Common and specific proteins and pathways in heart and cerebral ischemia.

OBJECTIVE: To understand the similarities and differences between acute ischemic stroke and acute myocardial infarction (AMI) to help in the development of specific or common treatment strategies. METHODS: Using an aptamer-based proteomic array, we measured and compared 1310 circulating proteins in the blood of 40 patients with AIS, 9 patients with AMI, and 31 healthy controls. Pathway enrichment analysis was performed using GSEA and g:profiler. RESULTS: Ninety-four proteins were differentially expressed in AIS, and 284 were differentially expressed in AMI. Of these, 8 were specific to cerebral ischemia, and 197 were specific to myocardial infarction. Forty-two proteins were altered in both ischemia processes. Most altered pathways in AIS could be classified as immune response, cell cycle processing, molecular transport, or signaling. Pathways altered in AMI were mostly related to lipid metabolism and transport, highlighting cholesterol metabolic processes and estrogen signaling. In both types of ischemia, we found pathways related to metabolism, specifically purine metabolism, and signaling processes, such as TNF signaling or MAPK1/3. CONCLUSIONS: The present study revealed proteins and pathways that were specifically altered in cerebral ischemia, in cardiac ischemia, or in both diseases, providing information on the similarities and differences of ischemic conditions. The role of common and specific proteins and pathways should be explored in detail to find possible therapeutic targets.

Inflammation: The Link between Neural and Vascular Impairment in the Diabetic Retina and Therapeutic Implications.

The etiology of diabetic retinopathy (DR) is complex, multifactorial and compromises all the elements of the retinal neurovascular unit (NVU). This diabetic complication has a chronic low-grade inflammatory component involving multiple inflammatory mediators and adhesion molecules. The diabetic milieu promotes reactive gliosis, pro-inflammatory cytokine production and leukocyte recruitment, which contribute to the disruption of the blood retinal barrier. The understanding and the continuous research of the mechanisms behind the strong inflammatory component of the disease allows the design of new therapeutic strategies to address this unmet medical need. In this context, the aim of this review article is to recapitulate the latest research on the role of inflammation in DR and to discuss the efficacy of currently administered anti-inflammatory treatments and those still under development.

Insights into Insulin Resistance and Calcification in the Myocardium in Type 2 Diabetes: A Coronary Artery Analysis.

Type 2 diabetes (T2D) is responsible for high incidence of cardiovascular (CV) complications leading to heart failure. Coronary artery region-specific metabolic and structural assessment could provide deeper insight into the extent of the disease and help prevent adverse cardiac events. Therefore, in this study, we aimed at investigating such myocardial dynamics for the first time in insulin-sensitive (mIS) and insulin-resistant (mIR) T2D patients. We targeted global and region-specific variations using insulin sensitivity (IS) and coronary artery calcifications (CACs) as CV risk factor in T2D patients. IS was computed using myocardial segmentation approaches at both baseline and after an hyperglycemic-insulinemic clamp (HEC) on [18F]FDG-PET images using the standardized uptake value (SUV) (ΔSUV = SUVHEC - SUVBASELINE) and calcifications using CT Calcium Scoring. Results suggest that some communicating pathways between response to insulin and calcification are present in the myocardium, whilst differences between coronary arteries were only observed in the mIS cohort. Risk indicators were mostly observed for mIR and highly calcified subjects, which supports previously stated findings that exhibit a distinguished exposure depending on the impairment of response to insulin, while projecting added potential complications due to arterial obstruction. Moreover, a pattern relating calcification and T2D phenotypes was observed suggesting the avoidance of insulin treatment in mIS but its endorsement in mIR subjects. The right coronary artery displayed more ΔSUV, whilst plaque was more present in the circumflex. However, differences between phenotypes, and therefore CV risk, were associated to left descending artery (LAD) translating into higher CACs regarding IR, which could explain why insulin treatment was effective for LAD at the expense of higher likelihood of plaque accumulation. Personalized approaches to assess T2D may lead to more efficient treatments and risk-prevention strategies.

