Pathogenesis Of Diabetic Macular Edema Research Articles

Beyond VEGF: Angiopoietin-Tie Signaling Pathway in Diabetic Retinopathy.

Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin-Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.

Evaluating Ocular Blood Flow in Diabetic Macular Edema using Three-dimensional Pseudocontinuous Arterial Spin Labeling.

Alterations in ocular blood flow play an important role in the pathogenesis of diabetic macular edema; however, this remains unclear. This study aimed to investigate ocular blood flow in eyes with or without diabetic macular edema using arterial spin labeling. This cross-sectional study included 118 eyes of 65 patients with diabetic retinopathy analyzed between November 2018 and December 2019. We included a total of 53 eyes without diabetic macular edema (mean [SD] age, 57.83 [7.23] years; 29 men [54.7%]) and 65 eyes with diabetic macular edema (mean [SD] age, 60.11 [7.63] years; 38 men [58.5%]). Using a 3.0-T magnetic resonance imaging, participants were imaged with arterial spin labeling with multiple post-labeling delays. The mean ocular blood flow at post-labeling delays of 1.5 and 2.5 s was significantly lower in eyes with diabetic macular edema among patients with diabetic retinopathy compared with the remaining subgroups (P=0.022 and P <0.001, respectively). The mean ocular blood flow exhibited a significant decrease in eyes with diabetic macular edema when the post-labeling delay was set at 2.5 s in the nonproliferative and proliferative diabetic retinopathy groups, compared with the remaining subgroups (P=0.005 and P=0.002, respectively). The cutoff points of ocular blood flow at post-labeling delays of 1.5 s and 2.5 s were 9.40 and 11.10 mL/100 g/min, respectively. Three-dimensional pseudocontinuous arterial spin labeling can identify differences in the ocular blood flow of patients with diabetic eyes with and without diabetic macular edema.

Diabetic Macular Edema Management: A Review of Anti-Vascular Endothelial Growth Factor (VEGF) Therapies.

Diabetic macular edema (DME) is a major cause of vision impairment in diabetic individuals, characterized by fluid accumulation in the macula due to a breakdown of the blood-retinal barrier (BRB). This review article explores the role of anti-vascular endothelial growth factor (anti-VEGF) therapies in the management of DME. Anti-VEGF treatments, including ranibizumab, bevacizumab, and aflibercept, have revolutionized DME management by targeting VEGF, a key mediator in DME pathogenesis. We critically examined the efficacy of these therapies in reducing macular edema and improving visual acuity, assessed their safety and tolerability, and explored the variability in treatment response. The review highlights the latest advancements and future directions in anti-VEGF therapy, including novel drug delivery systems and emerging treatment paradigms. By providing a comprehensive overview of current anti-VEGF therapies, this review seeks to inform clinical practice, guide future research, and contribute to improved patient outcomes in DME management.

Terapia cukrzycowego obrzęku plamki

Diabetic macular edema is an ocular complication of diabetes mellitus, leading to significant visual impairment. The pathogenesis of diabetic macular edema occurs through the interaction of multiple molecular mediators, including the overexpression of several growth factors, including vascular endothelial growth factor, angiopoietin-1, and -2, insulin-like growth factor-1, etc. These growth factors mediate endothelial cell proliferation, angiogenesis, protease production. Treatment for diabetic macular edema involves primary management of diabetes mellitus, laser photocoagulation, and pharmacotherapeutics targeting mediators, namely, the anti-vascular endothelial growth factor pathway. The introduction of anti-vascular endothelial growth factor therapies has resulted in significant clinical improvements compared to laser photocoagulation alone. However, the presence of anti-vascular endothelial growth factor non-responders and multiple factors influencing the visual outcome after anti-vascular endothelial growth factor treatment have necessitated the development of new therapeutic approaches. In this review, we provide an analysis of current management strategies to the treatment of diabetic macular edema

Study of aqueous humour inflammatory mediators’ levels in a cohort of Egyptian patients with diabetic macular oedema

