[Evaluation of the management and follow-up of diabetic patients in the prevention of diabetic retinopathy]. / Evaluación del manejo y seguimiento de los pacientes diabéticos en la prevención de la retinopatía diabética.

OBJECTIVE: Diabetes mellitus is a chronic disease with high morbidity and mortality, affecting 537 million adults worldwide. Spain is the second European country in prevalence, with 14.8% in the population aged twenty/seventy-nine years; with 11.6 cases per 1,000 people/year. Diabetic retinopathy (DR) is the fifth cause of vision loss worldwide and the seventh cause of blindness/visual impairment among members of the National Organization of the Blind in Spain (ONCE). Early detection of DR prevents blindness in diabetics and is conditioned by glycosylated hemoglobin. The aim of this paper was to analyze the management of diabetic patients in Aljarafe region (Seville) and identify opportunities for improvement in the coordination of their follow-up between the Primary Care physician and the ophthalmologist. METHODS: A retrospective observational study (2016-2019) was carried out, with patients registered in the diabetic census of the twenty-eight municipalities of Aljarafe. The primary care and hospital health history, and telemedicine program were consulted. About statistical analysis, for qualitative variables, totals and percentages were calculated; for quantitative variables, mean and standard deviation (if normally distributed) and median and quartiles (if non-normally distributed). RESULTS: There were 17,175 diabetics registered in Aljarafe (5.7% of the population); 14,440 patients (84.1%) had some determination of hemoglobin during the period, 9,228 (63.9%) had all of them in the appropriate range. Fundoscopic control was performed on 12,040 diabetics (70.1%), and of those who did not, 346 (10.6%) had all of them out of range. There were 1,878 (10.9%) patients without fundoscopic or metabolic control, 1,019 (54.3%) were women, 1,219 (64.9%) were under sixty-five years of age, 1,019 (54.3%) had severe comorbidity. CONCLUSIONS: Most patients have adequate screening, and more than half have determinations within range. However, a significant percentage with no glycated hemoglobin within range lack fundoscopic control, and another smaller group lack fundoscopic or metabolic control, with inter-municipal variability. We propose to improve communication channels between levels.

OBJECTIVE: La diabetes mellitus es una enfermedad crónica con alta morbimortalidad que afecta a 537 millones de adultos en el mundo. España es el segundo país europeo en prevalencia, con un 14,8% en población de veinte-setenta y nueve años, con 11,6 casos por cada 1.000 personas/año. La retinopatía diabética (RD) es la quinta causa de pérdida de visión a nivel mundial y la séptima causa de ceguera/discapacidad visual entre afiliados a la Organización Nacional de Ciegos de España (ONCE). La detección precoz de RD previene la ceguera en diabéticos y está condicionada por la hemoglobina glicosilada. El objetivo de este trabajo fue analizar el manejo de los pacientes diabéticos en la comarca del Aljarafe (Sevilla) e identificar oportunidades de mejora en la coordinación de su seguimiento entre el médico de Atención Primaria y el médico oftalmólogo. METHODS: Se realizó un estudio observacional retrospectivo (2016-2019) con los pacientes registrados en el censo de diabéticos de los veintiocho municipios del Aljarafe. Se consultó la historia de salud de Atención Primaria y Hospital, así como el programa de Telemedicina. En cuanto al análisis estadístico, para variables cualitativas se calcularon totales y porcentajes; para variables cuantitativas, media y distribución estándar (si distribución normal), y la mediana y cuartiles (distribución no normal). RESULTS: Se registraron 17.175 diabéticos en el Aljarafe (5,7% de población); 14.440 pacientes (84,1%) tenían alguna determinación de hemoglobina durante el periodo, 9.228 (63,9%) las tenían todas en rango adecuado. Tenían control fundoscópico 12.040 diabéticos (70,1%), y de los que no, 346 (10,6%) tenían todas fuera de rango. Hubo 1.878 (10,9%) pacientes sin control fundoscópico ni metabólico, 1.019 (54,3%) eran mujeres, 1.219 (64,9%) menores de sesenta y cinco años, 1.019 (54,3%) con comorbilidad grave. CONCLUSIONS: La mayoría de los pacientes presentan un cribado adecuado y, más de la mitad, determinaciones en rango. Sin embargo, un porcentaje relevante con ninguna hemoglobina glicosilada en rango carecen de control fundoscópico, y otro grupo menor está sin control fundoscópico ni metabólico, con variabilidad intermunicipios. Planteamos mejorar los circuitos de comunicación entre niveles.

