Unveiling the mechanisms of proliferative diabetic retinopathy: PVAT-derived inflammatory and angiogenic mediators as potential biomarkers in vitreous and serum

Unveiling the mechanisms of proliferative diabetic retinopathy: PVAT-derived inflammatory and angiogenic mediators as potential biomarkers in vitreous and serum | 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 Article Unveiling the mechanisms of proliferative diabetic retinopathy: PVAT-derived inflammatory and angiogenic mediators as potential biomarkers in vitreous and serum Tuna Ozan Dogan, Ozgur Artunay, Erdem Erdoğdu, Şehnaz Özçalışkan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6614523/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract OBJECTIVES This study aimed to explore the role of perivascular adipose tissue (PVAT)-derived mediators in vitreous and serum samples from patients with proliferative diabetic retinopathy (PDR). METHODS Serum and vitreous samples were prospectively collected between February and April 2023 from 22 patients undergoing surgery for PDR and 22 patients with macular hole (MH) or epiretinal membrane (ERM) as the control group. The levels of adiponectin (ADP), visfatin (VF), adipocyte fatty acid-binding protein (a-FABP), and apelin were analyzed. RESULTS The serum and vitreous ADP levels in the PDR group were significantly lower than those in the control group (MH-ERM) ( p = 0.003 and p < 0.001). In contrast, the serum and vitreous apelin levels were significantly greater in the PDR group ( p < 0.001). Serum and vitreous a-FABP levels were significantly increased in the PDR group compared with those in the control group ( p = 0.025 and p = 0.002,). VF levels in the serum and vitreous were significantly greater in the PDR group than in the control group ( p = 0.003 and p < 0.001, respectively). CONCLUSION Changes in ADP, apelin, a-FABP, and VF levels in serum and vitreous suggest their potential as novel biomarkers and therapeutic targets for PDR classification, disease progression assessment, and treatment strategies. Health sciences/Pathogenesis/Immunopathogenesis Health sciences/Medical research/Biomarkers/Prognostic markers Health sciences/Biomarkers/Prognostic markers Health sciences/Pathogenesis/Inflammation perivascular adipose tissue proliferative diabetic retinopathy vitreoretinal surgery INTRODUCTION Diabetes is a significant public health issue, and one of its most critical microvascular complications is diabetic retinopathy (DR). More than 100 million people worldwide are affected by DR [ 1 ]. The pathogenesis of DR involves a complex interplay of inflammatory, angiogenic, and apoptotic cascades. Despite extensive research, the underlying mechanisms remain incompletely understood. Recent studies have emphasized the significance of perivascular adipose tissue (PVAT), which encases blood vessels, in regulating vascular homeostasis. The impact of PVAT-derived adipokines, including adiponectin (ADP), visfatin (VF), fatty acid binding protein (a-FABP) and apelin, on cardiovascular, renal and large vessel pathologies has been well documented [ 2 ]. Adiponectin (ADP), a vasodilatory adipokine present in high concentrations in human circulation, has been linked to a lower risk of type 2 diabetes, enhanced insulin sensitivity, and improved vascular function. ADP has the potential to lower proinflammatory cytokine levels while also exerting a beneficial effect on insulin signaling pathways [ 3 ]. Under normal conditions, the expression ADP in humans, as assessed by enzyme-linked immunosorbent assay (ELISA), has been shown to be significantly greater in the RPE layer, choroid than in the neural retinal layers [ 4 ]. Studies indicate that ADP can suppress retinal neovascularization by preventing basal tube formation in primary cultures of umbilical vein, human retinal microvascular endothelial cells, and choroidal endothelial cells [ 5 ]. Therefore, ADP may serve as a therapeutic target in the treatment of angiogenesis. This effect is linked to the altered function of vascular endothelial growth factor, a key contributor to angiogenesis in diabetic retinopathy [ 6 ]. Visfatin (VF) is a 52-kDa protein with a dimeric structure consisting of two monomers, each containing 491 amino acids in humans [ 7 ]. Primarily synthesized and secreted by visceral fat, VF is a novel adipokine involved in inflammatory responses, lipid metabolism regulation, differentiation promotion, participation in the atherosclerosis process. Hyperglycemia increases plasma VF levels, and this increase worsens as hyperglycemia progresses. Other studies have demonstrated that glucose concentrations exceeding 8.3 mmol/L significantly increase plasma VF levels in healthy men [ 8 ]. The increase in plasma VF levels observed under hyperglycemic conditions is likely associated with oxidative stress. Hyperglycemia is widely recognized for promoting the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which in turn initiate oxidative stress, leading to abnormal gene expression, impaired signal transduction, and apoptosis [ 9 ]. However, whether VF induces neovascularization in diabetic patients and the underlying mechanisms remain uncertain. Fatty acid binding protein 4 (FABP4) belongs to a family of lipid chaperones characterized by proteins with a molecular weight of approximately 14–15 kDa. FABPs facilitate the transport of lipid molecules to different intracellular compartments, contributing to processes like oxidation, signaling, gene transcription regulation, and storage [ 10 ]. More than nine FABPs have been identified, with FABP4 being produced primarily by adipocytes and macrophages. A recent single-cell transcriptome analysis of the human retina identified the expression of multiple FABPs in different retinal cell types, indicating their potential involvement in both normal physiological functions and pathological conditions [ 11 ]. Our understanding of the role of FABPs in retinal physiology and pathology is still incomplete. Apelin-77 (pre-pro-apelin) acts as a precursor to multiple pharmacologically active apelin isoforms (e.g., apelin-12, 13, 17, 36), with homologs found in both humans and mice [ 12 ]. Tatemoto et al. [ 13 ] and Boucher et al. [ 14 ] revealed that apelin is both synthesized and secreted by adipocytes. In humans, apelin gene expression in adipose tissue is influenced by hyperinsulinemia, which also enhances apelin secretion through pathways dependent on protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K) 15]. Apelin expression in adipocytes has been shown to increase in mouse obesity models associated with hyperinsulinemia [ 16 ]. This study aims to identify the specific stages at which PVAT-associated adiponectin and other adipokines contribute to the pathogenesis of diabetic retinopathy. METHODS This study included 44 patients who were evaluated at the Retina Unit of Beyoglu Eye Training and Research Hospital, University of Health Sciences Turkey, between February and April 2023. The study group comprised 22 patients diagnosed with PDR and scheduled for vitreoretinal surgery due to tractional retinal detachment (TRD) and/or vitreous hemorrhage. The control group consisted of 22 patients with idiopathic macular holes (MHs) or vitreomacular traction (VMT) requiring surgery, with no history of systemic disease. Ethical approval was granted by the Hamidiye Scientific Research Ethics Committee of University Health Sciences, Turkey. All participants received detailed information about the study’s objectives and procedures, and written informed consent was secured prior to enrollment. Patients with ocular conditions associated with increased inflammation or oxidative stress, including uveitis, glaucoma, and age-related macular degeneration, were excluded. Individuals with a history of prior ocular surgery (except cataract surgery) or trauma were also excluded. To ensure homogeneity, the control group excluded individuals with systemic diseases, and pediatric patients (< 18 years) were not included in either group. Sample collection Pars plana vitrectomy (PPV) was used for vitreous sample collection. Undiluted vitreous fluid samples were obtained via an aspiration cannula immediately after three-port trocar insertion and subsequent vitrectomy. A minimum of 100 µL vitreous fluid was collected in microcentrifuge tubes (Eppendorf®) for further analysis. Peripheral blood samples were drawn from all participants before surgery and centrifuged at 3 000 × rpm (10 minutes) to isolate serum. The sample collection process lasted approximately two months. The collected samples were stored in a -80°C freezer to preserve their integrity. All samples were collected by specialist ophthalmologists in the retina unit, with no complications arising from vitreous fluid collection during any of the surgeries. Owing to ethical considerations, vitreous fluid was not collected from healthy individuals without an ocular condition requiring surgery. Thus, the control group included patients with idiopathic MHs and VMT who were scheduled for surgery and had no systemic diseases. The samples