BackgroundThe aim was to study aqueous humour inflammatory mediators’ levels in a cohort of Egyptian patients with diabetic macular oedema (DMO).MethodsThis was a case-control prospective study conducted on 2 groups: 25 eyes of 22 (11 females) patients seeking treatment for DMO as patients group, and 10 eyes of 10 (4 females) cataract patients as a control group. Aqueous humour was aspirated before intravitreal injection (patients’ group) or cataract surgery (control group). Inflammatory mediators in aqueous humour were measured using a multiplex bead immunoassay kit of 27 pre-mixed cytokines.ResultsEotaxin, interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1/CCL2) and interleukin-8 (IL-8/CXCL8) were found significantly higher in patients’ group compared to control group (p = 0.043, 0.037, 0.001, 0.015 respectively). On the contrary, interferon-gamma (IFN-gamma) and granulocyte colony-stimulating factor (G-CSF) were found significantly higher in control group than patients’ group (p = 0.003, 0.019 respectively). Basic fibroblast growth factor (Basic-FGF/FGF-2) and interleukin-1 receptor antagonist (IL-1ra) were found higher (but not statistically significant) in controls (p = 0.100 and 0.070 respectively). Additionally, a negative and significant correlation was found between Eotaxin level in aqueous humour and central macular thickness.ConclusionsSome mediators might be implicated in the pathogenesis of DMO either augmenting or suppressing role. Eotaxin, IP-10, MCP-1 and IL-8 might have a role in cases not responding to standard anti-vascular endothelial growth factor (VEGF) therapy. IL-1ra might have a protective role; therefore, the effectiveness of intravitreal injection of IL-1ra homologue needs to be studied in future clinical trials.

Pathogenesis of diabetic macular edema: role of the glial factor (literature review and own data)

The review presents modern data on the pathogenesis of diabetic macular edema. Today, a new understanding of the pathophysiology of diabetic retinal lesions includes structural dysfunction of the neurovascular unit (NVU) of the retina. NVU includes astrocytes and Müller cells, it is a physical and biochemical link between neurons, glia, vascular network in situ, acts as an interface between neurons and the vascular system, and is a key regulator of neuronal metabolism. The close interdependence of glial cells, pericytes and neurons contributes to the formation of a barrier between the blood and the retina, which controls the flow of fluid and hemotransmissive metabolites into the glial parenchyma of eye tissue. Glial components of NVU contribute to the survival of neuronal ganglion cells and photoreceptors, stabilization of the retinal structure, and modulation of inflammatory and immune reactions. It has been shown that intercellular interactions between blood vessels and neurons play a critical role in the formation of blood-retinal barrier whose activity is modulated by the state of retinal endothelial communications. In diabetes, the blood-retinal barrier breaks down already at the early stage of diabetic retino­pathy, changing the structure and function of most types of cells in the retina; however, the molecular mechanisms of this pathological process in diabetes are not sufficiently studied and require the search for new therapeutic strategies, in particular, with the participation of clusterin. Emphasis is placed on the significance of dysfunction in the neurovascular unit of the retina for the deve­lopment of complications in diabetes. Increased attention is paid to microglial activation, Müller cell dysfunction, damage to the blood-retinal barrier, as well as the role of clusterin and fractalkine in barrier cytoprotection.

Turnover of Microaneurysms After Intravitreal Injections of Faricimab for Diabetic Macular Edema.

Microaneurysm (MA) plays an important role in the pathogenesis of diabetic macular edema (DME) progression and response to anti-vascular endothelial growth factor (VEGF) therapy. This study aimed to investigate the effect of faricimab, a bispecific antibody against angiopoietin-2 and VEGF, on the number of MAs and their turnover in the treatment of DME. We included that patients with DME who underwent three monthly injections of faricimab in one eye, with the other eye as control. We examined central retinal thickness (CRT) based on optical coherence tomography (OCT) and best-corrected visual acuity. Turnover, including loss and newly formed MAs, and the total number of MAs were counted based on merged images of the OCT map and fluorescein angiography. We enrolled 28 patients with DME. After 3 monthly injections of faricimab, CRT significantly improved, 66.0 ± 16.2% of MAs disappeared, and 6.71 ± 5.6% of new MAs were generated, resulting in total reduction to 40.7 ± 15.2%. In the treated eyes, MA disappearance (P < 0.0001) and turnover (P = 0.007) were significantly greater, and new formation was smaller (P < 0.0001) than in non-treated eyes. The size of the retained MAs decreased after treatment. Microaneurysm turnover was not significantly different between areas with and without edema before treatment. In the process of improving edema in DME with faricimab, MAs shrink and disappear, and formation of MAs are inhibited, resulting in decreased total number of MAs. Intravitreal administration of faricimab suppresses vascular permeability and improves vascular structure.