Protective Effect of Pemafibrate Treatment against Diabetic Retinopathy in Spontaneously Diabetic Torii Fatty Rats.

Diabetic retinopathy (DR) can cause visual impairment and blindness, and the increasing global prevalence of diabetes underscores the need for effective therapies to prevent and treat DR. Therefore, this study aimed to evaluate the protective effect of pemafibrate treatment against DR, using a Spontaneously Diabetic Torii (SDT) fatty rat model of obese type 2 diabetes. SDT fatty rats were fed either a diet supplemented with pemafibrate (0.3 mg/kg/d) for 16 weeks, starting at 8 weeks of age (Pf SDT fatty: study group), or normal chow (SDT fatty: controls). Normal chow was provided to Sprague-Dawley (SD) rats (SD: normal controls). Electroretinography (ERG) was performed at 8 and 24 weeks of age to evaluate the retinal neural function. After sacrifice, retinal thickness, number of retinal folds, and choroidal thickness were evaluated, and immunostaining was performed for aquaporin-4 (AQP4). No significant differences were noted in food consumption, body weight, or blood glucose level after pemafibrate administration. Triglyceride levels were reduced, and high-density lipoprotein cholesterol levels were increased. Extension of oscillatory potential (OP)1 and OP3 waves on ERG was suppressed in the Pf SDT fatty group. Retinal thickness at 1500 microns from the optic disc improved in the Pf SDT fatty group. No significant improvements were noted in choroidal thickness or number of retinal folds. Quantitative analyses showed that AQP4-positive regions in the retinas were significantly larger in the Pf SDT fatty group than in the SDT fatty group. The findings suggest that pemafibrate treatment can exert protective effects against DR.

Nrf-2-dependent antioxidant and anti-inflammatory effects underlie the protective effect of esculeoside A against retinal damage in streptozotocin-induced diabetic rats.

Esculeoside A (ESA) is a tomato-derived glycoside with antioxidant and anti-inflammatory properties. The protective effect of ESA against diabetic retinopathy is not well-investigated and was the core objective of this study. In addition, we tested if such protection involves the activation of Nrf2 signaling. Type 1 diabetes mellitus (T1DM) was induced in adult Wistar male rats by an intraperitoneal injection of streptozotocin (65 mg/kg). Non-diabetic and T1DM rats were divided into two subgroup groups given either the vehicle or ESA (100 mg)/kg. An additional T1DM group was given ESA (100 mg/kg) and an Nrf2 inhibitor (2 mg/kg) (n=8 rats/group). Treatments continued for 12 weeks. In this study, according to the histological features, ESA improved the structure of ganglionic cells and increased the number of cells of the inner nuclear and plexiform layers in the retinas of T1DM rats. Concomitantly, it reduced the retina levels of malondialdehyde (lipid peroxides), vascular endothelial growth factor, interleukin-6, tumor necrosis factor-α, Bax, and caspase-3. In the retinas of the control and diabetic rats, ESA boosted the levels of total glutathione, superoxide dismutase, heme-oxygenase-1, and Bcl2, reduced the mRNA levels of REDD1, and enhanced cytoplasmic and nuclear levels of Nrf2. However, ESA failed to alter the mRNA levels of Nrf2 and keap1, protein levels of keap1, plasma glucose, plasma insulin, serum triglycerides, cholesterol, and LDL-c in both the control and T1DM rats. In conclusion, ESA alleviates retinopathy in T1DM rats by suppressing REDD1-associated degradation and inhibiting the Nrf2/antioxidant axis.

AI Can Improve the Economics of Blindness Prevention in Canada.

Diabetic retinopathy is a leading cause of vision loss in Canada and creates significant economic and social burden on patients. Diabetic retinopathy is largely a preventable complication of diabetes mellitus. Yet, hundreds of thousands of Canadians continue to be at risk and thousands go on to develop vision loss and disability. Blindness has a significant impact on the Canadian economy, on families and the quality of life of affected individuals. This paper provides an economic analysis on two potential interventions for preventing blindness and concludes that use of AI to identify high-risk individuals could significantly decrease the costs of identifying, recalling, and screening patients at risk of vision loss, while achieving similar results as a full-fledged screening and recall program. We propose that minimal data interoperability between optometrists and family physicians combined with artificial intelligence to identify and screen those at highest risk of vision loss can lower the costs and increase the feasibility of screening and treating large numbers of patients at risk of going blind in Canada.

Protective effects and mechanisms of Momordica charantia polysaccharide on early-stage diabetic retinopathy in type 1 diabetes.