were transferred under appropriate transport conditions to the Department of Medical Biochemistry, Hamidiye Faculty of Medicine, University of Health Sciences, where the analyses were conducted. Protein measurement in vitreous samples Vitreous protein concentrations were measured using a colorimetric assay (E-BC-K318-M, Elabscience, Houston, Texas, USA). Total protein concentration was quantified via a bicinchoninic acid assay (BCA), which relies on the reduction of Cu²⁺ to Cu⁺ by proteins under alkaline conditions, forming a colorimetric complex with BCA reagent that absorbs maximally at 562 nm. This assay operates on the principle that protein molecules bind to Coomassie dye under acidic conditions, causing a color change from brown to blue. Under alkaline conditions, Cu²⁺ is reduced to Cu⁺ by proteins, leading to the formation of a purple complex with the BCA reagent, which exhibits a peak absorbance at 562 nm. The absorbance is directly proportional to the protein concentration, enabling protein quantification based on optical density (OD). For the analysis, 20 µL vitreous samples diluted 1:10 in 1x PBS were added to microplate wells. Subsequently200 µL of BCA solution was introduced, and the plates were kept at 37°C for 30 minutes for incubation. The samples were then measured at 562 nm using a spectrophotometer (BioTek, Synergy™ HTX Multi-Mode Reader). Protein concentrations were determined by comparison with a standard curve. ELISA analysis Serum and vitreous levels of ADP, apelin, a-FABP, and VF were quantified utilizing enzyme-linked immunosorbent assay (ELISA) kits (Apelin: SunRed 201-12-2015; ADP: SunRed 201-12-1551; a-FABP: SunRed 201-12-2015; Visfatin: SunRed 201-12-0026), following the manufacturer’s protocols. For each analysis, 40 µL of each serum sample and 10 µL of the apelin/ADP/a-FABP/VF antibodies were added to the microplate, followed by the addition of 50 µL of streptavidin-HRP. The plates were kept at 37°C for 60 minutes. Following incubation, the wells were rinsed five times with the washing solution. Next, 50 µL of substrate A and 50 µL of substrate B were introduced into each well, followed by incubation at 37°C for 10 minutes in a dark setting. The reaction was terminated by adding 50 µL of stop solution to each well, and absorbance was recorded at 450 nm using a spectrophotometer. (BioTek, Synergy™ HTX Multi-Mode Reader). The levels of apelin, ADP, a-FABP, and VF in vitreous samples were normalized to total protein concentrations and expressed as mg of protein. RESULTS This study included a total of 44 patients: 22 patients diagnosed with PDR who underwent surgery and 22 patients in the control group, consisting of individuals diagnosed with idiopathic ERMs or MHs who had no systemic diseases and were scheduled for surgery. Out of the participants, 23 (52.3%) were female, while 21 (47.7%) were male. The average age of the PDR group was 54.0 (±9.0) years, while the control group had a mean age of 58.4 (±11.4) years. The clinical and demographic characteristics of the patients are shown in Table 1. There was no notable variation in age or gender distribution between the PDR and control groups. ( p> 0.05). Serum and vitreous ADP levels In this study, the median serum ADP level in the diabetic group was 13.2 ng/L (13.9 (±5.6) ng/L), which was significantly lower than the median serum ADP level of 26.0 ng/L (25.8 (±12.7) ng/L) in the control group ( p= 0.003). Similarly, the median vitreous ADP level in the diabetic group was 5.6 ng/L (8.9 (±7.2) ng/L), which was significantly lower than the median vitreous ADP level of 38.7 ng/L (59.1 (±69.8) ng/L) in the control group ( p 0.05), vitreous ADP levels were significantly lower than serum ADP levels in the diabetic group ( p< 0.05). Moreover, the variation in serum and vitreous ADP levels between the groups reached statistical significance ( p< 0.05), with the control group exhibiting higher vitreous ADP levels and the diabetic group displaying higher serum ADP levels (Table 2). Serum and vitreous apelin levels The median serum apelin level in the diabetic group was 90.6 ng/L (89.2 (±33.5) ng/L), which was significantly greater than the median serum apelin level of 44.7 ng/L (46.9 (±16.6) ng/L) in the control group ( p< 0.001). Similarly, the median vitreous apelin level in the diabetic group was 90.1 ng/L (199 (±284.5) ng/L), which was significantly greater than the median vitreous apelin level of 21.8 ng/L (29.3 (±22.2) ng/L) in the control group ( p 0.05). However, the vitreous apelin level was significantly higher in the diabetic group compared to the control group. ( p< 0.05). The difference in serum and vitreous apelin levels between the groups was statistically significant ( p< 0.05), with higher apelin levels observed in both serum and vitreous in the diabetic group compared to the control group. (Table 3) Serum and vitreous a-FABP levels The median serum a-FABP level in the diabetic group was 22.1 ng/L (19.9 (±6.3) ng/L), which was significantly greater than the median serum a-FABP level of 17.4 ng/L (17.0 (±2.9) ng/L) in the control group ( p= 0.025). Similarly, the median vitreous a-FABP level in the diabetic group was 13.7 ng/L (18.2 (±19.2) ng/L), which was significantly greater than the median vitreous a-FABP level of 3.3 ng/L (4.4 (±4.6) ng/L) in the control group ( p= 0.002). No notable difference was found between vitreous and serum a-FABP levels in the diabetic group. ( p> 0.05), whereas vitreous a-FABP levels were significantly lower than serum a-FABP levels in the control group ( p< 0.05). The difference in serum and vitreous a-FABP levels was statistically significant between the groups ( p< 0.05), with a greater reduction in vitreous a-FABP levels in the control group than diabetic group (Table 4). Serum and vitreous VF levels The median serum VF level in the diabetic group was 5.9 ng/L (5.9 (±3.5) ng/L), which was significantly greater than the median serum VF level of 2.5 ng/L (3.4 (±2.2) ng/L) in control group ( p= 0.003). Similarly, the median vitreous VF level in the diabetic group was 6.1 ng/L (9.8 (±11.6) ng/L), which was significantly greater than the median vitreous VF level of 1.08 ng/L (1.3 (±0.77) ng/L) in the control group ( p 0.05); however, the vitreous VF levels were significantly lower than the serum VF levels in the control group ( p< 0.05). The variation in serum and vitreous VF levels across the groups was statistically significant ( p< 0.05), with higher VF levels detected in both serum and vitreous in the diabetic group compared to the control group. (Table 5) DISCUSSION The worldwide incidence of diabetes has been rising at a concerning pace. On the basis of current data, The International Diabetes Federation estimates that the number of people living with diabetes will rise to 592 million by 2035 [ 17 ]. Macrovascular and microvascular changes caused by diabetes are linked to a variety of pathways, and the underlying mechanisms of these changes have not been completely clarified yet. The primary objective of our study was to determine the role of PVAT-derived adipokines, including ADP, apelin, and a-FABP, VF in the pathophysiology of DR. Bråkenhielm et al. [ 18 ] demonstrated that ADP functions as an inhibitor of angiogenesis in various endothelial cells, including human dermal microvascular, bovine capillary, and porcine aortic endothelial cells, by suppressing VEGF- or FGF-2-induced proliferation. In 2004, Yılmaz et al. [ 19 ] reported reduced serum ADP levels in patients with PDR. In our study, the serum ADP level in patients diagnosed with PDR (13.9 (± 5.6 ng/L) was also lower than that in the control group (25.8 (± 12.7) ng/L). Compared with the methods in the literature, no differences were observed in the methods used for serum ADP measurement; ELISA was utilized in our study, which is consistent with previous research. In 2013, Srinivasan et al. [ 6 ] examined ADP levels in the vitreous of DR patients were found to be elevated compared to those in the control group. The authors attributed this paradoxical increase to the protective effects of ADP. In contrast, our study revealed significantly lower vitreous ADP levels in patients with PDR (8.9 (± 7.2) ng/L) than in the control group (59.1 (± 69.8) ng/L) ( p < 0.001) [ 6 ]. A recent research has shown that VF promotes angiogenesis in endothelial cell human umbilical vein by triggering signaling pathways that engage the mammalian target of rapamycin 20]. Thus, VF could contribute to the development of DR. To date, only one study has examined serum and vitreous VF levels in DR patients. This study is the first to explore the association between serum and vitreous VF levels and the presence and severity of DR. The findings revealed that serum and vitreous VF levels were markedly higher in patients with PDR compared to control subjects, as well as diabetic patients without DR and those with non-proliferative diabetic retinopathy (NPDR). Furthermore, vitreous VF levels were higher in NPDR patients than in diabetic patients without DR [ 21 ]. Similarly, in our study, serum and vitreous VF levels were