Prediction of clinical events by liver stiffness and chronic kidney disease by NAFLD in patients with type-2 diabetes.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with poorer glycemic control and a higher risk of type-2 diabetes (T2D) complications, extrahepatic and cardiovascular disease (CVD). Our study aim was to evaluate the association between NAFLD, T2D complications, and the development of overall clinical events (OCE) (CV, liver-related, and mortality) in patients with T2D. METHODS: Prospective single-center study comprising T2D subjects with no history of CVD and non-T2D matched controls. Patients were selected from the Outpatient Diabetes Clinic of Vall d'Hebron Hospital and related primary care centers. RESULTS: 186 diabetics and 57 controls were included. Amongst T2D, 124/186 subjects had NAFLD (66.6%). T2D-NAFLD subjects showed a heavier metabolic burden and higher median liver stiffness (5.6kPa [4.5-7.3] vs 4.8 [4.2-5.8]; p=0.004) compared to non-NAFLD diabetics. During a median follow-up of 5.6 years, 33 (17.7%) T2D patients developed OCE vs 4 (7.0%) controls (p=0.049). No differences were found for OCE between NAFLD and non-NAFLD diabetics (16.9% vs 19.4%; p=0.68). CV was the most reported outcome and only one liver event occurred. NAFLD diabetics showed more often chronic kidney disease (CKD), whereas T2D complications and subclinical CVD rates were similar. A higher liver stiffness, older age, and male gender were independently associated with OCE amongst the entire T2D population and NAFLD diabetics. CONCLUSIONS: NAFLD and liver stiffness were associated with CKD and clinical outcomes in diabetics, respectively. A hepatic evaluation is recommended to identify high-risk T2D patients that would benefit from early referral to specialized care.

Advanced Glycations End Products in the Skin as Biomarkers of Cardiovascular Risk in Type 2 Diabetes.

The incidence and prevalence of diabetes are increasing worldwide, and cardiovascular disease (CVD) is the leading cause of death among subjects with type 2 diabetes (T2D). The assessment and stratification of cardiovascular risk in subjects with T2D is a challenge. Advanced glycation end products are heterogeneous molecules produced by non-enzymatic glycation of proteins, lipids, or nucleic acids. Accumulation of advanced glycation end products is increased in subjects with T2D and is considered to be one of the major pathogenic mechanism in developing complications in diabetes. Skin AGEs could be assessed by skin autofluorescence. This method has been validated and related to the presence of micro and macroangiopathy in individuals with type 2 diabetes. In this context, the aim of this review is to critically summarize current knowledge and scientific evidence on the relationship between skin AGEs and CVD in subjects with type 2 diabetes, with a brief reference to other diabetes-related complications.

Standardization of Optical Coherence Tomography Angiography Imaging Biomarkers in Diabetic Retinal Disease.

Optical coherence tomography Angiography (OCT-A) represents a revolution in the noninvasive evaluation of retinal and choroidal circulation especially in detecting early clinical signs of diabetic retinal disease (DRD). With appropriate use, OCT-A characteristics and measurements have the potential to become new imaging biomarkers in managing and treating DRD. Major challenges include (a) provision of standardized outputs from different OCT-A instruments providing standardized terminology to correctly interpret data; (b) the presence of artifacts; (c) the absence of standardized grading or interpretation method in the evaluation of DRD, similar to that already established in fundus photography; and (d) establishing how OCT-A might be able to provide surrogate markers to demonstrate blood retinal barrier breakdown and vascular leakage, commonly associated with DRD. In fact, OCT-A guidelines for DRD are still evolving. The outputs of quantitative OCT-A data offer a unique opportunity to develop tools based on artificial intelligence to assist the clinicians in diagnosing, monitoring, and managing patients with diabetes. In addition, OCT-A has the potential to become a useful tool for the evaluation of cardiovascular diseases and different neurological diseases including cognitive impairment. This article written by the members of Diabetic Retinopathy expert committee of the European Vision Clinical Research network will review the available evidence on the use of OCT-A as an imaging biomarker in DRD and discuss the limits and the current application as well as future developments for its use in both clinical practice and research trials of DRD.

Diabetic Retinopathy in the Context of Patients with Diabetes.

Diabetic retinopathy (DR) is the most frequent complication of diabetes. The main risk factors are disease duration, a poor glycemic control, and the presence of hypertension. However, there is an important variation in risk which indicates that other factors, such as genetic heritability or glycemic variability, play an important role in accounting for the susceptibility to DR development. Another important concept is that DR is an independent predictor of both microvascular and macrovascular complications. Thus, the presence of DR should be taken into account when evaluating the cardiovascular risk of a diabetic subject. Moreover, the evaluation of retinal neurodegeneration could help to identify those diabetic subjects at risk of cognitive impairment, an emerging complication of the type 2 diabetic population. When evaluating a diabetic subject, the awareness of the presence of DR has also therapeutic implications. In this regard, a worsening of DR could occur after a rapid improvement of blood glucose. In summary, a critical review on the importance of the presence of DR in the general management of subjects with diabetes is provided.

Effects of Liposomal Formulation of Citicoline in Experimental Diabetes-Induced Retinal Neurodegeneration.