Momordica charantia polysaccharide (MCP) is a potential drug for the prevention and alleviation of diabetes mellitus (DM) and diabetic retinopathy (DR). This study aimed to investigate the potential protective effects of MCP on early-stage DR and explore the underlying mechanisms. The model group (DM group) and treatment group (D+H group) were established by inducing type 1 DM using a single dose of streptozotocin (STZ) at 60 mg/kg. After modeling, the D+H group was orally administered a 500 mg/kg dose of MCP solution once daily for 12 weeks. Monitoring of systemic indicators (FBG, body weight, general condition) and retinal tissue inflammation and apoptosis (HE staining, IL-6, MCP-1, TNF-α, VEGF, NF-κB, Caspase-3) in this study demonstrated that MCP intervention alleviated both DM and DR. MCP improved the body weight and general condition of DM rats by reducing FBG levels. It also enhanced the anti-inflammatory and anti-apoptotic capabilities of retinal neurons and microvessels by modulating the actions of cytokines, thereby further regulating the inflammation and apoptosis of retinal neurons and microvessels. The underlying mechanisms may be associated with the downregulation of NF-κB and Caspase-3 pathway protein expression, as well as the downregulation of mRNA expression of NF-κB and Caspase-3 pathway genes. Further research is needed to elucidate the potential mechanisms underlying the protective effects of MCP on DR. MCP may emerge as a selective medication for the prevention and alleviation of DM and a novel natural medicine for the prevention and alleviation of DR.

Retinoid X Receptor Activation Prevents Diabetic Retinopathy in Murine Models.

Previously, the RXR agonist UAB126 demonstrated therapeutic potential to treat obese mice by controlling blood glucose levels (BGL) and altering the expression of genes associated with lipid metabolism and inflammatory response. The purpose of the study was to assess the effects of UAB126 on the progression of diabetic retinopathy (DR) in rodent models of type 1 diabetes (T1D), streptozotocin-induced, and type 2 diabetes (T2D), in db/db mice. UAB126 treatment was delivered either by oral gavage for 6 weeks or by topical application of eye drops for 2 weeks. At the end of the treatment, the retinal function of diabetic mice was assessed by electroretinography (ERG), and their retinal tissue was harvested for protein and gene expression analyses. Bone-marrow cells were isolated and differentiated into bone marrow-derived macrophages (BMDMs). The glycolysis stress test and the 2-DG glucose uptake analysis were performed. Our results demonstrated that in the UAB126-treated diabetic BMDMs, the ECAR rate and the 2-DG uptake were improved as compared to untreated diabetic BMDMs. In UAB126-treated diabetic mice, hyperglycemia was reduced and associated with the preservation of ERG amplitudes and enhanced AMPK activity. Retinas from diabetic mice treated with topical UAB126 demonstrated an increase in Rxr and Ppar and the expression of genes associated with lipid metabolism. Altogether, our data indicate that RXR activation is beneficial to preclinical models of DR.

A Mediterranean Diet May Be Protective in the Development of Diabetic Retinopathy.

The Mediterranean diet is recognized as one of the healthiest available dietary patterns. This perception results from its beneficial effects on the cardiovascular system and, also, on hypertension, diabetes, and cancer compared with other diets. Its impact on the course of diabetes is assessed in the available scientific literature; however, little information is available about its impact on diabetic retinopathy. The MD is characterized mainly by the consumption of fish, seafood, foods of plant origin, and fresh fruit and vegetables. It is also recommended to consume legumes, which are a source of folic acid, magnesium, iron, and dietary fiber. High consumption of nuts and unrefined grains is also recommended in the MD. Marine fish provide polyunsaturated acids from the omega-3 group. Olive oil plays a very important role, especially olive oil obtained from mechanical pressing. Additionally, olive oil contains vitamins E, K, and polyphenols. Polyphenols, which are present in a diverse range of vegetables, fruits, and seeds, have the ability to decrease oxidative stress, inflammation, and insulin resistance. Resveratrol is naturally found in grape skins and seeds, as well as in peanuts and berries, and is a constituent of red wine. Resveratrol can inhibit increased vascular leakage and loss of pericytes and regulate the level of VEGF protein in the retina, thus inhibiting the development of DR. Consumption of fruits, vegetables, fish, and olive oil may be correlated with a lower risk of diabetic retinopathy. This paper presents the definition of the Mediterranean diet and its influence on the course of diabetes and diabetic retinopathy.

Vaccinium as Potential Therapy for Diabetes and Microvascular Complications.