found to be significantly greater in the case group than in the control group. a-FABP is a variant of fatty acid-binding proteins, predominantly found in adipose tissue and macrophages. The function of a-FABP includes binding to hydrophobic molecules like long-chain fatty acids and aiding in their transport to designated cellular compartments, in a study conducted by Hui et al. [ 22 ]. Another study found that a-FABP exhibits proinflammatory properties resembling those of C-reactive protein (CRP) in relation to insulin resistance [ 23 ]. In a study conducted by Kaku Itoh, Masato Furuhashi, and colleagues, vitreous samples obtained from 20 patients who underwent vitrectomy for PDR presented FABP4 levels were considerably elevated compared to those in the control group [ 24 ]. In our study, a-FABP levels in serum samples from diabetic patients were greater than those in the control group. Similarly, vitreous a-FABP levels were notably higher in diabetic patients compared to the control group. Apelin is an adipokine that has recently become a focus of interest. There are only a few studies available in the literature on this protein. It has been demonstrated that apelin expression in adipocytes increases in various mouse obesity models associated with hyperinsulinemia [ 16 ]. In mice, apelin expression in adipocytes during fasting and refeeding parallels plasma insulin levels. Additionally, a previous study investigated apelin levels in retinopathies secondary to hypoxia in a rat model. Collectively, these findings strongly suggest that the apelin/APJ system could be a key factor in pathological retinal angiogenesis [ 25 ]. Blocking this system could present new therapeutic possibilities for treating ischemic retinopathy. In our study, the median serum apelin level in the control group was 44.7 ng/L (46.9 (± 16.6) ng/L), which was significantly lower than the median serum apelin level of 90.6 ng/L (89.2 (± 33.5) ng/L) in the PDR group ( p < 0.001). Similarly, the median vitreous apelin level in the diabetic group was 90.1 ng/L (199 (± 284.5) ng/L), which was significantly greater than the median vitreous apelin level of 21.8 ng/L (29.3 (± 22.2) ng/L) in the control group ( p < 0.001). To our knowledge, no studies in the literature have investigated apelin levels in vitreous. This study aimed to clarify the involvement of PVAT-derived adipokines in the development of DR. We propose that these adipokines may emerge as novel biomarkers for predicting DR development, assessing its progression, and assisting in its classification. Furthermore, these proteins hold promise as potential therapeutic targets for DR treatment. Declarations SUMMARY A study has been performed to elucidate the role of PVAT-derived adipokines, including adiponectin, apelin, a-FABP, and visfatin, in the pathogenesis of diabetic retinopathy. COMPETING INTERESTS The authors confirm that they have no financial affiliations or conflicts of interest relevant to this manuscript ACKNOWLEDGMENTS The authors appreciate the English language editing support provided by professional language editing services, which helped enhance the quality of this manuscript. References Teo ZL, Tham YC, Yu M, Chee ML, Rim TH, Cheung N, et al. Global prevalence of diabetic retinopathy and projection of burden through 2045. Ophthalmology 2021;128:1580–1591. Balakumar P, Alqahtani A, Khan NA, Alqahtani T, Thangathirupathi A, Jagadeesh G . The physiologic and physiopathologic roles of perivascular adipose tissue and its interactions with blood vessels and the renin-angiotensin system. Pharmacol Res 2021;173:105890. Luo N, Liu J, Chung BH, Yang Q, Klein RL, Garvey WT, et al. Macrophage adiponectin expression improves insulin sensitivity and protects against inflammation and atherosclerosis. Diabetes 2010;59:791–799. Lin T, He F, Lei B. Expressions of adiponectin and its receptors in the retina of normal and type 1 diabetic mice. Nan Fang Yi Ke Da Xue Xue Bao 2012;32:1543–1547. Palanisamy K, Nareshkumar RN, Sivagurunathan S, Raman R, Sulochana KN, Chidambaram S. Anti-angiogenic effect of adiponectin in human primary microvascular and macrovascular endothelial cells. Microvasc Res 2019;122:136–145. Srinivasan V, Chidambaram S, Karunakaran C, Rishi P, Konerirajapuram S.Measurement of adiponectin in vitreous and plasma of patients with proliferative diabetic retinopathy and its correlation with vascular endothelial growth factor, pigment epithelial derived factor and insulin like growth factor-1. Int J Pharma Bio Sci 2013;4:B993–B1005. Kim MK, Lee JH, Kim H, Park SJ, Kim SH, Kang GB, et al. Crystal structure of visfatin/Pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866. J Mol Biol 2006;362:66–77 Gunduz FO, Yildirmak ST, Temizel M, Faki Y, Cakmak M, Durmuscan M, et al. Serum visfatin and fetuin-a levels and glycemic control in patients with obese type 2 diabetes mellitus. Diabetes Metab J 2011;35:523–528. de Luis DA, Aller R, Gonzalez Sagrado M, Conde R, Izaola O, Perez Castrillon JL, et al. Serum visfatin concentrations are related to dietary intake in obese patients. Ann Nutr Metab 2010;57:265–270. Stejskal D, Karpisek M. Adipocyte fatty acid binding protein in a Caucasian population: a new marker of metabolic syndrome? Eur J Clin Investig 2006;36:621–625. Zhang XZ, Tu WJ, Wang H, Zhao Q, Liu Q, Sun L, et al. Circulating serum fatty acid-binding protein 4 levels predict the development of diabetic retinopathy in type 2 diabetic patients. Am J Ophthalmol 2018;187:71–79. Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 1998;251:471–476. Tatemoto K, Zou MX, Takayama K, Yu X, Kumano K, Fujimiya M. Apelin: a novel regulatory peptide discovered as an endogenous ligand for the orphan G protein-coupled receptor APJ. Regul Pept 2000;94:4. Boucher J, Masri B, Daviaud D, Gesta S, Guigné C, Mazzucotelli A, et al. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology 2005;146:1764–1771. Y, Bai YJ, Jiang YR, Yu WZ, Shi X, Chen L, et al. Apelin-13 Is an early promoter of cytoskeleton and tight junction in diabetic macular edema via PI-3K/Akt and MAPK/Erk signaling pathways. BioMed Res Int 2018;2018:3242574. Yue P, Jin H, Aillaud M, Deng AC, Azuma J, Asagami T, et al. Apelin is necessary for the maintenance of insulin sensitivity. Am J Physiol, Endocrinol Metab 2010;298:E59–E67. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137–149. Bråkenhielm E, Veitonmäki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, et al. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A 2004;101:2476–2481. Yilmaz MI, Sonmez A, Acikel C, Celik T, Bingol N, Pinar M, et al. Adiponectin may play a part in the pathogenesis of diabetic retinopathy. Eur J Endocrinol 2004;151:135–140. Park JW, Kim WH, Shin SH, Kim JY, Yun MR, Park KJ, et al. Visfatin exerts angiogenic effects on human umbilical vein endothelial cells through the mTOR signaling pathway. Biochim Biophys Acta (BBA) Mol Cell Res 2011;1813:763–771. Wang Y, Yuan Y, Jiang H. Serum and vitreous levels of visfatin in patients with diabetic retinopathy. Med Sci Monit Int Med J Exp Clin Res 2014;20:2729–2732. Hui X, Li H, Zhou Z, Lam KS, Xiao Y, Wu D, et al. Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1. J Biol Chem 2010;285:10273–10280. Horakova D, Pastucha D, Stejskal D, Kollarova H, Azeem K, Janout V . Adipocyte fatty acid binding protein and C-reactive protein levels as indicators of insulin resistance development. Biomed Pap 2011;155:355–359. Itoh K, Furuhashi M, Ida Y, Ohguro H, Watanabe M, Suzuki S, et al. Detection of significantly high vitreous concentrations of fatty acid-binding protein 4 in patients with proliferative diabetic retinopathy. Sci Rep 2021;11:12382. Kasai A. Pathological role of apelin in angiogenic eye disease. Yakugaku Zasshi 2011;131:1201–1206. Tables Table 1: Demographic Characteristics of The Patients Control Group Case Group p-Value Mean±SD/n-% Median Mean.±SD/n-% Median Age 58.5 ± 11.4 57.5 54.0 ± 9.0 55.5 0.168 † Sex Female 9 40.9% 14 63.6% 0.131 * Male 13 59.1% 8 36.4% *Chi-squared test / † Mann-whitney u test Table 2. Comparison of ADP levels in serum and vitreous Control Group Case Group p-Value Mean±SD/n-% Median Mean.