Optical coherence tomography angiography analysis of choroidal microvasculature in various forms of diabetic macular edema

Optical coherence tomography angiography (OCTA) research in diabetic macular edema (DME) has focused on the retinal microvasculature with little attention to the choroid. The goal of this study was to analyze the association between quantitative choroidal OCTA parameters and various forms of DME observed on optical coherence tomography. We conducted a retrospective study of 61 eyes of 53 patients with DME. DME was classified as early or advanced, and as sponge-like diffuse retinal thickening (DRT), cystoid macular edema (CME) or serous retinal detachment (SRD). Quantitative OCTA parameters (vessel density [VD] in the superficial capillary plexus [SCP], middle capillary plexus [MCP], deep capillary plexus [DCP] and choriocapillaris [CC]) were recorded. The VD in the CC and SCP was significantly higher in patients with early DME compared to patients with advanced DME (P value<0.01). CC VD was lower in subjects with SRD compared to DRT and CME (P value<0.001). Moreover, it was lower in CME compared to DRT (P value<0.05). No statistical differences were found between VD in the MCP and DCP (P value>0.05). Furthermore, CC VD was lower in patients with increased retinal thickness, disruption of the ellipsoid zone (EZ) or external limiting membrane (ELM), and disorganization of the inner retinal layers (DRIL) (P value<0.05). CC ischemia plays an important role in the pathogenesis of DME. We demonstrated a decrease in CC VD in patients with severe DME, SRD, retinal thickening, EZ and/or ELM disruption and DRIL.

The correlation between peripheral complete blood count parameters and diabetic macular edema in proliferative diabetic retinopathy patients: a cross-sectional study.

Numerous studies have demonstrated that retinal chronic inflammation plays a critical role in the pathogenesis of diabetic macular edema (DME). However, studies about the association between peripheral complete blood count, an inexpensive and easily measurable laboratory index, and DME are limited. The current study was a hospital-based, cross-sectional study. The participants were inpatients with type 2 diabetes who underwent vitrectomy for PDR, and the contralateral eyes in these PDR patients meeting the criteria were included in the study. Central macular thickness (CMT) was measured automatically and the DME was characterized as CMT ≥ 300 μm. A total of 239 PDR participants were enrolled. The average age was 55.46 ± 10.08 years old, and the average CMT was 284.23 ± 122.09 μm. In the fully adjusted model, for CMT, the results revealed a significantly negative association between CMT and both white blood cell (WBC) count and neutrophil count (β = -11.95, 95% CI: -22.08, -1.82; p = 0.0218; β = -14.96, 95% CI: -28.02, -1.90; p = 0.0259, respectively); for DME, the results showed an inverse association between DME and WBC count, monocyte count, and eosinophil count (OR = 0.75, 95% CI: 0.59, 0.95; p = 0.0153; OR = 0.07, 95% CI: 0.00, 0.92; p = 0.0431; OR = 0.03, 95% CI: 0.00, 0.88; p = 0.0420, respectively). In conclusion, our results suggest that WBC and its subtypes in circulation may play an important role in the pathogenesis of DME in PDR patients.

Effect of diabetic macular oedema on serum iron status indicators

ABSTRACT Clinical relevance The role of subclinical inflammation in the pathophysiology of diabetic macular oedema (DME), which is known to be quite complex, is of much interest. Serum ferritin level, which is an indicator of body iron stores, is both an inflammatory marker for various neurodegenerative diseases and an important indicator in the evaluation of iron-induced oxidative stress. Background Iron metabolism indicators play a role in the formation and development of diabetic retinopathy, which is known to be associated with subclinical inflammation, and may also play a role in the pathogenesis of DME. The aim of this study was to investigate the role of serum iron metabolism markers in the pathogenesis of DME. Materials and methods The files of all nonproliferative diabetic retinopathy (NPDR) patients who were scheduled for the first intravitreal injection for DME in the eye clinic between January 2019 and January 2020 were reviewed retrospectively. By examining the files of all diabetes mellitus patients who attended the outpatient eye clinic on the same dates, those without retinopathy and those with NPDR but not DME were recorded. All results, including a comprehensive ophthalmological examination, laboratory data of fasting blood tests, and an internal medicine outpatient examination were collected for analysis. Results Of the 157 participants, 44 were NPDR patients with oedema, 50 were NPDR patients without oedema, and 63 were patients without retinopathy. There was a significant difference between the groups in respect of creatinine, high-density lipoprotein, mean corpuscular volume, serum iron and ferritin, total iron binding capacity and transferrin saturation (p < 0.050). Ferritin values were found to be significantly higher in patients with macular oedema. Other iron status markers were found to be significantly lower (p < 0.050). Conclusion Evaluation of serum iron status indicators in the routine follow-up of diabetic patients may be of diagnostic and/or prognostic benefit in terms of DME.