Diabetes mellitus is one of the most critical global health concerns, with a fast-growing prevalence. The incidence of diabetic vascular complications is also rapidly increasing, exacerbating the burden on individuals with diabetes and the consumption of public medical resources. Despite the overall improvements in the prevention, diagnosis, and treatment of diabetic microvascular complications in recent years, safe and effective alternative or adjunctive therapies are urgently needed. The mechanisms underlying diabetic vascular complications are complex, with hyperglycemia-induced oxidative stress and inflammation being the leading causes. Therefore, glycemic control, antioxidation, and anti-inflammation are considered the main targets for the treatment of diabetes and its vascular comorbidities. Vaccinium L. (Ericaceae) is a genus of plants enriched with polyphenolic compounds in their leaves and fruits. Vaccinium and its extracts have demonstrated good bioactivity in reducing blood glucose, oxidative stress, and inflammation, making them excellent candidates for the management of diabetes and diabetic vascular complications. Here, we review recent preclinical and clinical studies on the potential effect of Vaccinium on ameliorating diabetes and diabetic complications, particularly diabetic kidney disease and diabetic retinopathy.

The Mediterranean Diet and Age-Related Eye Diseases: A Systematic Review.

The Mediterranean diet (MD) is a healthy diet pattern that can prevent chronic age-related diseases, especially age-related eye diseases (AREDs) including cataract, glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR) and dry eye syndrome (DES). In this study, we systematically reviewed studies in the literature that had reported associations between adherence to the MD and the five above-mentioned AREDs. Randomized controlled trials as well as prospective and retrospective observational studies were included; 1164 studies were identified, of which 1, 2, 9, 2 and 4 studies met our eligibility criteria for cataract, glaucoma, AMD, DR, and DES, respectively. According to these studies, higher MD adherence was associated with reduced risks of incident DR, incident AMD and progression to late AMD, but whether early and neovascular AMD could be alleviated remained to be debated. The results regarding the effects of the MD on DES were mixed, with three studies reporting an associations between MD and decreased severity or incidence of DES, whereas one study reported the opposite. No significant associations were observed between the MD and cataract or glaucoma. Generally, convincing evidence suggested a protective effect of the MD against AMD and DR. However, the evidence for cataract, glaucoma, and DES was less conclusive, and high-quality studies are needed for comprehensive evaluations of the potential benefits of MD on these eye diseases.

The gut-retina axis: a new perspective in the prevention and treatment of diabetic retinopathy.

Diabetic retinopathy (DR) is a microvascular lesion that occurs as a complication of diabetes mellitus. Many studies reveal that retinal neurodegeneration occurs early in its pathogenesis, and abnormal retinal function can occur in patients without any signs of microvascular abnormalities. The gut microbiota is a large, diverse colony of microorganisms that colonize the human intestine. Studies indicated that the gut microbiota is involved in the pathophysiological processes of DR and plays an important role in its development. On the one hand, numerous studies demonstrated the involvement of gut microbiota in retinal neurodegeneration. On the other hand, alterations in gut bacteria in RD patients can cause or exacerbate DR. The present review aims to underline the critical relationship between gut microbiota and DR. After a brief overview of the composition, function, and essential role of the gut microbiota in ocular health, and the review explores the concept of the gut-retina axis and the conditions of the gut-retina axis crosstalk. Because gut dysbiosis has been associated with DR, the review intends to determine changes in the gut microbiome in DR, the hypothesized mechanisms linking to the gut-retina axis, and its predictive potential.

Acteoside inhibits high glucose-induced oxidative stress injury in RPE cells and the outer retina through the Keap1/Nrf2/ARE pathway.