±SD/n-% Median ADP Serum 25.8 ± 12.7 26.0 13.9 ± 5.6 13.2 0.003 † Vitreous 59.1 ± 69.8 38.7 8.9 ± 7.2 5.6 0.000 † Difference 32.4 ± 72.5 20.0 -4.4 ± 7.8 -6.1 0.037 † Within-Group Difference p-Value 0.058 ‡ 0.023 ‡ †Mann-whitney u test / ‡ Wilcoxon test Table 3. Comparison of Apelin levels in serum and vitreous Control Group Case Group p-Value Mean±SD/n-% Median Mean±SD/n-% Median Apelin Serum 89.2 ± 33.5 90.6 46.9 ± 16.6 44.7 0.000 † Vitreous 199.0 ± 284.5 90.1 29.3 ± 22.2 21.8 0.000 † Difference 124.5 ± 291.0 48.0 -16.3 ± 28.8 -25.0 0.005 † Within-Group Difference p-Value 0.059 ‡ 0.020 ‡ †Mann-whitney u test / ‡ Wilcoxon test Table 4. Comparison of a-FABP levels in serum and vitreous Control Group Case Group p-Value Mean±SD/n-% Median Mean±SD/n-% Median A-FABP Serum 19.9 ± 6.3 22.1 17.0 ± 2.9 17.4 0.025 † Vitreous 18.2 ± 19.2 13.7 4.4 ± 4.6 3.3 0.002 † Difference -0.69 ± 20.4 -6.2 -12.6 ± 5.5 -14.0 0.009 † Within-Group Difference p-Value 0.159 ‡ 0.000 ‡ †Mann-whitney u test / ‡Wilcoxon test Table 5. Comparison of VF levels in serum and vitreous Control Group Case Group p-value Mean±SD/n-% Median Mean±SD/n-% Median VF Serum 5.9 ± 3.5 5.9 3.4 ± 2.2 2.5 0.003 † Vitreous 9.8 ± 11.6 6.1 1.3 ± 0.77 1.08 0.000 † Difference 3.7 ± 11.6 2.4 -2.1 ± 2.4 -1.4 0.025 † Within-Group Difference p-Value 0.217 ‡ 0.000 ‡ †Mann-whitney u test / ‡ Wilcoxon test Additional Declarations There is no conflict of interest Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6614523","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":471755009,"identity":"21cafcf2-c143-4cf4-9d5a-d6d4e3ec0aa6","order_by":0,"name":"Tuna Ozan Dogan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYDCCA3AWM4gpIUOEFmYYiy0BpIWHFC08BmCSoA6+2+ePSRfU2Njzz+75/OpGjQUPA/vhoxvwaZE8l8wmPeNYGrPEnbPbrHOOAR3Gk5Z2A58WgzPMbNI8bIfZGG7kbjPOYQNqkeAxI0LLv8M88jdynhnn/CNWC2/bYQmDGznMj3PbiNAieYbZ2Jq3L83A8EaaGXNunwQPGyG/8J1hfHib55uNvdyN5Mefc77VyfGzHz6GVwsyYJMAk8QqBwHmD6SoHgWjYBSMgpEDAL6SQQ4GKKsVAAAAAElFTkSuQmCC","orcid":"","institution":"University of Health Sciences Turkey, Beyoglu Eye Training and Research Hospital","correspondingAuthor":true,"prefix":"","firstName":"Tuna","middleName":"Ozan","lastName":"Dogan","suffix":""},{"id":471755010,"identity":"2309cc85-5f12-43c8-83e9-474249fd0fab","order_by":1,"name":"Ozgur Artunay","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ozgur","middleName":"","lastName":"Artunay","suffix":""},{"id":471755011,"identity":"872287bf-f5a0-45a3-b67c-ce858885521e","order_by":2,"name":"Erdem Erdoğdu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Erdem","middleName":"","lastName":"Erdoğdu","suffix":""},{"id":471755012,"identity":"444f16ad-c97b-4465-919f-ea9a04a870cc","order_by":3,"name":"Şehnaz Özçalışkan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Şehnaz","middleName":"","lastName":"Özçalışkan","suffix":""},{"id":471755013,"identity":"5174b822-7b58-4048-b380-8c28f18590c3","order_by":4,"name":"Kübra Bozali","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Kübra","middleName":"","lastName":"Bozali","suffix":""},{"id":471755014,"identity":"54692e45-36a6-4085-81c9-0aaf869d4328","order_by":5,"name":"Eray Guler","email":"","orcid":"https://orcid.org/0000-0003-4351-1719","institution":"Bezmialem Vakif University","correspondingAuthor":false,"prefix":"","firstName":"Eray","middleName":"","lastName":"Guler","suffix":""}],"badges":[],"createdAt":"2025-05-07 18:45:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6614523/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6614523/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91348719,"identity":"d13a7916-ac18-4e9e-aef5-26e1946147e7","added_by":"auto","created_at":"2025-09-15 14:15:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":685901,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6614523/v1/ff51c973-6a2b-4690-834e-32a10f077f20.pdf"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Unveiling the mechanisms of proliferative diabetic retinopathy: PVAT-derived inflammatory and angiogenic mediators as potential biomarkers in vitreous and serum","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eDiabetes is a significant public health issue, and one of its most critical microvascular complications is diabetic retinopathy (DR). More than 100\u0026nbsp;million people worldwide are affected by DR [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The pathogenesis of DR involves a complex interplay of inflammatory, angiogenic, and apoptotic cascades. Despite extensive research, the underlying mechanisms remain incompletely understood. Recent studies have emphasized the significance of perivascular adipose tissue (PVAT), which encases blood vessels, in regulating vascular homeostasis. The impact of PVAT-derived adipokines, including adiponectin (ADP), visfatin (VF), fatty acid binding protein (a-FABP) and apelin, on cardiovascular, renal and large vessel pathologies has been well documented [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdiponectin (ADP), a vasodilatory adipokine present in high concentrations in human circulation, has been linked to a lower risk of type 2 diabetes, enhanced insulin sensitivity, and improved vascular function. ADP has the potential to lower proinflammatory cytokine levels while also exerting a beneficial effect on insulin signaling pathways [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Under normal conditions, the expression ADP in humans, as assessed by enzyme-linked immunosorbent assay (ELISA), has been shown to be significantly greater in the RPE layer, choroid than in the neural retinal layers [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Studies indicate that ADP can suppress retinal neovascularization by preventing basal tube formation in primary cultures of umbilical vein, human retinal microvascular endothelial cells, and choroidal endothelial cells [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Therefore, ADP may serve as a therapeutic target in the treatment of angiogenesis. This effect is linked to the altered function of vascular endothelial growth factor, a key contributor to angiogenesis in diabetic retinopathy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVisfatin (VF) is a 52-kDa protein with a dimeric structure consisting of two monomers, each containing 491 amino acids in humans [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Primarily synthesized and secreted by visceral fat, VF is a novel adipokine involved in inflammatory responses, lipid metabolism regulation, differentiation promotion, participation in the atherosclerosis process. Hyperglycemia increases plasma VF levels, and this increase worsens as hyperglycemia progresses. Other studies have demonstrated that glucose concentrations exceeding 8.3 mmol/L significantly increase plasma VF levels in healthy men [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The increase in plasma VF levels observed under hyperglycemic conditions is likely associated with oxidative stress. Hyperglycemia is widely recognized for promoting the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which in turn initiate oxidative stress, leading to abnormal gene expression, impaired signal transduction, and apoptosis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, whether VF induces neovascularization in diabetic patients and the underlying mechanisms remain uncertain.\u003c/p\u003e \u003cp\u003eFatty acid binding protein 4 (FABP4) belongs to a family of lipid chaperones characterized by proteins with a molecular weight of approximately 14\u0026ndash;15 kDa. FABPs facilitate the transport of lipid molecules to different intracellular compartments, contributing to processes like oxidation, signaling, gene transcription regulation, and storage [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. More than nine FABPs have been identified, with FABP4 being produced primarily by adipocytes and macrophages. A recent single-cell transcriptome analysis of the human retina identified the expression of multiple FABPs in different retinal cell types, indicating their potential involvement in both normal physiological functions and pathological conditions [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Our understanding of the role of FABPs in retinal physiology and pathology is still incomplete.\u003c/p\u003e \u003cp\u003eApelin-77 (pre-pro-apelin) acts as a precursor to multiple pharmacologically active apelin isoforms (e.g., apelin-12, 13, 17, 36), with homologs found in both humans and mice [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Tatemoto et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and Boucher et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] revealed that apelin is both synthesized and secreted by adipocytes. In humans, apelin gene expression in adipose tissue is influenced by hyperinsulinemia, which also enhances apelin secretion through pathways dependent on protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K) 15]. Apelin expression in adipocytes has been shown to increase in mouse obesity models associated with hyperinsulinemia [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This study aims to identify the specific stages at which PVAT-associated adiponectin and other adipokines contribute to the pathogenesis of diabetic retinopathy.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis study included 44 patients who were evaluated at the Retina Unit of Beyoglu Eye Training and Research Hospital, University of Health Sciences Turkey, between February and April 2023. The study group comprised 22 patients diagnosed with PDR and scheduled for vitreoretinal surgery due to tractional retinal detachment (TRD) and/or vitreous hemorrhage. The control group consisted of 22 patients with idiopathic macular holes (MHs) or vitreomacular traction (VMT) requiring surgery, with no history of systemic disease.