Serum Elabela Levels are Negatively Associated with Retinopathy in Type 2 Diabetic Patients

Serum Elabela Levels are Negatively Associated with Retinopathy in Type 2 Diabetic Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Serum Elabela Levels are Negatively Associated with Retinopathy in Type 2 Diabetic Patients Wen-Sha Gu, Min Shi, Juan Chen, Yuting Liu, Hong Zhang, Xiao-Ming Mao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9114712/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Aims Abnormal expression of Elabela (ELA) is associated with various diseases, including diabetic nephropathy. However, the roles of ELA on developing diabetic retinopathy (DR) are not known. The aim of this study is to confirm the relationship between serum Elabela (ELA) levels and DR in patients with type 2 diabetes mellitus (T2DM). Methods A total of 90 healthy donors (Control group ) and 270 patients with T2DM were recruited. The were divided into three groups: Normal T2DM without DR, T2DM with nonproliferlative DR and T2DM with proliferative DR, 90 patients including in each group. Basic general clinical characteristics were collected and serum ELA levels were determined using the ELISA kit. Results The results showed that there was no significant difference in serum ELA levels between normal control and T2DM patients, but it significantly decreased in nonproliferlative DR and proliferative DR patients compared with T2DM without DR. Compared with nonproliferlative DR patients, the serum ELA levels further significantly decreased in proliferative DR patients. ELA has a significantly negative correlation with DR, duration of diabetes, age, systolic blood pressure(SBP), Blood urea nitrogen(BUN), serum creatinine(Cre) and urinary albumin/creatinine ratio (ACR), and is positively correlated with body mass index (BMI) and estimated glomerular filtration rate (eGFR). Furthermore, the univariate and multivariate linear regression analysis showed that DR, duration of diabetes and BMI were the risk factors for ELA after adjusting for relevant confounding factors (P < 0.05).According to the ROC curve analysis, ELA could identify subjects with DR with a sensitivity of 54.4% and a specificity of 73.3%. Conclusions With the deterioration of DR, the level of serum ELA decreases gradually. ELA may be involved in the occurrence and development of DR, and ELA may be a potential clinical predictor and therapeutic target of DR. Type 2 diabetes Diabetic retinopathy(DR) Elabela (ELA) Figures Figure 1 Figure 2 Introduction Diabetic retinopathy (DR), a frequent complication of diabetes mellitus (DM), is a leading cause of vision impairment and blindness in diabetic patients. So choosing the optimal method for diagnosing and treating the DR is vital to improve the quality of life and relieve the medical expenses. The main pathological changes of DR are blood retinal barrier destruction, nerve injury, neovascularization and fibroproliferative membrane formation. The pathogenesis of DR is complex and is the result of the combined action of multiple factors. Current pathological mechanisms mainly include the theory of chronic inflammation, autophagy, retinal hemodynamic changes, and oxidative stress[ 1 , 2 ]. At present, the treatment of DR mainly include the control of blood glucose and blood pressure, glucocorticoids, laser photocoagulation and intravitreal injection of anti-vascular endothelial growth factor (VEGF). Vitrectomy can delay the progression of DR and prevent severe loss of visual function. However, most of these therapeutic interventions do not target the pathological mechanism and influencing factors that lead to the occurrence and development of DR, and cannot completely prevent the blinding damage caused by the progression. So it is necessary to find new mechanisms or drug targets. ELA, also known as Apela and Toddler, is a small molecule polypeptide discovered for the first time in 2013, consisting of 54 amino acids. It is a small molecule polypeptide encoded by AK092578 gene from the human genome region [ 3 ]. Studies have found that when ELA gene is knocked out in zebrafish, fetal cardiac dysplasia or no cardiac development occurs, which has a strikingly similar phenotype to apelin receptor knockout (APJ or aplnr), so ELA is considered to be another endogenous ligand of APJ in addition to apelin [ 4 , 5 ]. Current studies have found that ELA is widely distributed in the body, expressed in embryonic stem cells, cardiomyocytes, myocardial interstitial cells, fibroblasts, renal tubular epithelial cells and vascular endothelial cells, and can also be detected in vertebrate embryos, placentas, hearts, kidneys, blood vessels and various tumor tissues [ 6 – 9 ]. ELA is also closely related to the occurrence and development of a variety of diseases. According to previous studies, ELA plays a crucial role in the development of cardiovascular system and can induce the formation of blood vessels [ 10 ]. As we all know, neovascularization plays an important role in the occurrence and development of diabetic retinopathy. So we speculated that ELA and DR are related, and this paper conducted preliminary clinical research and exploration. 1. Materials and Methods 1.1 Subjects and examination A total of 90 healthy donors (Control group )and 270 patients with T2DM were recruited. They were hospitalized in the Department of Endocrinology of our hospital (Huai'an First Hospital Affiliated to Nanjing Medical University) from December 2023 to September 2025 and were divided into three groups: Normal T2DM without DR (n = 90 cases), T2DM with nonproliferlative DR (n = 90 cases) and T2DM with proliferative DR (n = 90 cases), 90 patients including in each group. This study was carried out according to the guidelines of the Declaration of Helsinki. Informed consents were obtained from all participants. The inclusion criteria for patients are as follows: (1) All patients with type 2 diabetes met WHO diagnostic and classification criteria in 1999; (2) HbA1c was between 6.0% and 13.0%; (3) Body mass index (BMI) was 18.5 ~ 28.0 kg/m 2 ; (4) Those aged 18 and above. Exclusion criteria: (1) Previous history of non-diabetic retinal disease; (2) Acute complications of diabetes mellitus; (3) Heart failure, pregnancy, rheumatism and autoimmune diseases; (4) History of steroid and other special drug use. 1.2 Observation indexes and experimental methods Basic data of the enrolled subjects were recorded: gender, age, duration of diabetes, BMI, SBP, diastolic blood pressure(DBP), fasting blood glucose(FPG), glycosylated hemoglobin(HbA1c), total cholesterol(t-CHOL), triglycerides(TG), high density lipoprotein cholesterol(HDL-C), low density lipoprotein cholesterol(LDL-C), BUN, serum creatinine(Cre), fundus examination report and other clinical data. High performance liquid chromatography (HPLC) was performed on EDTA whole blood samples (D10; Bio-Rad, Hercules, CA, USA) detected HbA1c. The estimated GFR (eGFR) was calculated using the MDRD formula. Fundus examination was based on slit-lamp or fundus angiography results (including phase I-VI). Serum ELA levels were determined using the ELABELA kit (Peninsula Laboratories International). The coefficient of variation between batches and coefficient of variation within batches were less than 8% and 5%, respectively. 1.3 Diagnostic criteria and definitions Diabetic retinopathy is diagnosed based on blurred vision and/or slit-lamp or fundus angiography (including stage I-VI). 1.4 Statistical methods SPSS 26.0 software was used for statistical analysis. Normal distribution measurement datas were expressed as X ± S, and ANOVA test was used for independent sample comparison between the four groups. Non-normal distribution measurement data expressed in median and quartile interval [M (QL, QU)], using Mann-Whitney U test. Pearson correlation test was used to analyze the correlation between ELA level and other clinical laboratory parameters. In order to find the factors independently related to ELA level, Univariate linear regression analysis and multivariate linear regression analyses were used. P < 0.05 means the difference was statistically significant. 2. Results 2.1 Characteristics of study subjects Serum Elabela measurement was successfully obtained from all participants included in the study. Table 1 presents a statistical summary of characteristics of all subjects. A total of 90 healthy donors (Control group )and 270 patients with T2DM were recruited.Group 1: Control group (n = 90 cases). Group 2: Normal T2DM without DR (n = 90 cases). Group 3: T2DM with nonproliferlative DR (n = 90 cases). Group 4: T2DM with proliferative DR (n = 90 cases). There were no statistical significance in sex, age, BMI and LDL-C among the 4 groups (all P > 0.05). From group 1 to group 4, duration of diabetes, FPG, HbA1c, SBP, DBP, t-CHOL, TG, BUN, UA, Cre and ACR increased, while eGFR decreased. There were no significant differences between control group and type 2 diabetes without diabetic retinopathy, a decreased level of serum ELA in patients with nonproliferative diabetic retinopathy (P < 0.05), further reduction of ELA level in patients with proliferative diabetic retinopathy. (P < 0.05) (see Fig. 1 and Table 1 ). These 360 participants also were divided into 2 groups according to their serum ELA levels: High ELA group and Low ELA group. There were no statistical significance in sex, age, BMI, FPG, HbA1c, DBP, t-CHOL, TG, LDL-C, HDL-C and UA among the 2 groups (all P > 0.05). Compared with High ELA group, the duration of diabetes is longer, the prevalence of diabetic retinopathy, SBP, Cre, BUN and ACR were higher, while eGFR was lower in Low ELA group(P<0. 05)(see Table 2 ). 2.2 Correlation analysis between ELA and clinical indicators Pearson correlation analysis showed that ELA has a significantly negative correlation with DR (r = -0.333, P = 0.000), duration of diabetes (r = -0.263, P = 0.000), age (r = -0.134, P = 0.027), SBP (r =-0.125, P = 0.039), BUN (r =-0.161, P = 0.008), Cre (r = -0.236, P = 0.000), ACR (r =-0.248, P = 0.000), and is positively correlated with BMI (r = 0.127, P = 0.038) and eGFR (r = 0.194, P = 0.001). There was no significant correlation between sex, FPG, HbA1c, DBP, t-CHOL,TG, LDL-C, HDL-C and UA with ELA (all P > 0.05) (see Table 3 ). 