Diabetes retinopathy (DR) is one of the most common microvascular complications of diabetes. Retinal pigment epithelial (RPE) cells exposed to a high glucose environment experience a series of functional damages, which is an important factor in promoting the progression of DR. Acteoside (ACT) has strong antioxidant and anti-apoptotic properties, but the mechanism of ACT in DR is not completely clear. Therefore, the purpose of the present study was to explore whether ACT inhibits the damage to RPE cells in a high glucose environment through antioxidative effects to alleviate the DR process. The DR in vitro cell model was constructed by treating RPE cells with high glucose, and the DR in vivo animal model was constructed by injecting streptozotocin (STZ) into the peritoneal cavity of mice to induce diabetes. The proliferation and apoptosis of RPE cells were detected by CCK-8 and flow cytometry assays, respectively. The expression changes in Nrf2, Keap1, NQO1 and HO-1 were evaluated by qRT‒PCR, Western blot and immunohistochemistry analyses. The MDA, SOD, GSH-Px and T-AOC contents were detected by kits. The changes in ROS and nuclear translocation of Nrf2 were observed by immunofluorescence assays. HE staining was used to measure the thickness of the outer nuclear layer (ONL) of the retina, and TUNEL staining was used to detect the number of apoptotic cells in the retinas of mice. In the present study, ACT effectively ameliorated outer retina damage in diabetic mice. In high glucose (HG)-induced RPE cells, ACT treatment had the following effects: improved proliferation, decreased apoptosis, inhibited Keap1 expression, promoted the nuclear translocation and expression of Nrf2, upregulated NQO1 and HO-1 (the target genes of Nrf2) expression, decreased ROS concentration, and increased the levels of the SOD, GSH-Px and T-AOC antioxidant indicators. However, knockdown of Nrf2 reversed the above phenomena, which indicated that the protective function of ACT in HG-induced RPE cells are closely related to Nrf2. In summary, the present study demonstrated that HG-induced oxidative stress injury is inhibited by ACT in RPE cells and the outer retina through the Keap1/Nrf2/ARE pathway.

Sortilin Inhibition Protects Neurons From Degeneration in the Diabetic Retina.

Purpose: To investigate the level and localization of the multifunctional receptor sortilin in the diabetic retina, as well as the effect of sortilin inhibition on retinal neurodegeneration in experimental diabetes. Methods: The localization of sortilin and colocalization with the p75 neurotrophin receptor (p75NTR) and Müller cell (MC) markers were determined using immunofluorescence on retinal sections from human patients with diabetes and streptozotocin-induced diabetic C57BL/6J male mice. In the diabetic mice, levels were further quantified using Western blot and quantitative PCR. Therapeutic studies were performed on diabetic mice using intravitreally injected anti-sortilin antibodies. Neuroprotection was evaluated in vivo by optical coherence tomography and by quantification of retinal ganglion cells (RGCs) in flat mounts. Results: Increased levels of sortilin were observed in human and murine diabetic retinas compared with nondiabetic control retinas. Sortilin was highly localized to retinal MCs, and, notably, colocalization with p75NTR was only seen in diabetic retinas. A remarkable protective effect of sortilin inhibition on inner retinal cells was observed in diabetic mice. At eight weeks after diabetes induction, inner retinal thickness was reduced by 9.7% (-12.7%, -6.6%; P < 0.0001; n = 11-12) in the PBS-injected control group compared with the anti-sortilin injected group. Similarly, the count of RGCs was reduced by 20.5% (-30.8%, -10.2%; P = 0.0009) in the PBS-injected control group compared with the anti-sortilin-injected group. Conclusions: Sortilin is upregulated in the diabetic retina, and sortilin inhibition effectively protects against neuronal loss. Thus sortilin emerges as a novel pharmacological target in diabetic retinal neurodegeneration-an important early event in the pathogenesis of diabetic retinopathy.

Ulmus davidiana 60% edible ethanolic extract for prevention of pericyte apoptosis in diabetic retinopathy.

Diabetic retinopathy (DR) is a disease that causes visual deficiency owing to vascular leakage or abnormal angiogenesis. Pericyte apoptosis is considered one of the main causes of vascular leakage in diabetic retina, but there are few known therapeutic agents that prevent it. Ulmus davidiana is a safe natural product that has been used in traditional medicine and is attracting attention as a potential treatment for various diseases, but its effect on pericyte loss or vascular leakage in DR is not known at all. In the present study, we investigated on the effects of 60% edible ethanolic extract of U. davidiana (U60E) and catechin 7-O-ß-D-apiofuranoside (C7A), a compound of U. davidiana, on pericyte survival and endothelial permeability. U60E and C7A prevented pericyte apoptosis by inhibiting the activation of p38 and JNK induced by increased glucose and tumor necrosis factor alpha (TNF-α) levels in diabetic retina. Moreover, U60E and C7A reduced endothelial permeability by preventing pericyte apoptosis in co-cultures of pericytes and endothelial cells. These results suggest that U60E and C7A could be a potential therapeutic agent for reducing vascular leakage by preventing pericyte apoptosis in DR.

Efficiency co-delivery of ellagic acid and oxygen by a non-invasive liposome for ameliorating diabetic retinopathy.