\u003c/p\u003e \u003cp\u003eEthical approval was granted by the Hamidiye Scientific Research Ethics Committee of University Health Sciences, Turkey. All participants received detailed information about the study\u0026rsquo;s objectives and procedures, and written informed consent was secured prior to enrollment. Patients with ocular conditions associated with increased inflammation or oxidative stress, including uveitis, glaucoma, and age-related macular degeneration, were excluded. Individuals with a history of prior ocular surgery (except cataract surgery) or trauma were also excluded. To ensure homogeneity, the control group excluded individuals with systemic diseases, and pediatric patients (\u0026lt;\u0026thinsp;18 years) were not included in either group.\u003c/p\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSample collection\u003c/h2\u003e \u003cp\u003ePars plana vitrectomy (PPV) was used for vitreous sample collection. Undiluted vitreous fluid samples were obtained via an aspiration cannula immediately after three-port trocar insertion and subsequent vitrectomy. A minimum of 100 \u0026micro;L vitreous fluid was collected in microcentrifuge tubes (Eppendorf\u0026reg;) for further analysis. Peripheral blood samples were drawn from all participants before surgery and centrifuged at 3 000 \u0026times; rpm (10 minutes) to isolate serum.\u003c/p\u003e \u003cp\u003eThe sample collection process lasted approximately two months. The collected samples were stored in a -80\u0026deg;C freezer to preserve their integrity. All samples were collected by specialist ophthalmologists in the retina unit, with no complications arising from vitreous fluid collection during any of the surgeries. Owing to ethical considerations, vitreous fluid was not collected from healthy individuals without an ocular condition requiring surgery. Thus, the control group included patients with idiopathic MHs and VMT who were scheduled for surgery and had no systemic diseases. The samples were transferred under appropriate transport conditions to the Department of Medical Biochemistry, Hamidiye Faculty of Medicine, University of Health Sciences, where the analyses were conducted.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProtein measurement in vitreous samples\u003c/h3\u003e\n\u003cp\u003eVitreous protein concentrations were measured using a colorimetric assay (E-BC-K318-M, Elabscience, Houston, Texas, USA). Total protein concentration was quantified via a bicinchoninic acid assay (BCA), which relies on the reduction of Cu\u0026sup2;⁺ to Cu⁺ by proteins under alkaline conditions, forming a colorimetric complex with BCA reagent that absorbs maximally at 562 nm. This assay operates on the principle that protein molecules bind to Coomassie dye under acidic conditions, causing a color change from brown to blue. Under alkaline conditions, Cu\u0026sup2;⁺ is reduced to Cu⁺ by proteins, leading to the formation of a purple complex with the BCA reagent, which exhibits a peak absorbance at 562 nm. The absorbance is directly proportional to the protein concentration, enabling protein quantification based on optical density (OD).\u003c/p\u003e \u003cp\u003eFor the analysis, 20 \u0026micro;L vitreous samples diluted 1:10 in 1x PBS were added to microplate wells. Subsequently200 \u0026micro;L of BCA solution was introduced, and the plates were kept at 37\u0026deg;C for 30 minutes for incubation. The samples were then measured at 562 nm using a spectrophotometer (BioTek, Synergy\u0026trade; HTX Multi-Mode Reader). Protein concentrations were determined by comparison with a standard curve.\u003c/p\u003e\n\u003ch3\u003eELISA analysis\u003c/h3\u003e\n\u003cp\u003eSerum and vitreous levels of ADP, apelin, a-FABP, and VF were quantified utilizing enzyme-linked immunosorbent assay (ELISA) kits (Apelin: SunRed 201-12-2015; ADP: SunRed 201-12-1551; a-FABP: SunRed 201-12-2015; Visfatin: SunRed 201-12-0026), following the manufacturer\u0026rsquo;s protocols. For each analysis, 40 \u0026micro;L of each serum sample and 10 \u0026micro;L of the apelin/ADP/a-FABP/VF antibodies were added to the microplate, followed by the addition of 50 \u0026micro;L of streptavidin-HRP. The plates were kept at 37\u0026deg;C for 60 minutes. Following incubation, the wells were rinsed five times with the washing solution. Next, 50 \u0026micro;L of substrate A and 50 \u0026micro;L of substrate B were introduced into each well, followed by incubation at 37\u0026deg;C for 10 minutes in a dark setting. The reaction was terminated by adding 50 \u0026micro;L of stop solution to each well, and absorbance was recorded at 450 nm using a spectrophotometer. (BioTek, Synergy\u0026trade; HTX Multi-Mode Reader). The levels of apelin, ADP, a-FABP, and VF in vitreous samples were normalized to total protein concentrations and expressed as mg of protein.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThis study included a total of 44 patients: 22 patients diagnosed with PDR who underwent surgery and 22 patients in the control group, consisting of individuals diagnosed with idiopathic ERMs or MHs who had no systemic diseases and were scheduled for surgery. Out of the participants, 23 (52.3%) were female, while 21 (47.7%) were male. The average age of the PDR group was 54.0 (±9.0) years, while the control group had a mean age of 58.4 (±11.4) years. The clinical and demographic characteristics of the patients are shown in Table 1. There was no notable variation in age or gender distribution between the PDR and control groups. (\u003cem\u003ep\u0026gt;\u003c/em\u003e0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSerum and vitreous ADP levels\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, the median serum ADP level in the diabetic group was 13.2 ng/L (13.9 (±5.6) ng/L), which was significantly lower than the median serum ADP level of 26.0 ng/L (25.8 (±12.7) ng/L) in the control group (\u003cem\u003ep=\u003c/em\u003e0.003). Similarly, the median vitreous ADP level in the diabetic group was 5.6 ng/L (8.9 (±7.2) ng/L), which was significantly lower than the median vitreous ADP level of 38.7 ng/L (59.1 (±69.8) ng/L) in the control group (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.001). No notable difference was detected in vitreous and serum ADP levels within the control group. (\u003cem\u003ep\u0026gt;\u003c/em\u003e0.05), vitreous ADP levels were significantly lower than serum ADP levels in the diabetic group (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.05). Moreover, the variation in serum and vitreous ADP levels between the groups reached statistical significance\u0026nbsp;(\u003cem\u003ep\u0026lt;\u003c/em\u003e0.05), with the control group exhibiting higher vitreous ADP levels and the diabetic group displaying higher serum ADP levels (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSerum and vitreous apelin levels\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median serum apelin level in the diabetic group was 90.6 ng/L (89.2 (±33.5) ng/L), which was significantly greater than the median serum apelin level of 44.7 ng/L (46.9 (±16.6) ng/L) in the control group (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.001). Similarly, the median vitreous apelin level in the diabetic group was 90.1 ng/L (199 (±284.5) ng/L), which was significantly greater than the median vitreous apelin level of 21.8 ng/L (29.3 (±22.2) ng/L) in the control group (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.001). No notable difference was detected between the vitreous and serum apelin levels in the control group (\u003cem\u003ep\u0026gt;\u003c/em\u003e0.05). However, the vitreous apelin level was significantly higher in the diabetic group compared to the control group. (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.05). The difference in serum and vitreous apelin levels between the groups was statistically significant (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.05), with higher apelin levels observed in both serum and vitreous in the diabetic group compared to the control group. (Table 3)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSerum and vitreous a-FABP levels\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median serum a-FABP level in the diabetic group was 22.1 ng/L (19.9 (±6.3) ng/L), which was significantly greater than the median serum a-FABP level of 17.4 ng/L (17.0 (±2.9) ng/L) in the control group (\u003cem\u003ep=\u003c/em\u003e0.025). Similarly, the median vitreous a-FABP level in the diabetic group was 13.7 ng/L (18.2 (±19.2) ng/L), which was significantly greater than the median vitreous a-FABP level of 3.3 ng/L (4.4 (±4.6) ng/L) in the control group (\u003cem\u003ep=\u003c/em\u003e0.002). No notable difference was found between vitreous and serum a-FABP levels in the diabetic group. (\u003cem\u003ep\u0026gt;\u003c/em\u003e0.05), whereas vitreous a-FABP levels were significantly lower than serum a-FABP levels in the control group (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.05). The difference in serum and vitreous a-FABP levels was statistically significant between the groups (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.05), with a greater reduction in vitreous a-FABP levels in the control group than diabetic group (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSerum and vitreous VF levels\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median serum VF level in the diabetic group was 5.9 ng/L (5.9 (±3.5) ng/L), which was significantly greater than the median serum VF level of 2.5 ng/L (3.4 (±2.2) ng/L) in control group (\u003cem\u003ep=\u003c/em\u003e0.003). Similarly, the median vitreous VF level in the diabetic group was 6.1 ng/L (9.8 (±11.6) ng/L), which was significantly greater than the median vitreous VF level of 1.08 ng/L (1.3 (±0.77) ng/L) in the control group (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.001). No significant variation was observed between vitreous and serum VF levels in the diabetic group (\u003cem\u003ep\u0026gt;\u003c/em\u003e0.05); however, the vitreous VF levels were significantly lower than the serum VF levels in the control group (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.05). The variation in serum and vitreous VF levels across the groups was statistically significant (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.05), with higher VF levels detected in both serum and vitreous in the diabetic group compared to the control group. (Table 5)\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe worldwide incidence of diabetes has been rising at a concerning pace. On the basis of current data, The International Diabetes Federation estimates that the number of people living with diabetes will rise to 592\u0026nbsp;million by 2035 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Macrovascular and microvascular changes caused by diabetes are linked to a variety of pathways, and the underlying mechanisms of these changes have not been completely clarified yet. The primary objective of our study was to determine the role of PVAT-derived adipokines, including ADP, apelin, and a-FABP, VF in the pathophysiology of DR.\u003c/p\u003e \u003cp\u003eBr\u0026aring;kenhielm et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] demonstrated that ADP functions as an inhibitor of angiogenesis in various endothelial cells, including human dermal microvascular, bovine capillary, and porcine aortic endothelial cells, by suppressing VEGF- or FGF-2-induced proliferation. In 2004, Yılmaz et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] reported reduced serum ADP levels in patients with PDR. In our study, the serum ADP level in patients diagnosed with PDR (13.9 (\u0026plusmn;\u0026thinsp;5.6 ng/L) was also lower than that in the control group (25.8 (\u0026plusmn;\u0026thinsp;12.7) ng/L). Compared with the methods in the literature, no differences were observed in the methods used for serum ADP measurement; ELISA was utilized in our study, which is consistent with previous research.\u003c/p\u003e \u003cp\u003eIn 2013, Srinivasan et al. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] examined ADP levels in the vitreous of DR patients were found to be elevated compared to those in the control group. The authors attributed this paradoxical increase to the protective effects of ADP. In contrast, our study revealed significantly lower vitreous ADP levels in patients with PDR (8.9 (\u0026plusmn;\u0026thinsp;7.2) ng/L) than in the control group (59.1 (\u0026plusmn;\u0026thinsp;69.8) ng/L) (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A recent research has shown that VF promotes angiogenesis in endothelial cell human umbilical vein by triggering signaling pathways that engage the mammalian target of rapamycin 20]. Thus, VF could contribute to the development of DR. To date, only one study has examined serum and vitreous VF levels in DR patients. This study is the first to explore the association between serum and vitreous VF levels and the presence and severity of DR. The findings revealed that serum and vitreous VF levels were markedly higher in patients with PDR compared to control subjects, as well as diabetic patients without DR and those with non-proliferative diabetic retinopathy (NPDR). Furthermore, vitreous VF levels were higher in NPDR patients than in diabetic patients without DR [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Similarly, in our study, serum and vitreous VF levels were found to be significantly greater in the case group than in the control group.\u003c/p\u003e \u003cp\u003ea-FABP is a variant of fatty acid-binding proteins, predominantly found in adipose tissue and macrophages. The function of a-FABP includes binding to hydrophobic molecules like long-chain fatty acids and aiding in their transport to designated cellular compartments, in a study conducted by Hui et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Another study found that a-FABP exhibits proinflammatory properties resembling those of C-reactive protein (CRP) in relation to insulin resistance [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In a study conducted by Kaku Itoh, Masato Furuhashi, and colleagues, vitreous samples obtained from 20 patients who underwent vitrectomy for PDR presented FABP4 levels were considerably elevated compared to those in the control group [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In our study, a-FABP levels in serum samples from diabetic patients were greater than those in the control group. Similarly, vitreous a-FABP levels were notably higher in diabetic patients compared to the control group.\u003c/p\u003e \u003cp\u003eApelin is an adipokine that has recently become a focus of interest. There are only a few studies available in the literature on this protein. It has been demonstrated that apelin expression in adipocytes increases in various mouse obesity models associated with hyperinsulinemia [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In mice, apelin expression in adipocytes during fasting and refeeding parallels plasma insulin levels. Additionally, a previous study investigated apelin levels in retinopathies secondary to hypoxia in a rat model. Collectively, these findings strongly suggest that the apelin/APJ system could be a key factor in pathological retinal angiogenesis [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Blocking this system could present new therapeutic possibilities for treating ischemic retinopathy. In our study, the median serum apelin level in the control group was 44.7 ng/L (46.9 (\u0026plusmn;\u0026thinsp;16.6) ng/L), which was significantly lower than the median serum apelin level of 90.6 ng/L (89.2 (\u0026plusmn;\u0026thinsp;33.5) ng/L) in the PDR group ( \u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001). Similarly, the median vitreous apelin level in the diabetic group was 90.1 ng/L (199 (\u0026plusmn;\u0026thinsp;284.5) ng/L), which was significantly greater than the median vitreous apelin level of 21.8 ng/L (29.3 (\u0026plusmn;\u0026thinsp;22.2) ng/L) in the control group (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001). To our knowledge, no studies in the literature have investigated apelin levels in vitreous.\u003c/p\u003e \u003cp\u003eThis study aimed to clarify the involvement of PVAT-derived adipokines in the development of DR. We propose that these adipokines may emerge as novel biomarkers for predicting DR development, assessing its progression, and assisting in its classification. Furthermore, these proteins hold promise as potential therapeutic targets for DR treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eSUMMARY\u003c/h2\u003e \u003cp\u003eA study has been performed to elucidate the role of PVAT-derived adipokines, including adiponectin, apelin, a-FABP, and visfatin, in the pathogenesis of diabetic retinopathy.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCOMPETING INTERESTS\u003c/h2\u003e \u003cp\u003eThe authors confirm that they have no financial affiliations or conflicts of interest relevant to this manuscript\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eACKNOWLEDGMENTS\u003c/h2\u003e \u003cp\u003eThe authors appreciate the English language editing support provided by professional language editing services, which helped enhance the quality of this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTeo ZL, Tham YC, Yu M, Chee ML, Rim TH, Cheung N, et al. Global prevalence of diabetic retinopathy and projection of burden through 2045. Ophthalmology 2021;128:1580\u0026ndash;1591.\u003c/li\u003e\n\u003cli\u003eBalakumar P, Alqahtani A, Khan NA, Alqahtani T, Thangathirupathi A, Jagadeesh G . The physiologic and physiopathologic roles of perivascular adipose tissue and its interactions with blood vessels and the renin-angiotensin system. Pharmacol Res 2021;173:105890.\u003c/li\u003e\n\u003cli\u003eLuo N, Liu J, Chung BH, Yang Q, Klein RL, Garvey WT, et al. Macrophage adiponectin expression improves insulin sensitivity and protects against inflammation and atherosclerosis. Diabetes 2010;59:791\u0026ndash;799.\u003c/li\u003e\n\u003cli\u003eLin T, He F, Lei B. Expressions of adiponectin and its receptors in the retina of normal and type 1 diabetic mice. Nan Fang Yi Ke Da Xue Xue Bao 2012;32:1543\u0026ndash;1547.