Current Opinion on Long-Lasting Therapy in CI-DME

Diabetes has been recognized by the World Health Organization (WHO) as a noncommunicable, chronic disease and a 21st century epidemic. Diabetic retinopathy (DR) is one of the three leading causes of blindness among the working-age population aged 20 to 74 years.&#x0D; Diabetic macular edema (DME) is the most common cause of vision loss in diabetic patients, and the impact of DME on quality of life is very significant. Currently, first-line treatment recommendations for center-involved DME (CI-DME) include intravitreal anti-VEGF injections on a monthly or bimonthly regimen. It is essential to understand the burden that treatment regimens have on patients, as well as on healthcare systems. The most significant improvement to the regimen would be to have fewer injections and monitoring visits while maintaining satisfactory vision outcomes. A lower number of intravitreal injections could optimize disease outcomes by improving patient compliance.&#x0D; This article discusses novel agents targeting alternative pathways and mechanisms involved in the pathogenesis of DME, as well as high-dose drugs and novel approaches to treatment regimens aimed at extending treatment intervals, decreasing treatment burden, and increasing treatment efficacy. This knowledge will enhance the selection of treatments, thereby improving patient compliance with therapy and optimizing healthcare system resources.

The impact of intravitreal therapy of diabetic macular edema on the local and systemic production of cytokines

Purpose: to analyze the levels of cytokines in intraocular fluid (IF) and blood plasma of patients with diabetic macular edema (DME) previously untreated by intravitreal therapy before and after the therapy by angiogenesis inhibitor or a corticosteroid. Material and methods. We examined 90 people — 47 females (52.2 %) and 43 males (47.8 %), mean age 64.54 ± 11.30 years. Of these, 60 had DME, and 30 formed the control group. The levels of 41 cytokines/chemokines in IF were determined by Milliplex® Map Human Cytokine/ Chemokine Panel; while the concentration of IL-18, MCP-1/CCL2, EPO, IL-10, IL-4, IL-6, IL-8, IFNα, VEGF-A in blood plasma was measured by enzyme-linked immunosorbent assay kits (Vector-Best, Russia). Patients with DME received intravitreal injections of an angiogenesis inhibitor (aflibercept. 50 eyes) or a corticosteroid (dexamethasone implant, 30 eyes). Results. Significant differences were revealed in 10 cytokine concentrations between the DME patients and the control group. The concentrations of IL-7, IL-15 and MCP-1/CCL2 levels in IF of DME patients were, respectively, 20.5, 20.3, and 11.02 times higher, than in the control group (р ˂ 0.05). Besides, a pairwise comparison of cytokines concentrations in IF of patients from either treatment group with the controls demonstrated a statistically significant increase in GROα/CXCL1 level. The pairwise comparison also revealed significant differences between the control and the corticosteroid therapy for systemic concentrations of IL-18 (p = 0.017), MCP-1/CCL2 (p = 0.009) and VEGF-A (p = 0.016). Conclusion. A pronounced and significant increase of the levels of a number of cytokines (e.g., IL-7, IL-15. FRACTALKINE/CX3CL1) were only sparsely reported before or remained undetermined at all. Our results on systemic cytokines levels may serve as prerequisite for further research into the role of systemic inflammation in DME pathogenesis. The analysis of associations of our results with those of other clinical biomarkers will contribute to the development of individualized treatment strategies.