Diabetic retinopathy (DR) is one of the serious complications of diabetes, which has become the fourth leading cause of vision loss worldwide. Current treatment of DR relies on intravitreal injections of antiangiogenic agents, which has made considerable achievements in reducing visual impairment. However, long-term invasive injections require advanced technology and can lead to poor patient compliance as well as the incidence of ocular complications including bleeding, endophthalmitis, retinal detachment and others. Hence, we developed non-invasive liposomes (EA-Hb/TAT&isoDGR-Lipo) for efficiency co-delivery of ellagic acid and oxygen, which can be administered intravenously or by eye drops. Among that, ellagic acid (EA), as an aldose reductase inhibitor, could remove excessive reactive oxygen species (ROS) induced by high glucose for preventing retinal cell apoptosis, as well as reduce retinal angiogenesis through the blockage of VEGFR2 signaling pathway; carried oxygen could ameliorate DR hypoxia, and further enhanced the anti-neovascularization efficacy. Our results showed that EA-Hb/TAT&isoDGR-Lipo not only effectively protected retinal cells from high glucose-induced damage, but also inhibited VEGF-induced vascular endothelial cells migration, invasion, and tube formation in vitro. In addition, in a hypoxic cell model, EA-Hb/TAT&isoDGR-Lipo could reverse retinal cell hypoxia, thereby reducing the expression of VEGF. Significantly, after being administered as an injection or eye drops, EA-Hb/TAT&isoDGR-Lipo obviously ameliorated the structure (central retinal thickness and retinal vascular network) of retina by eliminating ROS and down-regulating the expression of GFAP, HIF-1α, VEGF and p-VEGFR2 in a DR mouse model. In summary, EA-Hb/TAT&isoDGR-Lipo holds great potentials in improvement of DR, which provides a novel approach for the treatment of DR.

Blockade of Annexin A2 Prevents Early Microvasculopathy in Murine Models of Diabetic Retinopathy.

Purpose: We examined the role of annexin A2 (A2) in the development of diabetic retinal vasculopathy by testing the effect of Anxa2 gene deletion as well as administration of anti-A2 antibodies on pericyte dropout and retinal neovascularization in diabetic Akita mice, and in mice subjected to oxygen-induced retinopathy. Methods: We analyzed diabetic Ins2AKITA mice with or without global deletion of Anxa2, as well as Ins2AKITA mice that received intravitreal anti-A2 IgG or control antibody at 2, 4, and 6 months, for retinal pericyte dropout at 7 months of age. In addition, we assessed the effect of intravitreal anti-A2 on oxygen-induced retinopathy (OIR) in neonatal mice by quantifying retinal neovascular and vaso-obliterative area, and by enumeration of neovascular tufts. Results: Both deletion of the Anxa2 gene and immunologic blockade of A2 prevented pericyte depletion in retinas of diabetic Ins2AKITA mice. Blockade of A2 also reduced vaso-obliteration and neovascularization in the OIR model of vascular proliferation. This effect was amplified when a combination of antivascular endothelial growth factor (VEGF) and anti-A2 antibodies was used. Conclusions: Therapeutic approaches that target A2, alone or in combination with anti-VEGF therapy, are effective in mice, and may also curtail the progression of retinal vascular disease in humans with diabetes.

Memantine mitigates ROS/TXNIP/NLRP3 signaling and protects against mouse diabetic retinopathy: Histopathologic, ultrastructural and bioinformatic studies.

Diabetic retinopathy (DRET) triggers vision loss in adults, however, little therapeutic options are existing. Memantine is an anti-Alzheimer drug that antagonizes the activity of glutamate at N-methyl-D-aspartate (NMDA) receptors. Glutamate and thioredoxin-interacting protein (TXNIP) are known to be overexpressed in diabetic retinas and can produce activation of NOD-like receptor protein 3 (NLRP3) with subsequent secretion of interlukin-1ß. This study repurposed memantine for its neuroprotective effect in experimental DRET and tested its impact on ROS/TXNIP/NLRP3. In addition, KEGG pathway database and STRING database identified the protein-protein interaction between glutamate receptors and TXNIP/NLRP3. Male Swiss albino mice received alloxan (180 mg/kg) to induce DRET. After 9 weeks, we divided the mice into groups: (a) saline, (ii) DRET, (iii and iv) DRET + oral memantine (5 or 10 mg per kg) for 28 days. Then, mice were euthanized, and eyeballs were removed. Retinal samples were utilized for biochemical, histopathological, and electron microscopy studies. Retinal levels of glutamate, TXNIP, NLRP3 and interlukin-1ß were estimated using ELISA technique as well as retinal malondialdehyde. Histopathological and ultrastructural examination demonstrated that oral memantine attenuated vacuolization and restored normal retinal cell layers. Moreover, memantine reduced TXNIP, NLRP3, interleukin-1ß and MDA concentrations. These results provide evidence demonstrating memantine' efficacy in alleviating DRET via suppressing reactive oxygen species/TXNIP/NLRP3 signaling cascade. Therefore, memantine might serve as a potential therapy for retinopathy after adequate clinical research.