Diabetic retinopathy (DR) has been classically considered a microcirculatory disease of the retina. However, there is growing evidence to suggest that retinal neurodegeneration is also an early event in the pathogenesis of DR. Citicoline has been successfully used as a neuroprotective agent in the treatment of glaucoma but their effects on DR remain to be elucidated. On this basis, the main aim of the present study was to evaluate the effect of topical administration of citicoline in liposomal formulation on retinal neurodegeneration in db/db mouse and to investigate the underlying mechanisms of action. The treatment (citicoline or vehicle) was topically administered twice daily for 15 days. Retinal analyses were performed in vivo by electroretinography and ex vivo by using Western blot and immunofluorescence measurements. We found that the liposomal formulation of citicoline prevented glial activation and neural apoptosis in the diabetic retina. The main mechanism implicated in these beneficial effects were the inhibition of the downregulation of synaptophysin and its anti-inflammatory properties by means of preventing the upregulation of NF-κB and TNF-α (Tumor Necrosis Factor α) induced by diabetes. Overall, these results suggest that topical administration of citicoline in liposomal formulation could be considered as a new strategy for treating the early stages of DR.

Topical Administration of Bosentan Prevents Retinal Neurodegeneration in Experimental Diabetes.

Experimental evidence suggests that endothelin 1 (ET-1) is involved in the development of retinal microvascular abnormalities induced by diabetes. The effects of ET-1 are mediated by endothelin A- and B-receptors (ETA and ETB). Endothelin B-receptors activation mediates retinal neurodegeneration but there are no data regarding the effectiveness of ETB receptor blockage in arresting retinal neurodegeneration induced by diabetes. The main aim of the present study was to assess the usefulness of topical administration of bosentan (a dual endothelin receptor antagonist) in preventing retinal neurodegeneration in diabetic (db/db) mice. For this purpose, db/db mice aged 10 weeks were treated with one drop of bosentan (5 mg/mL, n = 6) or vehicle (n = 6) administered twice daily for 14 days. Six non-diabetic (db/+) mice matched by age were included as the control group. Glial activation was evaluated by immunofluorescence using specific antibodies against glial fibrillary acidic protein (GFAP). Apoptosis was assessed by TUNEL method. A pharmacokinetic study was performed in rabbits. We found that topical administration of bosentan resulted in a significant decrease of reactive gliosis and apoptosis. The results of the pharmacokinetic study suggested that bosentan reached the retina through the trans-scleral route. We conclude that topical administration of bosentan was effective in preventing neurodegeneration in the diabetic retina and, therefore, could be a good candidate to be tested in clinical trials.

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes.

AIMS/HYPOTHESIS: The main aims of the present study were: (1) to assess the expression and content of dipeptidyl peptidase IV (DPP-IV) in human and db/db mouse retinas, and in human vitreous fluid; and (2) to determine whether the topical administration of the DPP-IV inhibitors (DPP-IVi) would prevent retinal neurodegeneration and vascular leakage in db/db mice by reducing endogenous glucagon-like peptide 1 (GLP-1) degradation. METHODS: To assess the expression and content of DPP-IV, human samples of vitreous fluid and retinas were obtained from participants with type 2 diabetes (n = 8) and age-matched non-diabetic individuals (n = 8), as well as from db/db (n = 72) and db/+ (n = 28) mice. The interventional study, which included 72 db/db mice, consisted of the topical administration (eye drops) of saxagliptin, sitagliptin or vehicle for 14 days. DPP-IV mRNA levels were assessed by RT-PCR, and protein content was measured by ELISA or western blotting. GLP-1 was assessed by immunofluorescence, and its downstream effector exchange protein activated by cAMP-1 (EPAC-1) was used as a measure of GLP-1 receptor activation. Retinal analyses were performed in vivo by electroretinography and ex vivo by RT-PCR (Epac-1, Iba-1 [also known as Aif1]), western blotting (EPAC-1, glial fibrillar acidic protein [GFAP], glutamate-aspartate transporter [GLAST]) and immunofluorescence measurements (GLP-1, GFAP, ionised calcium binding adaptor molecule 1 [IBA-1], TUNEL, GLAST, albumin and collagen IV). Glutamate was quantified by HPLC. In addition, vascular leakage was examined by the Evans Blue method. RESULTS: DPP-IV was present in human vitreous fluid but in a range 100-fold less than in plasma. Both mRNA levels and protein content were much lower in the retina than in the liver or bowel, but were significantly higher in retinal pigment epithelium (RPE) from diabetic donors in comparison to non-diabetic donors (p < 0.05). Topical treatment with DPP-IVi prevented glial activation, apoptosis and vascular leakage induced by diabetes in db/db mice (p < 0.05). Moreover, it also significantly prevented diabetes-induced functional abnormalities in the electroretinogram. A significant increase of both GLP-1 and EPAC-1 was found after treatment with DPP-IVi (p < 0.05). Furthermore, GLAST downregulation induced by diabetes was prevented, resulting in a significant reduction of extracellular glutamate concentrations. All these effects were observed without any changes in blood glucose levels. CONCLUSIONS/INTERPRETATION: The topical administration of DPP-IVi is effective in preventing neurodegeneration and vascular leakage in the diabetic retina. These effects can be attributed to an enhancement of GLP-1, but other mechanisms unrelated to the prevention of GLP-1 degradation cannot be ruled out.