\u003c/li\u003e\n\u003cli\u003ePalanisamy K, Nareshkumar RN, Sivagurunathan S, Raman R, Sulochana KN, Chidambaram S. Anti-angiogenic effect of adiponectin in human primary microvascular and macrovascular endothelial cells. Microvasc Res 2019;122:136\u0026ndash;145.\u003c/li\u003e\n\u003cli\u003eSrinivasan V, Chidambaram S, Karunakaran C, Rishi P, Konerirajapuram S.Measurement of adiponectin in vitreous and plasma of patients with proliferative diabetic retinopathy and its correlation with vascular endothelial growth factor, pigment epithelial derived factor and insulin like growth factor-1. Int J Pharma Bio Sci 2013;4:B993\u0026ndash;B1005.\u003c/li\u003e\n\u003cli\u003eKim MK, Lee JH, Kim H, Park SJ, Kim SH, Kang GB, et al. Crystal structure of visfatin/Pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866. J Mol Biol 2006;362:66\u0026ndash;77\u003c/li\u003e\n\u003cli\u003eGunduz FO, Yildirmak ST, Temizel M, Faki Y, Cakmak M, Durmuscan M, et al. Serum visfatin and fetuin-a levels and glycemic control in patients with obese type 2 diabetes mellitus. Diabetes Metab J 2011;35:523\u0026ndash;528.\u003c/li\u003e\n\u003cli\u003ede Luis DA, Aller R, Gonzalez Sagrado M, Conde R, Izaola O, Perez Castrillon JL, et al. Serum visfatin concentrations are related to dietary intake in obese patients. Ann Nutr Metab 2010;57:265\u0026ndash;270.\u003c/li\u003e\n\u003cli\u003eStejskal D, Karpisek M. Adipocyte fatty acid binding protein in a Caucasian population: a new marker of metabolic syndrome? Eur J Clin Investig 2006;36:621\u0026ndash;625.\u003c/li\u003e\n\u003cli\u003eZhang XZ, Tu WJ, Wang H, Zhao Q, Liu Q, Sun L, et al. Circulating serum fatty acid-binding protein 4 levels predict the development of diabetic retinopathy in type 2 diabetic patients. Am J Ophthalmol 2018;187:71\u0026ndash;79.\u003c/li\u003e\n\u003cli\u003eTatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 1998;251:471\u0026ndash;476.\u003c/li\u003e\n\u003cli\u003eTatemoto K, Zou MX, Takayama K, Yu X, Kumano K, Fujimiya M. Apelin: a novel regulatory peptide discovered as an endogenous ligand for the orphan G protein-coupled receptor APJ. Regul Pept 2000;94:4.\u003c/li\u003e\n\u003cli\u003eBoucher J, Masri B, Daviaud D, Gesta S, Guign\u0026eacute; C, Mazzucotelli A, et al. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology 2005;146:1764\u0026ndash;1771.\u003c/li\u003e\n\u003cli\u003eY, Bai YJ, Jiang YR, Yu WZ, Shi X, Chen L, et al. Apelin-13 Is an early promoter of cytoskeleton and tight junction in diabetic macular edema via PI-3K/Akt and MAPK/Erk signaling pathways. BioMed Res Int 2018;2018:3242574.\u003c/li\u003e\n\u003cli\u003eYue P, Jin H, Aillaud M, Deng AC, Azuma J, Asagami T, et al. Apelin is necessary for the maintenance of insulin sensitivity. Am J Physiol, Endocrinol Metab 2010;298:E59\u0026ndash;E67.\u003c/li\u003e\n\u003cli\u003eGuariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137\u0026ndash;149.\u003c/li\u003e\n\u003cli\u003eBr\u0026aring;kenhielm E, Veitonm\u0026auml;ki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, et al. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A 2004;101:2476\u0026ndash;2481.\u003c/li\u003e\n\u003cli\u003eYilmaz MI, Sonmez A, Acikel C, Celik T, Bingol N, Pinar M, et al. Adiponectin may play a part in the pathogenesis of diabetic retinopathy. Eur J Endocrinol 2004;151:135\u0026ndash;140.\u003c/li\u003e\n\u003cli\u003ePark JW, Kim WH, Shin SH, Kim JY, Yun MR, Park KJ, et al. Visfatin exerts angiogenic effects on human umbilical vein endothelial cells through the mTOR signaling pathway. Biochim Biophys Acta (BBA) Mol Cell Res 2011;1813:763\u0026ndash;771.\u003c/li\u003e\n\u003cli\u003eWang Y, Yuan Y, Jiang H. Serum and vitreous levels of visfatin in patients with diabetic retinopathy. Med Sci Monit Int Med J Exp Clin Res 2014;20:2729\u0026ndash;2732.\u003c/li\u003e\n\u003cli\u003eHui X, Li H, Zhou Z, Lam KS, Xiao Y, Wu D, et al. Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1. J Biol Chem 2010;285:10273\u0026ndash;10280.\u003c/li\u003e\n\u003cli\u003eHorakova D, Pastucha D, Stejskal D, Kollarova H, Azeem K, Janout V . Adipocyte fatty acid binding protein and C-reactive protein levels as indicators of insulin resistance development. Biomed Pap 2011;155:355\u0026ndash;359.\u003c/li\u003e\n\u003cli\u003eItoh K, Furuhashi M, Ida Y, Ohguro H, Watanabe M, Suzuki S, et al. Detection of significantly high vitreous concentrations of fatty acid-binding protein 4 in patients with proliferative diabetic retinopathy. Sci Rep 2021;11:12382.\u003c/li\u003e\n\u003cli\u003eKasai A. Pathological role of apelin in angiogenic eye disease. Yakugaku Zasshi 2011;131:1201\u0026ndash;1206.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Demographic Characteristics of The Patients\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"595\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 176px;\"\u003e\n \u003cp\u003eControl Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 176px;\"\u003e\n \u003cp\u003eCase Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 93px;\"\u003e\n \u003cp\u003ep-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD/n-%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMean.\u0026plusmn;SD/n-%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e58.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e57.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e54.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e9.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e55.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e0.168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e40.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e63.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 52px;\"\u003e\n \u003cp\u003e0.131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 41px;\"\u003e\n \u003cp\u003e*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e59.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e36.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Chi-squared test / \u0026dagger; Mann-whitney u test\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Comparison of ADP levels in serum and vitreous\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"573\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 176px;\"\u003e\n \u003cp\u003eControl Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 176px;\"\u003e\n \u003cp\u003eCase Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 70px;\"\u003e\n \u003cp\u003ep-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD/n-%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMean.\u0026plusmn;SD/n-%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eADP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eSerum\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e25.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e12.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e26.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e13.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e5.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e13.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.003\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eVitreous\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e59.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e69.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e38.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e8.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e7.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e5.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.000\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eDifference\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e32.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e72.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e20.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e-4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e7.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.037\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eWithin-Group Difference p-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 116px;\"\u003e\n \u003cp\u003e0.058\u0026nbsp;\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.023\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"13\" valign=\"bottom\" style=\"width: 573px;\"\u003e\n \u003cp\u003e\u003csup\u003e\u0026nbsp;\u0026nbsp;\u003c/sup\u003e\u0026dagger;Mann-whitney u test / \u0026Dagger; Wilcoxon test\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 3. Comparison of Apelin levels in serum and vitreous\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"573\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 176px;\"\u003e\n \u003cp\u003eControl Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 176px;\"\u003e\n \u003cp\u003eCase Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 70px;\"\u003e\n \u003cp\u003ep-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD/n-%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD/n-%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eApelin\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eSerum\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e89.