Blood pressure control for diabetic retinopathy.

BACKGROUND: Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Research has established the importance of blood glucose control to prevent development and progression of the ocular complications of diabetes. Concurrent blood pressure control has been advocated for this purpose, but individual studies have reported varying conclusions regarding the effects of this intervention. OBJECTIVES: To summarize the existing evidence regarding the effect of interventions to control blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs. SEARCH METHODS: We searched several electronic databases, including CENTRAL, and trial registries. We last searched the electronic databases on 3 September 2021. We also reviewed the reference lists of review articles and trial reports selected for inclusion. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which either type 1 or type 2 diabetic participants, with or without hypertension, were assigned randomly to more intense versus less intense blood pressure control; to blood pressure control versus usual care or no intervention on blood pressure (placebo); or to one class of antihypertensive medication versus another or placebo. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently reviewed the titles and abstracts of records identified by the electronic and manual searches and the full-text reports of any records identified as potentially relevant. The included trials were independently assessed for risk of bias with respect to outcomes reported in this review. MAIN RESULTS: We included 29 RCTs conducted in North America, Europe, Australia, Asia, Africa, and the Middle East that had enrolled a total of 4620 type 1 and 22,565 type 2 diabetic participants (sample sizes from 16 to 4477 participants). In all 7 RCTs for normotensive type 1 diabetic participants, 8 of 12 RCTs with normotensive type 2 diabetic participants, and 5 of 10 RCTs with hypertensive type 2 diabetic participants, one group was assigned to one or more antihypertensive agents and the control group to placebo. In the remaining 4 RCTs for normotensive participants with type 2 diabetes and 5 RCTs for hypertensive type 2 diabetic participants, methods of intense blood pressure control were compared to usual care. Eight trials were sponsored entirely and 10 trials partially by pharmaceutical companies; nine studies received support from other sources; and two studies did not report funding source. Study designs, populations, interventions, lengths of follow-up (range less than one year to nine years), and blood pressure targets varied among the included trials. For primary review outcomes after five years of treatment and follow-up, one of the seven trials for type 1 diabetics reported incidence of retinopathy and one trial reported progression of retinopathy; one trial reported a combined outcome of incidence and progression (as defined by study authors). Among normotensive type 2 diabetics, four of 12 trials reported incidence of diabetic retinopathy and two trials reported progression of retinopathy; two trials reported combined incidence and progression. Among hypertensive type 2 diabetics, six of the 10 trials reported incidence of diabetic retinopathy and two trials reported progression of retinopathy; five of the 10 trials reported combined incidence and progression. The evidence supports an overall benefit of more intensive blood pressure intervention for five-year incidence of diabetic retinopathy (11 studies; 4940 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.73 to 0.92; I2 = 15%; moderate certainty evidence) and the combined outcome of incidence and progression (8 studies; 6212 participants; RR 0.78, 95% CI 0.68 to 0.89; I2 = 42%; low certainty evidence). The available evidence did not support a benefit regarding five-year progression of diabetic retinopathy (5 studies; 5144 participants; RR 0.94, 95% CI 0.78 to 1.12; I2 = 57%; moderate certainty evidence), incidence of proliferative diabetic retinopathy, clinically significant macular edema, or vitreous hemorrhage (9 studies; 8237 participants; RR 0.92, 95% CI 0.82 to 1.04; I2 = 31%; low certainty evidence), or loss of 3 or more lines on a visual acuity chart with a logMAR scale (2 studies; 2326 participants; RR 1.15, 95% CI 0.63 to 2.08; I2 = 90%; very low certainty evidence). Hypertensive type 2 diabetic participants realized more benefit from intense blood pressure control for three of the four outcomes concerning incidence and progression of diabetic retinopathy. The adverse event reported most often (13 of 29 trials) was death, yielding an estimated RR 0.87 (95% CI 0.76 to 1.00; 13 studies; 13,979 participants; I2 = 0%; moderate certainty evidence). Hypotension was reported in two trials, with an RR of 2.04 (95% CI 1.63 to 2.55; 2 studies; 3323 participants; I2 = 37%; low certainty evidence), indicating an excess of hypotensive events among participants assigned to more intervention on blood pressure. AUTHORS' CONCLUSIONS: Hypertension is a well-known risk factor for several chronic conditions for which lowering blood pressure has proven to be beneficial. The available evidence supports a modest beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to five years, particularly for hypertensive type 2 diabetics. However, there was a paucity of evidence to support such intervention to slow progression of diabetic retinopathy or to affect other outcomes considered in this review among normotensive diabetics. This weakens any conclusion regarding an overall benefit of intervening on blood pressure in diabetic patients without hypertension for the sole purpose of preventing diabetic retinopathy or avoiding the need for treatment for advanced stages of diabetic retinopathy.