Role of Microaneurysms in the Pathogenesis and Therapy of Diabetic Macular Edema: A Descriptive Review

Background and Objectives: This study aims to elucidate the role of microaneurysms (MAs) in the pathogenesis and treatment of diabetic retinopathy (DR) and diabetic macular edema (DME), the major causes of acquired visual impairment. Materials and Methods: We synthesized the relevance of findings on the clinical characteristics, pathogenesis, and etiology of MAs in DR and DME and their role in anti-vascular endothelial growth factor (VEGF) therapy. Results: MAs, a characteristic feature in DR and DME, can be detected by fluorescein angiography, optical coherence tomography (OCT) and OCT angiography. These instrumental analyses demonstrated a geographic and functional association between MA and ischemic areas. MA turnover, the production and loss of MA, reflects the activity of DME and DR. Several cytokines are involved in the pathogenesis of MAs, which is characterized by pericyte loss and endothelial cell proliferation in a VEGF-dependent or -independent manner. Ischemia and MAs localized in the deep retinal layers are characteristic of refractory DME cases. Even in the current anti-VEGF era, laser photocoagulation targeting MAs in the focal residual edema is still an effective therapeutic tool, but it is necessary to be creative in accurately identifying the location of MAs and performing highly precise and minimally invasive coagulation. Conclusions: MAs play a distinctive and important role in the pathogenesis of the onset, progression of DR and DME, and response to anti-VEGF treatment. Further research on MA is significant not only for understanding the pathogenesis of DME but also for improving the effectiveness of treatment.

Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy.

Diabetic retinopathy, characterized as a microangiopathy and neurodegenerative disease, is the leading cause of visual impairment in diabetic patients. Many clinical features observed in diabetic retinopathy, such as capillary occlusion, acellular capillaries and retinal non-perfusion, aggregate retinal ischemia and represent relatively late events in diabetic retinopathy. In fact, retinal microvascular injury is an early event in diabetic retinopathy involving multiple biochemical alterations, and is manifested by changes to the retinal neurovascular unit and its cellular components. Currently, intravitreal anti-vascular endothelial growth factor therapy is the first-line treatment for diabetic macular edema, and benefits the patient by decreasing the edema and improving visual acuity. However, a significant proportion of patients respond poorly to anti-vascular endothelial growth factor treatments, indicating that factors other than vascular endothelial growth factor are involved in the pathogenesis of diabetic macular edema. Accumulating evidence confirms that low-grade inflammation plays a critical role in the pathogenesis and development of diabetic retinopathy as multiple inflammatory factors, such as interleukin-1β, monocyte chemotactic protein-1 and tumor necrosis factor -α, are increased in the vitreous and retina of diabetic retinopathy patients. These inflammatory factors, together with growth factors such as vascular endothelial growth factor, contribute to blood-retinal barrier breakdown, vascular damage and neuroinflammation, as well as pathological angiogenesis in diabetic retinopathy, complicated by diabetic macular edema and proliferative diabetic retinopathy. In addition, retinal cell types including microglia, Müller glia, astrocytes, retinal pigment epithelial cells, and others are activated, to secrete inflammatory mediators, aggravating cell apoptosis and subsequent vascular leakage. New therapies, targeting these inflammatory molecules or related signaling pathways, have the potential to inhibit retinal inflammation and prevent diabetic retinopathy progression. Here, we review the relevant literature to date, summarize the inflammatory mechanisms underlying the pathogenesis of diabetic retinopathy, and propose inflammation-based treatments for diabetic retinopathy and diabetic macular edema.

Aquaporin 11 alleviates retinal Müller intracellular edema through water efflux in diabetic retinopathy

Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear functions. This study aims to explore the role of AQP11 in the pathogenesis of intracellular edema of Müller glia in diabetic retinopathy (DR). Here, we found that AQP11 expression, primarily located at the endfeet of Müller glia, was down-regulated with diabetes progression, accompanied by intracellular edema, which was alleviated by intravitreal injection of lentivirus-mediated AQP11 overexpression. Similarly, intracellular edema of hypoxia-treated rat Müller cell line (rMC-1) was aggravated by AQP11 inhibition, while attenuated by AQP11 overexpression, accompanied by enhanced function in glutamate metabolism and reduced cell death. The down-regulation of AQP11 was also verified in the Müller glia from the epiretinal membranes (ERMs) of proliferative DR (PDR) patients. Mechanistically, down-regulation of AQP11 in DR was mediated by the HIF-1α-dependent and independent miRNA-AQP11 axis. Overall, we deciphered the AQP11 down-regulation, mediated by miRNA-AQP11 axis, resulted in Müller drainage dysfunction and subsequent intracellular edema in DR, which was partially reversed by AQP11 overexpression. Our findings propose a novel mechanism for the pathogenesis of DME, thus targeting AQP11 regulation provides a new therapeutic strategy for DME.

Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications.

Diabetic retinopathy (DR), with increasing incidence, is the major cause of vision loss and blindness worldwide in working-age adults. Diabetic macular edema (DME) remains the main cause of vision impairment in diabetic patients, with its pathogenesis still not completely elucidated. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of DR and DME. Currently, intravitreal injection of anti-VEGF agents remains as the first-line therapy in DME treatment due to the superior anatomic and functional outcomes. However, some patients do not respond satisfactorily to anti-VEGF injections. More than 30% patients still exist with persistent DME even after regular intravitreal injection for at least 4 injections within 24 weeks, suggesting other pathogenic factors, beyond VEGF, might contribute to the pathogenesis of DME. Recent advances showed nearly all the retinal cells are involved in DR and DME, including breakdown of blood-retinal barrier (BRB), drainage dysfunction of Müller glia and retinal pigment epithelium (RPE), involvement of inflammation, oxidative stress, and neurodegeneration, all complicating the pathogenesis of DME. The profound understanding of the changes in proteomics and metabolomics helps improve the elucidation of the pathogenesis of DR and DME and leads to the identification of novel targets, biomarkers and potential therapeutic strategies for DME treatment. The present review aimed to summarize the current understanding of DME, the involved molecular mechanisms, and the changes in proteomics and metabolomics, thus to propose the potential therapeutic recommendations for personalized treatment of DME.

Peripheral white blood cell subtypes and the development/progression of diabetic macular edema in type 2 diabetic patients: a comparative study.

Inflammation and immune dysregulation are involved in the pathogenesis of diabetic macular edema (DME). The progressive increase of neutrophils in peripheral blood can lead to the increase of the number of neutrophils in the retina, thus leading to the sustained damage of the retinal vascular system and the destruction of the blood retinal barrier (BRB); lymphocytes play a protective role in vascular diseases caused by type 2 diabetes mellitus (T2DM). The purpose of this study was to study the relationship between the changes of leukocytes and their classification in peripheral blood and the occurrence and progression of DME in patients with T2DM. A retrospective analysis was made on 81 patients with T2DM with DME (DME group) hospitalized in our hospital from January 2019 to December 2020. According to the morphological characteristics of macular edema in optical coherence tomography (OCT), they were divided into early DME group (n=33) and late DME group (n=48); 33 patients with diabetes retinopathy (DR) but without DME matched in age and course of disease served as the control group (NO-DME group). The clinical parameters assessed included eye examination, OCT results, WBCs and subtypes, blood glucose, and glycosylated hemoglobin. Compared with NO-DME group (n=33), Neutrophils% in DME group (n=81) was higher (57.37±9.52 vs. 63.27±7.85; P=0.001); Monocyte% (7.63±1.77 vs. 6.88±1.83; P=0.047) and lymphocyte% (30.35±9.51 vs. 27.26±6.59; P=0.032) were decreased. The optimal model was obtained with R 4.0.5 software. With other relevant variables being the same, females had a significantly increased risk of DME (b=1.273, P=0.015), %neutrophils was significantly associated with increased risk of DME (b=0.152, P=0.0006), and %lymphocytes was significantly associated with a reduced risk of DME (b=-0.027, P=0.179). However, in the early and late DME groups, no significant differences in biological markers were found, and a high-quality model was not obtained. In this preliminary study, %neutrophils is associated with increased risk of DME, whereas %lymphocytes is associated with a reduced risk of DME.

Current and Novel Therapeutic Approaches for Treatment of Diabetic Macular Edema.