2.3 Univariate linear regression analysis of the influencing factors for DR With ELA level as the dependent variable and combined with correlation analysis between ELA and clinical indicators, the factors that may affect ELA levels were used as independent variables with the univariate linear regression analysis. The results showed that DR, duration of diabetes, age, BMI, SBP, BUN, Cre, eGFR and ACR were the influencing factors for ELA (P < 0.05) (see Table 4 ). 2.4 Multivariate linear regression analysis of the influencing factors for DR ELA aslo has a significant correlation with DR, duration of diabetes and BMI after adjusting for relevant confounding factors by using the multivariate linear regression analysis (see Table 5 ). 2.5 Diagnostic value of ELA in diabetic retinopathy ROC curve results showed that when the Yoden index was the maximum, the critical value of ELA was 77.5 ng/ml, the sensitivity and specificity for the diagnosis of diabetic nephropathy were 54.4% and 73.3%, and the area under ROC curve was 0.676 (95% CI 0.621, 0.731), P = 0.000 (see Fig. 2 ). Table 1 The demographic, clinical and biochemical characteristics of all subjects based on DR Variables Group 1 Group 2 Group 3 Group 4 Case(M/F) 90(52/38) 90(59/31) 90(57/33) 90(60/28) Age (year) 53.79 ± 9.84 54.86 ± 12.19 55.82 ± 9.82 55.91 ± 9.90 Dur (year) 0 7.29 ± 5.96 a 10.70 ± 7.03 a,b 12.68 ± 6.16 a,b,c BMI (kg/m 2 ) 25.05 ± 2.89 25.51 ± 2.89 25.64 ± 3.34 25.08 ± 3.09 FPG(mmol/L) 4.99 ± 0.52 7.85 ± 2.28 a 8.16 ± 2.45 a 8.46 ± 3.15 a HbA1c (%) 5.63 ± 0.52 9.09 ± 1.67 a 9.49 ± 1.66 a 9.53 ± 2.12 a SBP(mmHg) 123.54 ± 12.31 133.32 ± 14.18 a 139.07 ± 18.27 a,b 146.44 ± 23.29 a,b,c DBP(mmHg) 75.40 ± 7.66 79.24 ± 9.03 a 81.13 ± 10.27 a 81.38 ± 10.65 a t-CHOL(mmol/L) 4.40 ± 0.90 4.45 ± 1.05 4.43 ± 1.23 4.80 ± 1.46 a,c TG (mmol/L) 1.39 ± 0.90 1.85 ± 1.33 a 1.80 ± 0.90 a 2.35 ± 1.81 a,b,c LDL-C(mmol/L) 2.73 ± 0.81 2.77 ± 0.90 2.69 ± 0.85 2.82 ± 1.25 HDL-C(mmol/L) 1.41 ± 0.41 1.10 ± 0.23 a 1.07 ± 0.27 a 1.20 ± 0.44 a,b,c Cre (umol/L) 66.90 ± 15.86 68.56 ± 13.01 77.83 ± 31.75 122.68 ± 74.61 a,b,c BUN(mmol/L) 5.38 ± 1.45 5.47 ± 1.59 6.87 ± 2.62 a,b 9.83 ± 7.41 a,b,c UA(umol/L) 301.54 ± 95.10 300.29 ± 85.16 311.04 ± 84.92 349.08 ± 101.91 a,b,c eGFR (mL/min/1.73 m 2 ) 101.94 ± 20.31 97.37 ± 22.97 90.92 ± 23.07 a 68.91 ± 33.28 a,b,c ACR (mg/g) 0.47(0.30,0.74) 8.35(4.44,12.16) 98.83(38.48,326.31) a,b 552.85(240.60,1848.55) a,b,c ELA(ng/ml) 79.12 ± 20.66 78.77 ± 16.28 71.22 ± 19.41 a,b 64.35 ± 18.77 a,b,c Note: Data are expressed as mean ± SEM or as median (interquartile range). Abbreviations: group 1: Control group, group 2: Type 2 diabetes without diabetic retinopathy, group 3: Nonproliferlative diabetic retinopathy, group 4: Proliferative diabetic retinopathy. Dur = duration of diabetes, DR = diabetic retinopathy, BMI = body mass index, FPG = fasting plasma glucose, HbA1c = glycosylated hemoglobin, SBP = systolic blood pressure, DBP = diastolic blood pressure, t-CHOL = total cholesterol, HDL-C = high density lipoprotein cholesterol, LDL-C = low density lipoprotein cholesterol, TG = Triglyceride, Cre = Serum creatinine, BUN = blood urine nitrogen, UA = uric acid, eGFR = estimated glomerular fltration rate, ACR = urinary albumin/ creatinine ratio. The data were expressed as means ± SEM for normally distributed data or median with 25th and 75th quartiles for skewed data. a P < 0.05, vs. group 1; b P < 0.05, vs. group 2; c P < 0.05, vs. group 3. group 1: Control group, group 2: Type 2 diabetes without diabetic retinopathy, group 3: Nonproliferlative diabetic retinopathy, group 4: Proliferative diabetic retinopathy, Data are expressed as mean ± SEM Table 2 The demographic, clinical and biochemical characteristics of all subjects based on ELA Variables Low-ELA Group High-ELA Group P Case(M/F) 123/57 107/73 0.080 Age (year) 56.14 ± 10.08 54.60 ± 11.13 0.168 Dur (year) 9.39 ± 7.34 5.92 ± 6.96 0.000 BMI (kg/m 2 ) 24.99 ± 2.95 25.61 ± 3.10 0.052 DR(%) 113(62.8) 67(37.2) 0.000 FPG(mmol/L) 7.57 ± 2.90 7.16 ± 2.45 0.152 HbA1c (%) 8.61 ± 2.27 8.24 ± 2.34 0.135 SBP(mmHg) 138.67 ± 21.94 132.52 ± 15.86 0.002 DBP(mmHg) 79.85 ± 9.66 78.73 ± 9.80 0.275 t-CHOL(mmol/L) 4.51 ± 1.37 4.58 ± 1.01 0.587 LDL-C(mmol/L) 2.72 ± 1.13 2.81 ± 0.92 0.387 HDL-C(mmol/L) 1.17 ± 0.39 1.20 ± 0.37 0.537 TG (mmol/L) 1.86 ± 1.43 1.82 ± 1.23 0.784 Cre (umol/L) 95.90 ± 60.27 72.08 ± 24.47 0.000 BUN(mmol/L) 7.70 ± 5.80 6.11 ± 2.23 0.001 UA(umol/L) 321.48 ± 95.26 309.49 ± 92.18 0.915 eGFR (mL/min/1.73 m 2 ) 83.29 ± 30.62 96.30 ± 24.10 0.000 ACR (mg/g) 87.83(7.62,556.92) 8.31(0.75,46.76) 0.000 ELA(ng/ml) 58.25 ± 10.74 88.49 ± 11.46 - Note: Data are expressed as mean ± SEM or as median (interquartile range). Dur = duration of diabetes, DR = diabetic retinopathy, BMI = body mass index, FPG = fasting plasma glucose, HbA1c = glycosylated hemoglobin, SBP = systolic blood pressure, DBP = diastolic blood pressure, t-CHOL = total cholesterol, HDL-C = high density lipoprotein cholesterol, LDL-C = low density lipoprotein cholesterol, TG = Triglyceride, Cre = Serum creatinine, BUN = blood urine nitrogen, UA = uric acid, eGFR = estimated glomerular fltration rate, ACR = urinary albumin/ creatinine ratio. The data were expressed as means ± SEM for normally distributed data or median with 25th and 75th quartiles for skewed data. Table 3 Pearson correlation analysis between serum ELA level and clinical parameters Variable r P DR -0.333 0.000 Dur (year) -0.263 0.000 Age (year) -0.134 0.027 BMI (kg/m 2 ) 0.127 0.038 SBP(mmHg) -0.125 0.039 BUN(mmol/L) -0.161 0.008 Cre(umol/L) -0.236 0.000 eGFR (mL/min/1.73 m 2 ) 0.194 0.001 ACR(mg/g) -0.248 0.000 Table 4 Univariate linear regression analysis of serum ELA level Variable Estimate Std. Error Beta t P DR -7.211 1.248 -0.333 -5.776 0.000 Dur (year) -0.690 0.155 -0.263 -4.457 0.000 Age (year) -0.223 0.101 -0.134 -2.220 0.027 BMI (kg/m 2 ) 0.721 0.345 0.127 2.088 0.038 SBP(mmHg) -0.113 0.055 -0.125 -2.070 0.039 BUN(mmol/L) -0.574 0.216 -0.161 -2.664 0.008 Cre(umol/L) -0.079 0.020 -0.236 -3.983 0.000 ACR(mg/g) -0.004 0.001 -0.248 -4.186 0.000 eGFR(mL/min/1.73 m 2 ) 0.117 0.036 0.194 3.233 0.001 Table 5 Multivariate linear regression analyses related to serum ELA level Variable Estimate Std. Error Beta t P DR -5.153 1.513 -0.238 -3.407 0.001 Dur (year) -0.370 0.165 -0.141 -2.242 0.026 BMI (kg/m 2 ) 0.656 0.39 0.115 1.993 0.047 3 Discussion Diabetic retinopathy is the leading cause of blindness in adults and seriously affects peoples' quality of life. DR is a microangiopathy and neurodegenerative disease, which is characterized by the appearance of microaneurysms, elevated vascular permeability, capillary blockage, and proliferation of neovasculature[ 11 ]. The etiology and mechanism of retinopathy remain unclear, and current therapeutic strategies are less effective. Using a biomarker with high sensitivity and specificity to early diagnosis of this complicationis is very essential for providing better therapeutic strategies[ 12 , 13 ]. ELA was first uncovered as a 54-amino acid peptide hormone during zebrafish development in 2013[ 4 ]. This peptide is then cleaved into a mature secreted protein, 32 amino acids long. It is another endogenous ligand of APJ and widely expressed and activates various G-protein-dependent signaling pathways. ELA is widely distributed in the body and its expression can be detected in a variety of tissues and cells. ELA has been studied in various diseases including hypertension, myocardial infarction, heart failure, prenatal eclampsia, diabetic nephropathy, acute kidney injury, cerebral ischemia/reperfusion injury, pulmonary hypertension, active ulcerative colitis and other diseases [ 13 – 22 , 9 ]. Data from previous studies have shown that ELA can promote blood vessel growth and can guide the migration of vascular cells in vasculogenesis. In the process of vascular development, the angioblasts rely on the intrinsic expression of APJ for their migration to the place where blood vessels are formed, which is mainly triggered by ELA [ 23 ]. Wang and his colleagues[ 24 ]found that ELA can induce angiogenesis of human umbilical vein endothelial cells (HUVECs) by activating the APJ signaling pathway. A study[ 25 ]found that treated by Fc-ELA-21 for 4 weeks in myocardial infarction model rats, and observed angiogenesis in the infarct area. Data from previous studies showed that ELA can promote angiogenesis after myocardial infarction (MI) by activating VEGF/VEGFR2 and Jagged1/Notch3 pathways [ 26 ]. Li and his colleagues found that the level of ELA was increased in the ischemic brain and ELA-32 can alleviate brain injury and promote the repairment of newly formed functional vessels after cerebral ischemia/reperfusion (I/R) damage. In addition, ELA-32 enhanced proliferation, migration, and tube formation of the mouse brain endothelial cells (bEnd.3 cells) under oxygen-glucose deprivation/reoxygenation (OGD/R) condition[ 19 ]. A previous study about ELA and oxygen-induced retinopathy model showed that ELA can inhibit ferroptosis to promote retinal angiogenesis under oxidative stress induced injury [ 27 ]. In summary, ELA plays an important role in the generation of neovascularization, which is the main pathological change of DR. So we speculated that ELA may be involved in the occurrence and development of DR. However, the role of ELA in DR remains inconclusive, so this paper preliminarily explored the relationship between ELA and DR. In the present study, We found that there was no significant difference in serum ELA levels between normal control and T2DM patients, but it significantly decreased in nonproliferlative DR and proliferative DR patients compared with T2DM without DR. Compared with nonproliferlative DR patients, the serum ELA levels further significantly decreased in proliferative DR patients. In addition, ELA has a significantly negative correlation with DR, duration of diabetes,age, SBP, BUN, Cre and ACR, and is positively correlated with BMI and eGFR. Furthermore, the univariate and multivariate linear regression analysis showed that DR, duration of diabetes and BMI were the risk factors for ELA after adjusting for relevant confounding factors (P < 0.05). The ROC curve analysis showed that ELA could identify subjects with DR with a sensitivity of 54.4% and a specificity of 73.3%. So we suspect that ELA may be involved in the occurrence and development of DR, and ELA may be a potential clinical predictor and therapeutic