The relationship between dietary patterns and ophthalmic disease.

PURPOSE OF REVIEW: There is a rising interest in the impact of diet on the pathogenesis of common ophthalmic conditions. The purpose of this review is to summarize the potential preventive and therapeutic power of dietary interventions described in recent basic science and epidemiological literature. RECENT FINDINGS: Basic science investigations have elucidated a variety of mechanisms by which diet may impact ophthalmic disease, particularly through its action on chronic oxidative stress, inflammation and macular pigmentation. Epidemiologic investigations have shown the real-world influence of diet on the incidence and progression of a number of ophthalmic diseases, particularly cataract, age-related macular degeneration (AMD) and diabetic retinopathy. A large observational cohort study found a 20% reduction in the incidence of cataract among vegetarians compared with nonvegetarians. Two recent systematic reviews found that higher adherence to Mediterranean dietary patterns was associated with a decreased risk of progression of AMD to later stages. Finally, large meta-analyses found that patients following plant-based and Mediterranean diets had significant reductions of mean haemoglobin A1c scores and incidence of diabetic retinopathy as compared with controls. SUMMARY: There is a significant and growing body of evidence that Mediterranean diet and plant-based diets - those that maximize fruits, vegetables, legumes, whole grains and nuts; and that minimize animal products and processed foods - help prevent vision loss from cataract, AMD and diabetic retinopathy. These diets may hold benefits for other ophthalmic conditions, as well. Nevertheless, there is a need for further randomized, controlled and longitudinal studies in this area.

Estrategia para la prevención de la retinopatía diabética en la atención primaria de salud / A Strategy for the Prevention of Diabetic Retinopathy in Primary Healthcare

Introducción: La retinopatía diabética puede prevenirse con el óptimo control de la diabetes mellitus; sin embargo, la constante llegada de pacientes con diagnóstico de retinopatía diabética avanzada a los centros oftalmológicos apunta a la insuficiente prevención primaria de esta enfermedad. Objetivo: Proponer herramientas prácticas vinculadas a los principales factores de riesgo que pueden ser controlados o modificados en pacientes diabéticos para lograr una prevención primaria de la retinopatía diabética más efectiva. Métodos: Se consultaron artículos referentes a la prevención de la retinopatía diabética en la atención primaria de salud durante los meses de noviembre-diciembre de 2020 y enero de 2021; publicados en diversas revistas e indexados en las bases de datos PubMed, SciELO, Medscape; otros textos afines, páginas web y blogs del año 2010 en adelante. Las sintaxis empleadas fueron retinopatía diabética, prevalencia y prevención de retinopatía diabética, prevención primaria, complicaciones oculares de la diabetes mellitus y factores de riesgo de la retinopatía diabética. Conclusiones: La adición de nuevas estrategias al control o modificación de los principales factores de riesgo en los pacientes diabéticos constituye una alternativa para perfeccionar la prevención primaria de la retinopatía diabética(AU)

Introduction: Diabetic retinopathy can be prevented with the optimal control of diabetes mellitus; however, the constant arrival of patients with a diagnosis of advanced diabetic retinopathy to ophthalmologic centers points to insufficient primary prevention of this disease. Objective: To propose practical tools related to the main risk factors that can be controlled or modified in diabetic patients to achieve a more effective primary prevention of diabetic retinopathy. Methods: Articles concerning the prevention of diabetic retinopathy in primary healthcare were consulted, covering the months of November-December 2020 and January 2021, published in various journals and indexed in the PubMed, SciELO and Medscape databases; together with other related texts, websites and blogs from 2010 onwards. The used syntaxes were retinopatía diabética [diabetic retinopathy], prevalencia y prevención de retinopatía diabética [prevalence and prevention of diabetic retinopathy], prevención primaria [primary prevention], complicaciones oculares de la diabetes mellitus [ocular complications of diabetes mellitus] and factores de riesgo de la retinopatía diabética [risk factors for diabetic retinopathy]. Conclusions: The addition of new strategies to the control or modification of the main risk factors in diabetic patients is an alternative to perfect primary prevention of diabetic retinopathy(AU)