Diabetic macular edema (DME) is a major ocular complication of diabetes mellitus (DM), leading to significant visual impairment. DME’s pathogenesis is multifactorial. Focal edema tends to occur when primary metabolic abnormalities lead to a persistent hyperglycemic state, causing the development of microaneurysms, often with extravascular lipoprotein in a circinate pattern around the focal leakage. On the other hand, diffusion edema is due to a generalized breakdown of the inner blood–retinal barrier, leading to profuse early leakage from the entire capillary bed of the posterior pole with the subsequent extravasation of fluid into the extracellular space. The pathogenesis of DME occurs through the interaction of multiple molecular mediators, including the overexpression of several growth factors, including vascular endothelial growth factor (VEGF), insulin-like growth factor-1, angiopoietin-1, and -2, stromal-derived factor-1, fibroblast growth factor-2, and tumor necrosis factor. Synergistically, these growth factors mediate angiogenesis, protease production, endothelial cell proliferation, and migration. Treatment for DME generally involves primary management of DM, laser photocoagulation, and pharmacotherapeutics targeting mediators, namely, the anti-VEGF pathway. The emergence of anti-VEGF therapies has resulted in significant clinical improvements compared to laser therapy alone. However, multiple factors influencing the visual outcome after anti-VEGF treatment and the presence of anti-VEGF non-responders have necessitated the development of new pharmacotherapies. In this review, we explore the pathophysiology of DME and current management strategies. In addition, we provide a comprehensive analysis of emerging therapeutic approaches to the treatment of DME.

Pathogenesis of diabetic macular edema: the role of pro-inflammatory and vascular factors. Aliterature review

The review presents data on the pathogenesis of diabetic macular edema (DME). DME is a major cause of visual impairment in type 2 diabetes mellitus (DM) patients. Non-specific inflammation is an important factor of the underlying processes of DME. The importance of vascular endothelial growth factor (VEGF), interleukin-6, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1, vascular cell adhesion molecule-1 in the development of diabetes microvascular complications is indicated. Intercellular adhesion molecules (ICAM), particularly, soluble ICAM-1 (sICAM-1), are a local inflammatory mediator involved in the pathogenesis of diabetic injury to the layers of the eye. The literature is scant on the assessment of sICAM-1 in type2 DM patients with diabetic injury to the neurovascular system of the eye (i.e. adhesion of leukocytes to the vascular endothelium (leukostasis) and the concurrent endothelial apoptosis). There are three main stages of microvascular changes due to nonspecific inflammation: dilation of capillaries and increased blood flow, microvascular structural changes and leakage of plasma proteins from the bloodstream, transmigration of leukocytes through the endothelium and accumulation at the site of injury. Vascular dysfunction in diabetic retinopathy (DR) and DMЕ is caused primarily by leukostasis, which is based on the recruitment and adhesion of leukocytes to the retinal vascular system. Leukostasis is the first step in the sequence of adhesion and activation events that lead to the infiltration of leukocytes through the endothelium. Leukocytes involved in leukostasis induce vascular permeability by releasing cytokines, including VEGF and TNF-α, contributing to endothelial protein binding, increasing levels of reactive oxidative substances, and killing pericytes and astrocytes surrounding the endothelium. Thus, the existing data on the main aspects of the pathogenesis of DMЕ indicate that inflammation is an important factor in the processes underlying the development of DMЕ and DR. But a new understanding of the physiology of the retina suggests that the pathogenesis of retinal lesions in type 2 DM can be considered as a change in the neurovascular unit of the retina.

Proteomic analysis of vitreous humour of eyes with diabetic macular oedema: a systematic review.

The pathophysiology of diabetic macular oedema (DME) remains poorly understood. Proteomic analysis of the vitreous using mass spectrometry (MS) can potentially identify proteins of pathophysiological importance. In this systematic review, we summarize the available evidence on protein changes in DME detected by MS. We systematically searched 13 literature databases on 19 September 2021. Eligible studies were defined as those using samples from human eyes with DME analysed with MS. Two authors assessed the studies for eligibility, extracted data and evaluated risk of bias independently. Six eligible studies were identified. All were designed in a cross-sectional fashion comparing results to either a non-diabetic control group or a control group without DME. A total of 62 eyes from 60 patients contributed as study group and 48 eyes from 48 patients served as control group. Proteomic analyses revealed significant differences in the vitreous protein levels in patients with DME when compared with controls. Three studies or more identified increased contents of apolipoprotein A-I, apolipoprotein A-II, apolipoprotein A-IV, apolipoprotein C-III, gelsolin, pigment epithelium-derived factor, serum albumin, transthyretin, vitamin D-binding protein in DME. Two studies found increased levels of complement factors B and C3. Protein changes reproduced across the studies suggested that DME was associated with retinal lipid accumulation, angiogenesis, retinal protective mechanisms, inflammation and complement activation. Proteome studies support the multifactorial pathogenesis of DME as proteins with highly different biological functions are regulated in DME. An important number of proteins differ, provide pathophysiological insight and suggest the direction for future research.