target of DR. Previous study has shown that dyslipidemia is correlated with development and progression of DR[ 28 ]. As we all known that DR and diabetic nephropathy are both diabetic microvascular complications, and their occurrence and development are closely related. However, the specific mechanism of ELA involvement in DR is unknown. ELA can guide the migration of vascular cells in vasculogenesis and also can promote blood vessel growth, which is crucial to the occurrence and development of DR. Accumulating evidences showed that low-grade inflammation plays a key role in the pathogenesis and development of DR, with multiple inflammatory factors increased in the vitreous and retina of patients with DR[ 29 ]. Ye et al [ 28 ][ 30 ]demonstrated that ELA can alleviate vascular remodeling in spontaneously hypertensive rats by anti-inflammatory. In this study, exogenous ELA-21 preconditioning mitigated inflammatory activation, but ELA knockdown aggravated inflammatory activation. So we predict that ELA can alleviate vascular remodeling in diabetic retinopathy by anti-inflammatory. Oxidative stress also plays an important role in the development of DR[ 31 ]. ELA can promote retinal angiogenesis by inhibiting ferroptosis under oxidative stress induced damage[ 27 ]. So we guess that ELA alleviates vascular remodeling through anti-oxidative stress. Additional experimental studies are also needed to investigate the mechanisms. Research has also demonstrated the significance of autophagy in DR, which is a key homeostasis mechanism for the destruction and restoration of cytoplasmic components[ 32 ]. Recent studies showed that inhibition of APJ signalling by knockout of ELA increased apoptosis in the placenta of mice[ 33 ]. We suspect that ELA may play an important role in diabetic retinopathy through autophagy. In the present study, we found that with the progressive of diabetic retinopathy, the level of serum ELA decreases gradually. We suspect that ELA can attenuate vascular remodeling in DR via anti-inflammatory or autophagy. To our knowledge, this is the first study which clinically explored the relationship between ELA levels and DR, and showed a significant correlation between ELA levels and the severity of DR. Nevertheless, this study had some limitations. Firstly, a relatively small sample size might not be very representative for the actual relationship between serum ELA levels and DR patients. Secondly, what we detected was ELA in venous blood, not in aqueous humor or vitreous fluid. Vitreous or aqueous humor sampling is invasive and it is not practical to use vitreous or aqueous humor markers to detect DR, so serum samples are critical. Finally, this study is limited to the analysis of clinical data, and there is a lack of research on its mechanism. Therefore, further large-scale, longitudinal and basic studies will help clarify the relationship between ELA levels and diabetic retinopathy. Abbreviations ACR urinary albumin/creatinine ratio BMI body mass index SBP systolic blood pressure DBP diastolic blood pressure FPG fasting blood glucose HbA1c glycosylated hemoglobin t-CHOL total cholesterol TG triglycerides HDL-C high density lipoprotein cholesterol LDL-C low density lipoprotein cholesterol BUN blood urea nitrogen Cre serum creatinine eGFR estimated glomerular filtration rate DR diabetic retinopathy HPLC High performance liquid chromatography Declarations Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Affiliated Huai’an No.1 People’s Hospital with Nanjing Medical University (KY-2023-031-01). Written informed consent was obtained from all participants. Consent for publication Not Applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Fundings The study was supported by the National Natural Science Foundation of China (Grant Award: 82000743 and 81700723), Northern Jiangsu Clinical Medicine Research Institute’ s 2024 Projects (Grant Award: HAKY20240000307), Key Research and Development Program of Jiangsu Provincial Department of Science and Technology-Social Development Project (Grant Award: BE2023745) and General Project of Natural Science Foundation of Jiangsu Provincial Department of Science and Technology (Grant Award: BK20191213). Authors' contributions Wensha Gu contributed to conducting the experiments and drafting the manuscript. Min Shi and Yuting Liu played a role in data collection and analysis. Juan Chen was responsible for refining the manuscript, while Hong Zhang assisted in designing the trial. Xiaoming Mao provided supervision and guidance throughout the entire project. 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Elabela-APJ axis attenuates cerebral ischemia/reperfusion injury by inhibiting neuronal ferroptosis.FREE RADICAL BIO MED. 2023-02-20;196:171–186. Hu Y, Jin L, Pan Y, Zou J, Wang Z. Apela gene therapy alleviates pulmonary hypertension in rats. FASEB J. 2022-07-01;36(7):e22431. Gulumsek E, Sumbul HE, Yesildal F, Kara B. Serum Elabela level is related to endoscopic activity index in patients with active ulcerative colitis.IRISH J MED SCI. 2022-06-01;191(3):1171–1176. elker CS, Schuermann A, Pollmann C, Chng SC, Kiefer F, Reversade B, Herzog W. The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis. Elife.2015;4. Wang X, Liang G, Guo Q, Cai W, Zhang X, Ni J, Tao Y, Niu X, Chen Shaobo. ELABELA improves endothelial cell function via the ELA-APJ axis by activating the PI3K/Akt signalling pathway in HUVECs and EA.hy926 cells. CLIN EXP PHARMACOL P. 2020-12-01;47(12):1953–1964. Wang Y. Recombinant Elabela-Fc fusion protein has extended plasma half-life and mitigates post-infarct heart dysfunction in rats. INT J CARDIOL. 2020-02-01;300:217–218. Xi Y, Li Y, Ren W, Bo W, Ma Y, Pan S, Gong D, Tian Z. ELABELA-APJ-Akt/YAP Signaling Axis: A Novel Mechanism of Aerobic Exercise in Cardioprotection of Myocardial Infarction Rats. MED SCI SPORT EXER. 2023-02-22, 0195–9131. Wang J, Zhang Q, Chen E, Zhao P, Xu Y. Elabela promotes the retinal angiogenesis by inhibiting ferroptosis during the vaso-obliteration phase in mouse oxygen-induced retinopathy model. FASEB J. 2022-05-01;36(5):e22257. Zhang C, Lin W, Xu Q, Li H, Xu C, Ma X, Hao M, Kuang H. Association between high-density lipoprotein cholesterol to apolipoprotein A ratio and diabetic retinopathy: A cross-sectional study. J DIABETES COMPLICAT. 2023-06-01; 37(6):108471. Tang L, Xu GT, Zhang JF. Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy.NEURAL REGEN RES. 2023-05-01;18(5):976–982. Ye C, Geng Z, Zhang LL, Xiong XQ, Zheng F, Zhou YB, Zhu GQ, Xiong XQ. Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory, anti-oxidative and anti-proliferative effects. ACTA PHARMACOL SIN. 202 2-10-01;43(10):2573–2584. Aiello JJ, Bogart MC, Chan WT, Holoman NC, Trobenter TD, Relf CE, Kleinman DM, DeVivo DC, Samuels IS. Systemic Reduction of Glut1 Normalizes Retinal Dysfunction, Inflammation, and Oxidative Stress in the Retina of Spontaneous Type 2 Diabetic Mice.AM J PATHOL. 2023-04-14. Cheng Y, Fan H, Liu K, Liu J, Zou H, You Z. TFEB attenuates hyperglycemia-induced retinal capillary endothelial cells injury via autophagy regulation.CELL BIOL INT. 2023-06-01; 47(6): 1092–1105. Song JJ, Yang M, Liu Y, Song JW, Wang J, Chi HJ, Liu X Y, Zuo K, Yang X C, Zhong JC. MicroRNA-122 aggravates angiotensin II-mediated apoptosis and autophagy imbalance in rat aortic adventitial fibroblasts via the modulation of SIRT6-elabela-ACE2 signaling. EUR J PHARMACOL. 2020-09-15; 883: 173374. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 05 Apr, 2026 Reviewers agreed at journal 05 Apr, 2026 Reviewers invited by journal 03 Apr, 2026 Editor assigned by journal 26 Mar, 2026 Editor invited by journal 24 Mar, 2026 Submission checks completed at journal 24 Mar, 2026 First submitted to journal 24 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9114712","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":618541422,"identity":"e9633ce7-d9ff-4d90-a1c7-928e8a85e03e","order_by":0,"name":"Wen-Sha Gu","email":"","orcid":"","institution":"Nanjing First Hospital, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wen-Sha","middleName":"","lastName":"Gu","suffix":""},{"id":618541424,"identity":"328ad5b7-9df8-4ecb-aae1-b4433cb09fa1","order_by":1,"name":"Min Shi","email":"","orcid":"","institution":"the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Shi","suffix":""},{"id":618541425,"identity":"470bb037-9aa2-4140-b38b-9d607b54c8d2","order_by":2,"name":"Juan Chen","email":"","orcid":"","institution":"the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Chen","suffix":""},{"id":618541426,"identity":"8cfbd7f1-ff0a-4117-9a47-490b2d851e80","order_by":3,"name":"Yuting Liu","email":"","orcid":"","institution":"the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuting","middleName":"","lastName":"Liu","suffix":""},{"id":618541427,"identity":"4cb9c487-cd9b-457a-9628-91c52a862c6e","order_by":4,"name":"Hong Zhang","email":"","orcid":"","institution":"the Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Zhang","suffix":""},{"id":618541428,"identity":"695432da-7712-4260-aaec-989a83ef60d5","order_by":5,"name":"Xiao-Ming Mao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsklEQVRIiWNgGAWjYNACAwYGfmbmww9I0yLZzpZmQKJF53kUJIhSqdt++JjUjYI7dpsP8wAtq7GJJqjF7ExasnGOwbPkbYd5DzxgOJaW20BQy4Ecw8c5BoeTzQ7zJRgwNhwmQsv5NwaHQVqMm3kMJIjTcgNii50BM/FanoH8cjhB4jAwkBOI8sv55GPSOX8O2/P3Hz784EONDWEtMJAIVplArHIQsCdF8SgYBaNgFIwwAAAKskABt380vwAAAABJRU5ErkJggg==","orcid":"","institution":"Nanjing First Hospital, Nanjing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Xiao-Ming","middleName":"","lastName":"Mao","suffix":""}],"badges":[],"createdAt":"2026-03-13 12:24:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9114712/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9114712/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106579872,"identity":"62d1d5f1-409b-4de8-b287-103b8ffc3497","added_by":"auto","created_at":"2026-04-10 06:34:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5171,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplot of ELA levels by Group\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9114712/v1/eab11d953689fbb276b20422.png"},{"id":106579873,"identity":"bef1cfb4-4906-4302-87b4-8011d21d43bb","added_by":"auto","created_at":"2026-04-10 06:34:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":14023,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve of serum ELA for DR diagnosis\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-9114712/v1/1746fec322db2e1008825243.png"},{"id":106726125,"identity":"b29aa7f1-a2ab-4b49-8640-137ae9cb17f0","added_by":"auto","created_at":"2026-04-12 18:35:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":851897,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9114712/v1/14babd1a-4327-45e8-b545-c6cde814ef0d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Serum Elabela Levels are Negatively Associated with Retinopathy in Type 2 Diabetic Patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDiabetic retinopathy (DR), a frequent complication of diabetes mellitus (DM), is a leading cause of vision impairment and blindness in diabetic patients. So choosing the optimal method for diagnosing and treating the DR is vital to improve the quality of life and relieve the medical expenses. The main pathological changes of DR are blood retinal barrier destruction, nerve injury, neovascularization and fibroproliferative membrane formation. The pathogenesis of DR is complex and is the result of the combined action of multiple factors. Current pathological mechanisms mainly include the theory of chronic inflammation, autophagy, retinal hemodynamic changes, and oxidative stress[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. At present, the treatment of DR mainly include the control of blood glucose and blood pressure, glucocorticoids, laser photocoagulation and intravitreal injection of anti-vascular endothelial growth factor (VEGF). Vitrectomy can delay the progression of DR and prevent severe loss of visual function. However, most of these therapeutic interventions do not target the pathological mechanism and influencing factors that lead to the occurrence and development of DR, and cannot completely prevent the blinding damage caused by the progression. So it is necessary to find new mechanisms or drug targets.\u003c/p\u003e \u003cp\u003eELA, also known as Apela and Toddler, is a small molecule polypeptide discovered for the first time in 2013, consisting of 54 amino acids. It is a small molecule polypeptide encoded by AK092578 gene from the human genome region [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Studies have found that when ELA gene is knocked out in zebrafish, fetal cardiac dysplasia or no cardiac development occurs, which has a strikingly similar phenotype to apelin receptor knockout (APJ or aplnr), so ELA is considered to be another endogenous ligand of APJ in addition to apelin [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Current studies have found that ELA is widely distributed in the body, expressed in embryonic stem cells, cardiomyocytes, myocardial interstitial cells, fibroblasts, renal tubular epithelial cells and vascular endothelial cells, and can also be detected in vertebrate embryos, placentas, hearts, kidneys, blood vessels and various tumor tissues [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. ELA is also closely related to the occurrence and development of a variety of diseases. According to previous studies, ELA plays a crucial role in the development of cardiovascular system and can induce the formation of blood vessels [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. As we all know, neovascularization plays an important role in the occurrence and development of diabetic retinopathy. So we speculated that ELA and DR are related, and this paper conducted preliminary clinical research and exploration.\u003c/p\u003e"},{"header":"1. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.1 Subjects and examination\u003c/h2\u003e \u003cp\u003eA total of 90 healthy donors (Control group )and 270 patients with T2DM were recruited. They were hospitalized in the Department of Endocrinology of our hospital (Huai'an First Hospital Affiliated to Nanjing Medical University) from December 2023 to September 2025 and were divided into three groups: Normal T2DM without DR (n\u0026thinsp;=\u0026thinsp;90 cases), T2DM with nonproliferlative DR (n\u0026thinsp;=\u0026thinsp;90 cases) and T2DM with proliferative DR (n\u0026thinsp;=\u0026thinsp;90 cases), 90 patients including in each group. This study was carried out according to the guidelines of the Declaration of Helsinki. Informed consents were obtained from all participants. The inclusion criteria for patients are as follows: (1) All patients with type 2 diabetes met WHO diagnostic and classification criteria in 1999; (2) HbA1c was between 6.0% and 13.0%; (3) Body mass index (BMI) was 18.5\u0026thinsp;~\u0026thinsp;28.0 kg/m\u003csup\u003e2\u003c/sup\u003e; (4) Those aged 18 and above. Exclusion criteria: (1) Previous history of non-diabetic retinal disease; (2) Acute complications of diabetes mellitus; (3) Heart failure, pregnancy, rheumatism and autoimmune diseases; (4) History of steroid and other special drug use.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e1.2 Observation indexes and experimental methods\u003c/h2\u003e \u003cp\u003eBasic data of the enrolled subjects were recorded: gender, age, duration of diabetes, BMI, SBP, diastolic blood pressure(DBP), fasting blood glucose(FPG), glycosylated hemoglobin(HbA1c), total cholesterol(t-CHOL), triglycerides(TG), high density lipoprotein cholesterol(HDL-C), low density lipoprotein cholesterol(LDL-C), BUN, serum creatinine(Cre), fundus examination report and other clinical data. High performance liquid chromatography (HPLC) was performed on EDTA whole blood samples (D10; Bio-Rad, Hercules, CA, USA) detected HbA1c. The estimated GFR (eGFR) was calculated using the MDRD formula. Fundus examination was based on slit-lamp or fundus angiography results (including phase I-VI). Serum ELA levels were determined using the ELABELA kit (Peninsula Laboratories International). The coefficient of variation between batches and coefficient of variation within batches were less than 8% and 5%, respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e1.3 Diagnostic criteria and definitions\u003c/h2\u003e \u003cp\u003eDiabetic retinopathy is diagnosed based on blurred vision and/or slit-lamp or fundus angiography (including stage I-VI).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e1.4 Statistical methods\u003c/h2\u003e \u003cp\u003eSPSS 26.0 software was used for statistical analysis. Normal distribution measurement datas were expressed as X\u0026thinsp;\u0026plusmn;\u0026thinsp;S, and ANOVA test was used for independent sample comparison between the four groups. Non-normal distribution measurement data expressed in median and quartile interval [M (QL, QU)], using Mann-Whitney U test. Pearson correlation test was used to analyze the correlation between ELA level and other clinical laboratory parameters. In order to find the factors independently related to ELA level, Univariate linear regression analysis and multivariate linear regression analyses were used. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 means the difference was statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"2. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Characteristics of study subjects\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eSerum Elabela measurement was successfully obtained from all participants included in the study. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents a statistical summary of characteristics of all subjects. A total of 90 healthy donors (Control group )and 270 patients with T2DM were recruited.Group 1: Control group (n\u0026thinsp;=\u0026thinsp;90 cases). Group 2: Normal T2DM without DR (n\u0026thinsp;=\u0026thinsp;90 cases). Group 3: T2DM with nonproliferlative DR (n\u0026thinsp;=\u0026thinsp;90 cases). Group 4: T2DM with proliferative DR (n\u0026thinsp;=\u0026thinsp;90 cases). There were no statistical significance in sex, age, BMI and LDL-C among the 4 groups (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). From group 1 to group 4, duration of diabetes, FPG, HbA1c, SBP, DBP, t-CHOL, TG, BUN, UA, Cre and ACR increased, while eGFR decreased. There were no significant differences between control group and type 2 diabetes without diabetic retinopathy, a decreased level of serum ELA in patients with nonproliferative diabetic retinopathy (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), further reduction of ELA level in patients with proliferative diabetic retinopathy. (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThese 360 participants also were divided into 2 groups according to their serum ELA levels: High ELA group and Low ELA group. There were no statistical significance in sex, age, BMI, FPG, HbA1c, DBP, t-CHOL, TG, LDL-C, HDL-C and UA among the 2 groups (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Compared with High ELA group, the duration of diabetes is longer, the prevalence of diabetic retinopathy, SBP, Cre, BUN and ACR were higher, while eGFR was lower in Low ELA group(P\u0026lt;0. 