well the measurement using air puff tonometer. Thirdly, this is a cross-sectional study. We recommend a prospective longitudinal study till adults will give a clearer information about CCT and IOP in patients with T1DM.
In conclusion, the mean CCT and mean IOP are shown to be statistically higher in children with T1DM than in children in the control group in our study. The duration of DM has a significant relationship with CCT and IOP, and increasing age is also associated with thicker corneas in children. Gender and HbA1c levels do not have any relationship with the mean CCT and the mean IOP.
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