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e33.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e90.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e46.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e16.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e44.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.000\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eVitreous\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e199.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e284.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e90.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e29.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e22.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e21.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.000\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eDifference\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e124.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e291.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e48.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e-16.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e28.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.005\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eWithin-Group Difference p-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 116px;\"\u003e\n \u003cp\u003e0.059 \u0026nbsp;\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.020\u003c/em\u003e\u003c/strong\u003e\u0026nbsp; \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"13\" valign=\"bottom\" style=\"width: 573px;\"\u003e\n \u003cp\u003e\u0026dagger;Mann-whitney u test / \u0026nbsp;\u0026Dagger; Wilcoxon test\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 4. Comparison of a-FABP levels in serum and vitreous\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"573\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 176px;\"\u003e\n \u003cp\u003eControl Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 176px;\"\u003e\n \u003cp\u003eCase Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 70px;\"\u003e\n \u003cp\u003ep-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD/n-%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD/n-%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eA-FABP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eSerum\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e19.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e22.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e17.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e17.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.025\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eVitreous\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e18.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e19.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e13.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.002\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eDifference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e-0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e20.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-6.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e-12.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e5.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-14.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.009\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eWithin-Group Difference p-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 116px;\"\u003e\n \u003cp\u003e0.159 \u0026nbsp;\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.000\u003c/em\u003e\u003c/strong\u003e\u0026nbsp; \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"13\" valign=\"bottom\" style=\"width: 573px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026dagger;Mann-whitney u test / \u0026nbsp;\u0026Dagger;Wilcoxon test\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 5. Comparison of VF levels in serum and vitreous\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"573\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 176px;\"\u003e\n \u003cp\u003eControl Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\" style=\"width: 176px;\"\u003e\n \u003cp\u003eCase Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 70px;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD/n-%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD/n-%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 136px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eVF\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eSerum\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e3.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.003\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eVitreous\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e9.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e11.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e1.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.000\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eDifference\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e11.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e-2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e-1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.025\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 136px;\"\u003e\n \u003cp\u003eWithin-Group Difference p-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 116px;\"\u003e\n \u003cp\u003e0.217 \u0026nbsp;\u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.000\u003c/em\u003e\u003c/strong\u003e\u0026nbsp; \u0026Dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 52px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"13\" valign=\"bottom\" style=\"width: 573px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026dagger;Mann-whitney u test / \u0026nbsp;\u0026Dagger; Wilcoxon test\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"perivascular adipose tissue, proliferative diabetic retinopathy, vitreoretinal surgery","lastPublishedDoi":"10.21203/rs.3.rs-6614523/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6614523/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eOBJECTIVES\u003c/h2\u003e \u003cp\u003eThis study aimed to explore the role of perivascular adipose tissue (PVAT)-derived mediators in vitreous and serum samples from patients with proliferative diabetic retinopathy (PDR).\u003c/p\u003e\u003ch2\u003eMETHODS\u003c/h2\u003e \u003cp\u003eSerum and vitreous samples were prospectively collected between February and April 2023 from 22 patients undergoing surgery for PDR and 22 patients with macular hole (MH) or epiretinal membrane (ERM) as the control group. The levels of adiponectin (ADP), visfatin (VF), adipocyte fatty acid-binding protein (a-FABP), and apelin were analyzed.\u003c/p\u003e\u003ch2\u003eRESULTS\u003c/h2\u003e \u003cp\u003eThe serum and vitreous ADP levels in the PDR group were significantly lower than those in the control group (MH-ERM) (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.003 and \u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001). In contrast, the serum and vitreous apelin levels were significantly greater in the PDR group (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001). Serum and vitreous a-FABP levels were significantly increased in the PDR group compared with those in the control group (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.025 and \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.002,). VF levels in the serum and vitreous were significantly greater in the PDR group than in the control group (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.003 and \u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001, respectively).\u003c/p\u003e\u003ch2\u003eCONCLUSION\u003c/h2\u003e \u003cp\u003eChanges in ADP, apelin, a-FABP, and VF levels in serum and vitreous suggest their potential as novel biomarkers and therapeutic targets for PDR classification, disease progression assessment, and treatment strategies.\u003c/p\u003e","manuscriptTitle":"Unveiling the mechanisms of proliferative diabetic retinopathy: PVAT-derived inflammatory and angiogenic mediators as potential biomarkers in vitreous and serum","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 09:34:05","doi":"10.21203/rs.3.rs-6614523/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"12b750c9-3e5a-4c53-b1cf-b2395781f97b","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":50093534,"name":"Health sciences/Pathogenesis/Immunopathogenesis"},{"id":50093535,"name":"Health sciences/Medical research/Biomarkers/Prognostic markers"},{"id":50093536,"name":"Health sciences/Biomarkers/Prognostic markers"},{"id":50093537,"name":"Health sciences/Pathogenesis/Inflammation"}],"tags":[],"updatedAt":"2025-09-15T14:06:56+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-18 09:34:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6614523","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6614523","identity":"rs-6614523","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}