05)(see Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Correlation analysis between ELA and clinical indicators\u003c/h2\u003e \u003cp\u003ePearson correlation analysis showed that ELA has a significantly negative correlation with DR (r = -0.333, P\u0026thinsp;=\u0026thinsp;0.000), duration of diabetes (r = -0.263, P\u0026thinsp;=\u0026thinsp;0.000), age (r = -0.134, P\u0026thinsp;=\u0026thinsp;0.027), SBP (r =-0.125, P\u0026thinsp;=\u0026thinsp;0.039), BUN (r =-0.161, P\u0026thinsp;=\u0026thinsp;0.008), Cre (r = -0.236, P\u0026thinsp;=\u0026thinsp;0.000), ACR (r =-0.248, P\u0026thinsp;=\u0026thinsp;0.000), and is positively correlated with BMI (r\u0026thinsp;=\u0026thinsp;0.127, P\u0026thinsp;=\u0026thinsp;0.038) and eGFR (r\u0026thinsp;=\u0026thinsp;0.194, P\u0026thinsp;=\u0026thinsp;0.001). There was no significant correlation between sex, FPG, HbA1c, DBP, t-CHOL,TG, LDL-C, HDL-C and UA with ELA (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (see Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Univariate linear regression analysis of the influencing factors for DR\u003c/h2\u003e \u003cp\u003eWith ELA level as the dependent variable and combined with correlation analysis between ELA and clinical indicators, the factors that may affect ELA levels were used as independent variables with the univariate linear regression analysis. The results showed that DR, duration of diabetes, age, BMI, SBP, BUN, Cre, eGFR and ACR were the influencing factors for ELA (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (see Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Multivariate linear regression analysis of the influencing factors for DR\u003c/h2\u003e \u003cp\u003eELA aslo has a significant correlation with DR, duration of diabetes and BMI after adjusting for relevant confounding factors by using the multivariate linear regression analysis (see Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Diagnostic value of ELA in diabetic retinopathy\u003c/h2\u003e \u003cp\u003eROC curve results showed that when the Yoden index was the maximum, the critical value of ELA was 77.5 ng/ml, the sensitivity and specificity for the diagnosis of diabetic nephropathy were 54.4% and 73.3%, and the area under ROC curve was 0.676 (95% CI 0.621, 0.731), P\u0026thinsp;=\u0026thinsp;0.000 (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe demographic, clinical and biochemical characteristics of all subjects based on DR\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroup 4\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase(M/F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90(52/38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90(59/31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90(57/33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90(60/28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53.79\u0026thinsp;\u0026plusmn;\u0026thinsp;9.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54.86\u0026thinsp;\u0026plusmn;\u0026thinsp;12.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55.82\u0026thinsp;\u0026plusmn;\u0026thinsp;9.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55.91\u0026thinsp;\u0026plusmn;\u0026thinsp;9.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDur (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.29\u0026thinsp;\u0026plusmn;\u0026thinsp;5.96\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.70\u0026thinsp;\u0026plusmn;\u0026thinsp;7.03\u003csup\u003ea,b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.68\u0026thinsp;\u0026plusmn;\u0026thinsp;6.16\u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.05\u0026thinsp;\u0026plusmn;\u0026thinsp;2.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.51\u0026thinsp;\u0026plusmn;\u0026thinsp;2.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.64\u0026thinsp;\u0026plusmn;\u0026thinsp;3.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.08\u0026thinsp;\u0026plusmn;\u0026thinsp;3.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFPG(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.85\u0026thinsp;\u0026plusmn;\u0026thinsp;2.28\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.16\u0026thinsp;\u0026plusmn;\u0026thinsp;2.45\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.46\u0026thinsp;\u0026plusmn;\u0026thinsp;3.15\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1.67\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.49\u0026thinsp;\u0026plusmn;\u0026thinsp;1.66\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.53\u0026thinsp;\u0026plusmn;\u0026thinsp;2.12\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSBP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e123.54\u0026thinsp;\u0026plusmn;\u0026thinsp;12.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e133.32\u0026thinsp;\u0026plusmn;\u0026thinsp;14.18\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e139.07\u0026thinsp;\u0026plusmn;\u0026thinsp;18.27\u003csup\u003ea,b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e146.44\u0026thinsp;\u0026plusmn;\u0026thinsp;23.29\u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDBP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75.40\u0026thinsp;\u0026plusmn;\u0026thinsp;7.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79.24\u0026thinsp;\u0026plusmn;\u0026thinsp;9.03\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e81.13\u0026thinsp;\u0026plusmn;\u0026thinsp;10.27\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e81.38\u0026thinsp;\u0026plusmn;\u0026thinsp;10.65\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003et-CHOL(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.45\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.43\u0026thinsp;\u0026plusmn;\u0026thinsp;1.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.80\u0026thinsp;\u0026plusmn;\u0026thinsp;1.46\u003csup\u003ea,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTG (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.39\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.85\u0026thinsp;\u0026plusmn;\u0026thinsp;1.33\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.80\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.81\u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL-C(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.82\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDL-C(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.44\u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCre (umol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66.90\u0026thinsp;\u0026plusmn;\u0026thinsp;15.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68.56\u0026thinsp;\u0026plusmn;\u0026thinsp;13.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77.83\u0026thinsp;\u0026plusmn;\u0026thinsp;31.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e122.68\u0026thinsp;\u0026plusmn;\u0026thinsp;74.61 \u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBUN(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.38\u0026thinsp;\u0026plusmn;\u0026thinsp;1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.47\u0026thinsp;\u0026plusmn;\u0026thinsp;1.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.87\u0026thinsp;\u0026plusmn;\u0026thinsp;2.62\u003csup\u003ea,b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.83\u0026thinsp;\u0026plusmn;\u0026thinsp;7.41\u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUA(umol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e301.54\u0026thinsp;\u0026plusmn;\u0026thinsp;95.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e300.29\u0026thinsp;\u0026plusmn;\u0026thinsp;85.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e311.04\u0026thinsp;\u0026plusmn;\u0026thinsp;84.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e349.08\u0026thinsp;\u0026plusmn;\u0026thinsp;101.91\u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101.94\u0026thinsp;\u0026plusmn;\u0026thinsp;20.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97.37\u0026thinsp;\u0026plusmn;\u0026thinsp;22.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90.92\u0026thinsp;\u0026plusmn;\u0026thinsp;23.07 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68.91\u0026thinsp;\u0026plusmn;\u0026thinsp;33.28 \u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACR (mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.47(0.30,0.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.35(4.44,12.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e98.83(38.48,326.31)\u003csup\u003ea,b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e552.85(240.60,1848.55) \u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eELA(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79.12\u0026thinsp;\u0026plusmn;\u0026thinsp;20.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78.77\u0026thinsp;\u0026plusmn;\u0026thinsp;16.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71.22\u0026thinsp;\u0026plusmn;\u0026thinsp;19.41\u003csup\u003ea,b\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e64.35\u0026thinsp;\u0026plusmn;\u0026thinsp;18.77\u003csup\u003ea,b,c\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: Data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM or as median (interquartile range). Abbreviations: group 1: Control group, group 2: Type 2 diabetes without diabetic retinopathy, group 3: Nonproliferlative diabetic retinopathy, group 4: Proliferative diabetic retinopathy. Dur\u0026thinsp;=\u0026thinsp;duration of diabetes, DR\u0026thinsp;=\u0026thinsp;diabetic retinopathy, BMI\u0026thinsp;=\u0026thinsp;body mass index, FPG\u0026thinsp;=\u0026thinsp;fasting plasma glucose, HbA1c\u0026thinsp;=\u0026thinsp;glycosylated hemoglobin, SBP\u0026thinsp;=\u0026thinsp;systolic blood pressure, DBP\u0026thinsp;=\u0026thinsp;diastolic blood pressure, t-CHOL\u0026thinsp;=\u0026thinsp;total cholesterol, HDL-C\u0026thinsp;=\u0026thinsp;high density lipoprotein cholesterol, LDL-C\u0026thinsp;=\u0026thinsp;low density lipoprotein cholesterol, TG\u0026thinsp;=\u0026thinsp;Triglyceride, Cre\u0026thinsp;=\u0026thinsp;Serum creatinine, BUN\u0026thinsp;=\u0026thinsp;blood urine nitrogen, UA\u0026thinsp;=\u0026thinsp;uric acid, eGFR\u0026thinsp;=\u0026thinsp;estimated glomerular fltration rate, ACR\u0026thinsp;=\u0026thinsp;urinary albumin/ creatinine ratio. The data were expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM for normally distributed data or median with 25th and 75th quartiles for skewed data. \u003csup\u003ea\u003c/sup\u003e P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, vs. group 1; \u003csup\u003eb\u003c/sup\u003e P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, vs. group 2; \u003csup\u003ec\u003c/sup\u003e P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, vs. group 3.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003egroup 1: Control group, group 2: Type 2 diabetes without diabetic retinopathy, group 3: Nonproliferlative diabetic retinopathy, group 4: Proliferative diabetic retinopathy, Data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe demographic, clinical and biochemical characteristics of all subjects based on ELA\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLow-ELA Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHigh-ELA Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase(M/F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e123/57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107/73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56.14\u0026thinsp;\u0026plusmn;\u0026thinsp;10.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54.60\u0026thinsp;\u0026plusmn;\u0026thinsp;11.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.168\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDur (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.39\u0026thinsp;\u0026plusmn;\u0026thinsp;7.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.92\u0026thinsp;\u0026plusmn;\u0026thinsp;6.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.99\u0026thinsp;\u0026plusmn;\u0026thinsp;2.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.61\u0026thinsp;\u0026plusmn;\u0026thinsp;3.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDR(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e113(62.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67(37.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFPG(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.57\u0026thinsp;\u0026plusmn;\u0026thinsp;2.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.16\u0026thinsp;\u0026plusmn;\u0026thinsp;2.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.152\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.61\u0026thinsp;\u0026plusmn;\u0026thinsp;2.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.24\u0026thinsp;\u0026plusmn;\u0026thinsp;2.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.135\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSBP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e138.67\u0026thinsp;\u0026plusmn;\u0026thinsp;21.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e132.52\u0026thinsp;\u0026plusmn;\u0026thinsp;15.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDBP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79.85\u0026thinsp;\u0026plusmn;\u0026thinsp;9.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78.73\u0026thinsp;\u0026plusmn;\u0026thinsp;9.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.275\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003et-CHOL(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.51\u0026thinsp;\u0026plusmn;\u0026thinsp;1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.58\u0026thinsp;\u0026plusmn;\u0026thinsp;1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.587\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL-C(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.72\u0026thinsp;\u0026plusmn;\u0026thinsp;1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.387\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDL-C(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.537\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTG (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.82\u0026thinsp;\u0026plusmn;\u0026thinsp;1.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.784\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCre (umol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95.90\u0026thinsp;\u0026plusmn;\u0026thinsp;60.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.08\u0026thinsp;\u0026plusmn;\u0026thinsp;24.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBUN(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.70\u0026thinsp;\u0026plusmn;\u0026thinsp;5.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.11\u0026thinsp;\u0026plusmn;\u0026thinsp;2.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUA(umol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e321.48\u0026thinsp;\u0026plusmn;\u0026thinsp;95.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e309.49\u0026thinsp;\u0026plusmn;\u0026thinsp;92.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.915\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83.29\u0026thinsp;\u0026plusmn;\u0026thinsp;30.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e96.30\u0026thinsp;\u0026plusmn;\u0026thinsp;24.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACR (mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87.83(7.62,556.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.31(0.75,46.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eELA(ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.25\u0026thinsp;\u0026plusmn;\u0026thinsp;10.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88.49\u0026thinsp;\u0026plusmn;\u0026thinsp;11.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eNote: Data are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM or as median (interquartile range). Dur\u0026thinsp;=\u0026thinsp;duration of diabetes, DR\u0026thinsp;=\u0026thinsp;diabetic retinopathy, BMI\u0026thinsp;=\u0026thinsp;body mass index, FPG\u0026thinsp;=\u0026thinsp;fasting plasma glucose, HbA1c\u0026thinsp;=\u0026thinsp;glycosylated hemoglobin, SBP\u0026thinsp;=\u0026thinsp;systolic blood pressure, DBP\u0026thinsp;=\u0026thinsp;diastolic blood pressure, t-CHOL\u0026thinsp;=\u0026thinsp;total cholesterol, HDL-C\u0026thinsp;=\u0026thinsp;high density lipoprotein cholesterol, LDL-C\u0026thinsp;=\u0026thinsp;low density lipoprotein cholesterol, TG\u0026thinsp;=\u0026thinsp;Triglyceride, Cre\u0026thinsp;=\u0026thinsp;Serum creatinine, BUN\u0026thinsp;=\u0026thinsp;blood urine nitrogen, UA\u0026thinsp;=\u0026thinsp;uric acid, eGFR\u0026thinsp;=\u0026thinsp;estimated glomerular fltration rate, ACR\u0026thinsp;=\u0026thinsp;urinary albumin/ creatinine ratio. The data were expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM for normally distributed data or median with 25th and 75th quartiles for skewed data.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePearson correlation analysis between serum ELA level and clinical parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDur (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSBP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBUN(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCre(umol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.194\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACR(mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate linear regression analysis of serum ELA level\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEstimate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStd. Error\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBeta\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003et\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-7.211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-5.776\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDur (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.690\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.155\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-4.457\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.220\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.721\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSBP(mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBUN(mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.574\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.216\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.161\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.664\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCre(umol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.079\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-3.983\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACR(mg/g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-4.186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR(mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.194\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate linear regression analyses related to serum ELA level\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEstimate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStd. Error\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBeta\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003et\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-5.153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.513\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.238\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-3.407\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDur (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.370\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.656\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.993\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"3 Discussion","content":"\u003cp\u003eDiabetic retinopathy is the leading cause of blindness in adults and seriously affects peoples' quality of life. DR is a microangiopathy and neurodegenerative disease, which is characterized by the appearance of microaneurysms, elevated vascular permeability, capillary blockage, and proliferation of neovasculature[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The etiology and mechanism of retinopathy remain unclear, and current therapeutic strategies are less effective. Using a biomarker with high sensitivity and specificity to early diagnosis of this complicationis is very essential for providing better therapeutic strategies[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eELA was first uncovered as a 54-amino acid peptide hormone during zebrafish development in 2013[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This peptide is then cleaved into a mature secreted protein, 32 amino acids long. It is another endogenous ligand of APJ and widely expressed and activates various G-protein-dependent signaling pathways. ELA is widely distributed in the body and its expression can be detected in a variety of tissues and cells. ELA has been studied in various diseases including hypertension, myocardial infarction, heart failure, prenatal eclampsia, diabetic nephropathy, acute kidney injury, cerebral ischemia/reperfusion injury, pulmonary hypertension, active ulcerative colitis and other diseases [\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Data from previous studies have shown that ELA can promote blood vessel growth and can guide the migration of vascular cells in vasculogenesis. In the process of vascular development, the angioblasts rely on the intrinsic expression of APJ for their migration to the place where blood vessels are formed, which is mainly triggered by ELA [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Wang and his colleagues[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]found that ELA can induce angiogenesis of human umbilical vein endothelial cells (HUVECs) by activating the APJ signaling pathway. A study[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]found that treated by Fc-ELA-21 for 4 weeks in myocardial infarction model rats, and observed angiogenesis in the infarct area. Data from previous studies showed that ELA can promote angiogenesis after myocardial infarction (MI) by activating VEGF/VEGFR2 and Jagged1/Notch3 pathways [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Li and his colleagues found that the level of ELA was increased in the ischemic brain and ELA-32 can alleviate brain injury and promote the repairment of newly formed functional vessels after cerebral ischemia/reperfusion (I/R) damage. In addition, ELA-32 enhanced proliferation, migration, and tube formation of the mouse brain endothelial cells (bEnd.3 cells) under oxygen-glucose deprivation/reoxygenation (OGD/R) condition[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A previous study about ELA and oxygen-induced retinopathy model showed that ELA can inhibit ferroptosis to promote retinal angiogenesis under oxidative stress induced injury [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In summary, ELA plays an important role in the generation of neovascularization, which is the main pathological change of DR. So we speculated that ELA may be involved in the occurrence and development of DR. However, the role of ELA in DR remains inconclusive, so this paper preliminarily explored the relationship between ELA and DR.\u003c/p\u003e \u003cp\u003eIn the present study, We found that there was no significant difference in serum ELA levels between normal control and T2DM patients, but it significantly decreased in nonproliferlative DR and proliferative DR patients compared with T2DM without DR. Compared with nonproliferlative DR patients, the serum ELA levels further significantly decreased in proliferative DR patients. In addition, ELA has a significantly negative correlation with DR, duration of diabetes,age, SBP, BUN, Cre and ACR, and is positively correlated with BMI and eGFR. Furthermore, the univariate and multivariate linear regression analysis showed that DR, duration of diabetes and BMI were the risk factors for ELA after adjusting for relevant confounding factors (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The ROC curve analysis showed that ELA could identify subjects with DR with a sensitivity of 54.4% and a specificity of 73.3%. So we suspect that ELA may be involved in the occurrence and development of DR, and ELA may be a potential clinical predictor and therapeutic target of DR.\u003c/p\u003e \u003cp\u003ePrevious study has shown that dyslipidemia is correlated with development and progression of DR[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. As we all known that DR and diabetic nephropathy are both diabetic microvascular complications, and their occurrence and development are closely related. However, the specific mechanism of ELA involvement in DR is unknown. ELA can guide the migration of vascular cells in vasculogenesis and also can promote blood vessel growth, which is crucial to the occurrence and development of DR. Accumulating evidences showed that low-grade inflammation plays a key role in the pathogenesis and development of DR, with multiple inflammatory factors increased in the vitreous and retina of patients with DR[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Ye et al [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e][\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]demonstrated that ELA can alleviate vascular remodeling in spontaneously hypertensive rats by anti-inflammatory. In this study, exogenous ELA-21 preconditioning mitigated inflammatory activation, but ELA knockdown aggravated inflammatory activation. So we predict that ELA can alleviate vascular remodeling in diabetic retinopathy by anti-inflammatory. Oxidative stress also plays an important role in the development of DR[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. ELA can promote retinal angiogenesis by inhibiting ferroptosis under oxidative stress induced damage[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. So we guess that ELA alleviates vascular remodeling through anti-oxidative stress. Additional experimental studies are also needed to investigate the mechanisms. Research has also demonstrated the significance of autophagy in DR, which is a key homeostasis mechanism for the destruction and restoration of cytoplasmic components[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Recent studies showed that inhibition of APJ signalling by knockout of ELA increased apoptosis in the placenta of mice[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. We suspect that ELA may play an important role in diabetic retinopathy through autophagy.\u003c/p\u003e \u003cp\u003eIn the present study, we found that with the progressive of diabetic retinopathy, the level of serum ELA decreases gradually. We suspect that ELA can attenuate vascular remodeling in DR via anti-inflammatory or autophagy. To our knowledge, this is the first study which clinically explored the relationship between ELA levels and DR, and showed a significant correlation between ELA levels and the severity of DR. Nevertheless, this study had some limitations. Firstly, a relatively small sample size might not be very representative for the actual relationship between serum ELA levels and DR patients. Secondly, what we detected was ELA in venous blood, not in aqueous humor or vitreous fluid. Vitreous or aqueous humor sampling is invasive and it is not practical to use vitreous or aqueous humor markers to detect DR, so serum samples are critical. Finally, this study is limited to the analysis of clinical data, and there is a lack of research on its mechanism. Therefore, further large-scale, longitudinal and basic studies will help clarify the relationship between ELA levels and diabetic retinopathy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eACR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eurinary albumin/creatinine ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebody mass index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSBP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esystolic blood pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDBP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ediastolic blood pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFPG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efasting blood glucose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHbA1c\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eglycosylated hemoglobin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003et-CHOL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etotal cholesterol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etriglycerides\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHDL-C\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehigh density lipoprotein cholesterol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLDL-C\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elow density lipoprotein cholesterol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBUN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eblood urea nitrogen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCre\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eserum creatinine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eeGFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eestimated glomerular filtration rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ediabetic retinopathy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHPLC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHigh performance liquid chromatography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Affiliated Huai’an No.1 People’s Hospital with Nanjing Medical University (KY-2023-031-01). Written informed consent was obtained from all participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp; Fundings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by the National Natural Science Foundation of China (Grant Award: 82000743 and 81700723), Northern Jiangsu Clinical Medicine Research Institute’ s 2024 Projects (Grant Award: HAKY20240000307), Key Research and Development Program of Jiangsu Provincial Department of Science and Technology-Social Development Project (Grant Award: BE2023745) and General Project of Natural Science Foundation of Jiangsu Provincial Department of Science and Technology (Grant Award: BK20191213).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWensha Gu contributed to conducting the experiments and drafting the manuscript. Min Shi and Yuting Liu played a role in data collection and analysis. Juan Chen was responsible for refining the manuscript, while Hong Zhang assisted in designing the trial. Xiaoming Mao provided supervision and guidance throughout the entire project. All authors have reviewed and approved the final version of the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge the support from all funding agencies and the participants in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLoukovaara S, Nurkkala H, Tamene F, Gucciardo E, Liu X, Repo P, Lehti K, Varjosalo M. Quantitative proteomics analysis of vitreous humor from diabetic retinopathy patients [J]. JProteome Res, 2015,14(12): 5131\u0026ndash;5143.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWen DJ, Ren XJ, Dong LJ, He Y, Li XR. New exploration of treatment target for proliferative diabetic retinopathy based on iTRAQ LC-MS/MS Proteomics[J]. Chin J Ophthalmol, 2019, 55(10): 769\u0026ndash;776.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHo L, van Dijk M, Chye STJ, Messerschmidt DM, Chng SC, Ong S, Yi L K, Boussata S, Goh GH, Afink GB, Lim CY, Dunn NR, Solter D, Knowles BB, Reversade B. ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice [J]. Science, 2017, 357(6352): 707\u0026thinsp;\u0026ndash;\u0026thinsp;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChng SC, Ho L, Tian J, Reversade B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev Cell. 2013, 27: 672\u0026ndash;680.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePauli A, Norris ML, Valen E, Chew GL, Gagnon JA, Zimmerman S, Mitchell A, Ma J, Dubrulle J, Reyon D, Tsai SQ, Joung JK, Saghatelian A, Schier AF. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science. 2014, 343: 1248636.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Z, Yu D, Wang M, Wang Q, Kouznetsova J, Yang R, Qian K, Wu W, Shuldiner A, Sztalryd C, Zou M, Zheng W, Gong DW. Elabela-apelin receptor signaling pathway is functional in mammalian systems[J]. Sci Rep, 2015, 5:8170.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeng C, Chen H, Yang N, Feng Y, Hsueh AW. Apela Regulates Fluid Homeostasis by Binding to the APJ Receptor to Activate Gi Signaling[J]. J Biol Chem, 2015, 290(30):18261\u0026ndash;18268.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang H, Gong D, Ni L, Zhang X. Serum Elabela/Toddler Levels Are Associated with Albuminuria in Patients with Type 2 Diabetes. Cell Physiol Biochem.2018, 48(3):1347\u0026ndash;1354.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen H, Wang L, Wang W, Huang K. ELABELA and an ELABELA Fragment Protect against AKI. J Am Soc Nephrol.2017, 28(9):2694\u0026ndash;2707.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Wang L, Shi H. The biological function of ELABELA and APJ signaling in the cardiovascular system and pre-eclampsia. Hypertens Res.2019, 42(7): 928\u0026ndash;934.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiral P, Rosenbaum D. Retinopathy progression in type 2 diabetes. N Engl J Med. 2010 11 25, 363(22):2172.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSood A, Baishnab S, Gautam I, et al. Exploring various novel diagnostic and therapeutic approaches in treating diabetic retinopathy. INFLAMMOPHARMACOLOGY. 2023-02-06.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen Z, Wu C, Liu Y, Wang L. ELABELA attenuates deoxycorticosterone acetate/salt-induced hypertension and renal injury by inhibition of NADPH oxidase/ROS/NLRP3 inflammasome pathway. Cell Death Dis.2020 08 22;11(8) :698.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu P, Ma S, Dai X, Cao F. Elabela alleviates myocardial ischemia reperfusion-induced apoptosis, fibrosis and mitochondrial dysfunction through PI3K/AKT signaling. Am J Transl Res.2020;12(8) :4467\u0026ndash;4477.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Y, Wang Y, Luo M, Miao L. Elabela protects against podocyte injury in mice with streptozocin-induced diabetes by associating with the PI3K/Akt/mTOR pathway. Peptides.2019 04;114 :29\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026ouml;nmez Y, Acele A. Increased Elabela levels in the acute ST segment elevation myocardial infarction patients. Medicine (Baltimore).2019, 98(43):e17645.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMa Z, Zhao L, Martin S, Yang XC. Lower Plasma Elabela Levels in Hypertensive Patients With Heart Failure Predict the Occurrence of Major Adverse Cardiac Events: A Preliminary Study. Front Cardiovasc Med.2021;8:638468.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu C, Wang F, Chen Y, Yang T. ELABELA antagonizes intrarenal renin-angiotensin system to lower blood pressure and protects against renal injury. Am J Physiol Renal Physiol.2020, 318(5):F1122-F1135.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi W, Xu P, Feng KL, Shen S, Huang N, Wang H, Xu W, Wang X, Wang X, Zhang G, Sun Y, Hu W, Liu W. X. Elabela-APJ axis mediates angiogenesis via YAP/TAZ pathway in cerebral ischemia/reperfusion injury.TRANSL RES. 2023-02-21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu P, Kong L, Tao C, Hu W. Elabela-APJ axis attenuates cerebral ischemia/reperfusion injury by inhibiting neuronal ferroptosis.FREE RADICAL BIO MED. 2023-02-20;196:171\u0026ndash;186.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu Y, Jin L, Pan Y, Zou J, Wang Z. Apela gene therapy alleviates pulmonary hypertension in rats. FASEB J. 2022-07-01;36(7):e22431.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGulumsek E, Sumbul HE, Yesildal F, Kara B. Serum Elabela level is related to endoscopic activity index in patients with active ulcerative colitis.IRISH J MED SCI. 2022-06-01;191(3):1171\u0026ndash;1176.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eelker CS, Schuermann A, Pollmann C, Chng SC, Kiefer F, Reversade B, Herzog W. The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis. Elife.2015;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, Liang G, Guo Q, Cai W, Zhang X, Ni J, Tao Y, Niu X, Chen Shaobo. ELABELA improves endothelial cell function via the ELA-APJ axis by activating the PI3K/Akt signalling pathway in HUVECs and EA.hy926 cells. CLIN EXP PHARMACOL P. 2020-12-01;47(12):1953\u0026ndash;1964.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y. Recombinant Elabela-Fc fusion protein has extended plasma half-life and mitigates post-infarct heart dysfunction in rats. INT J CARDIOL. 2020-02-01;300:217\u0026ndash;218.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXi Y, Li Y, Ren W, Bo W, Ma Y, Pan S, Gong D, Tian Z. ELABELA-APJ-Akt/YAP Signaling Axis: A Novel Mechanism of Aerobic Exercise in Cardioprotection of Myocardial Infarction Rats. MED SCI SPORT EXER. 2023-02-22, 0195\u0026ndash;9131.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang J, Zhang Q, Chen E, Zhao P, Xu Y. Elabela promotes the retinal angiogenesis by inhibiting ferroptosis during the vaso-obliteration phase in mouse oxygen-induced retinopathy model. FASEB J. 2022-05-01;36(5):e22257.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang C, Lin W, Xu Q, Li H, Xu C, Ma X, Hao M, Kuang H. Association between high-density lipoprotein cholesterol to apolipoprotein A ratio and diabetic retinopathy: A cross-sectional study. J DIABETES COMPLICAT. 2023-06-01; 37(6):108471.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTang L, Xu GT, Zhang JF. Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy.NEURAL REGEN RES. 2023-05-01;18(5):976\u0026ndash;982.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYe C, Geng Z, Zhang LL, Xiong XQ, Zheng F, Zhou YB, Zhu GQ, Xiong XQ. Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory, anti-oxidative and anti-proliferative effects. ACTA PHARMACOL SIN. 202 2-10-01;43(10):2573\u0026ndash;2584.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAiello JJ, Bogart MC, Chan WT, Holoman NC, Trobenter TD, Relf CE, Kleinman DM, DeVivo DC, Samuels IS. Systemic Reduction of Glut1 Normalizes Retinal Dysfunction, Inflammation, and Oxidative Stress in the Retina of Spontaneous Type 2 Diabetic Mice.AM J PATHOL. 2023-04-14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheng Y, Fan H, Liu K, Liu J, Zou H, You Z. TFEB attenuates hyperglycemia-induced retinal capillary endothelial cells injury via autophagy regulation.CELL BIOL INT. 2023-06-01; 47(6): 1092\u0026ndash;1105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSong JJ, Yang M, Liu Y, Song JW, Wang J, Chi HJ, Liu X Y, Zuo K, Yang X C, Zhong JC. MicroRNA-122 aggravates angiotensin II-mediated apoptosis and autophagy imbalance in rat aortic adventitial fibroblasts via the modulation of SIRT6-elabela-ACE2 signaling. EUR J PHARMACOL. 2020-09-15; 883: 173374.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Type 2 diabetes, Diabetic retinopathy(DR), Elabela (ELA)","lastPublishedDoi":"10.21203/rs.3.rs-9114712/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9114712/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eAims\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAbnormal expression of Elabela (ELA) is associated with various diseases, including diabetic nephropathy. However, the roles of ELA on developing diabetic retinopathy (DR) are not known. The aim of this study is to confirm the relationship between serum Elabela (ELA) levels and DR in patients with type 2 diabetes mellitus (T2DM).\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA total of 90 healthy donors (Control group ) and 270 patients with T2DM were recruited. The were divided into three groups: Normal T2DM without DR, T2DM with nonproliferlative DR and T2DM with proliferative DR, 90 patients including in each group. Basic general clinical characteristics were collected and serum ELA levels were determined using the ELISA kit.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe results showed that there was no significant difference in serum ELA levels between normal control and T2DM patients, but it significantly decreased in nonproliferlative DR and proliferative DR patients compared with T2DM without DR. Compared with nonproliferlative DR patients, the serum ELA levels further significantly decreased in proliferative DR patients. ELA has a significantly negative correlation with DR, duration of diabetes, age, systolic blood pressure(SBP), Blood urea nitrogen(BUN), serum creatinine(Cre) and urinary albumin/creatinine ratio (ACR), and is positively correlated with body mass index (BMI) and estimated glomerular filtration rate (eGFR). Furthermore, the univariate and multivariate linear regression analysis showed that DR, duration of diabetes and BMI were the risk factors for ELA after adjusting for relevant confounding factors (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).According to the ROC curve analysis, ELA could identify subjects with DR with a sensitivity of 54.4% and a specificity of 73.3%.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWith the deterioration of DR, the level of serum ELA decreases gradually. ELA may be involved in the occurrence and development of DR, and ELA may be a potential clinical predictor and therapeutic target of DR.\u003c/p\u003e","manuscriptTitle":"Serum Elabela Levels are Negatively Associated with Retinopathy in Type 2 Diabetic Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-10 06:34:36","doi":"10.21203/rs.3.rs-9114712/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-06T03:46:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"252741115594889372146523523065614076897","date":"2026-04-05T14:04:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-03T05:33:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-26T07:17:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-24T08:51:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-24T08:11:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2026-03-24T08:04:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"de24b1cb-351f-4fce-a4cc-56223c8e6e42","owner":[],"postedDate":"April 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-10T06:34:36+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-10 06:34:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9114712","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9114712","identity":"rs-9114712","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}