Is fenofibrate a reasonable treatment for diabetic microvascular disease?

Type 2 diabetes is a pandemic disease, and its prevalence is increasing mainly due to an increase in obesity and life expectancy. Diabetic complications and their comorbidities constitute the most important economic cost of the disease and represent a significant economic burden for the healthcare systems of developed countries. Despite improving standards of care, people with diabetes remain at risk of the development and progression of microvascular diabetic complications. Therefore, the identification of novel therapeutic approaches is necessary. The aim of this article is to provide an overview of the clinical benefits of fenofibrate on microvascular diabetic complications, with special emphasis on diabetic retinopathy. In addition, the potential mechanisms of action will be briefly discussed.

The usefulness of the retina for identifying people with type 2 diabetes with prodromal stages of dementia.

Type 2 diabetes (T2D) is associated with cognitive impairment and dementia. The detection of cognitive impairment is important because this population is at higher risk of experiencing difficulties in the self-management of diabetes. Mild cognitive impairment (MCI) often remains undiagnosed due to lack of simple tools for screening at large scale. This represents an important gap in the patients' management because subjects with diabetes and MCI are at high risk of progressing to dementia. Due to its developmental origin as a brain-derived tissue, the retina has been proposed as a potential means of non-invasive and readily accessible exploration of brain pathology. Recent evidence showed that retinal imaging and/or functional tests are correlated with the cognitive function and brain changes in T2D. Simple retinal functional tests (i.e. retinal microperimetry) have proven to be useful as reliable tool for the cognitive evaluation and monitoring in patients with T2D>65 years. This review gives an overall update on the usefulness of retinal imaging in identifying patients with T2D at risk of developing dementia.

Oral phytate supplementation on the progression of mild cognitive impairment, brain iron deposition and diabetic retinopathy in patients with type 2 diabetes: a concept paper for a randomized double blind placebo controlled trial (the PHYND trial).

Type 2 diabetes mellitus has a worldwide prevalence of 10.5% in the adult population (20-79 years), and by 2045, the prevalence is expected to keep rising to one in eight adults living with diabetes. Mild cognitive impairment has a global prevalence of 19.7% in adults aged 50 years. Both conditions have shown a concerning increase in prevalence rates over the past 10 years, highlighting a growing public health challenge. Future forecasts indicate that the prevalence of dementia (no estimations done for individuals with mild cognitive impairment) is expected to nearly triple by 2050. Type 2 diabetes mellitus is a risk factor for the development of cognitive impairment, and such impairment increase the likelihood of poor glycemic/metabolic control. High phytate intake has been shown to be a protective factor against the development of cognitive impairment in observational studies. Diary phytate intake might reduce the micro- and macrovascular complications of patients with type 2 diabetes mellitus through different mechanisms. We describe the protocol of the first trial (the PHYND trial) that evaluate the effect of daily phytate supplementation over 56 weeks with a two-arm double-blind placebo-controlled study on the progression of mild cognitive impairment, cerebral iron deposition, and retinal involvement in patients with type 2 diabetes mellitus. Our hypothesis proposes that phytate, by inhibiting advanced glycation end product formation and chelating transition metals, will improve cognitive function and attenuate the progression from Mild Cognitive Impairment to dementia in individuals with type 2 diabetes mellitus and mild cognitive impairment. Additionally, we predict that phytate will reduce iron accumulation in the central nervous system, mitigate neurodegenerative changes in both the central nervous system and retina, and induce alterations in biochemical markers associated with neurodegeneration.

Genetics in diabetic retinopathy: current concepts and new insights.

There is emerging evidence which indicates the essential role of genetic factors in the development of diabetic retinopathy (DR). In this regard it should be highlighted that genetic factors account for 25-50% of the risk of developing DR. Therefore, the use of genetic analysis to identify those diabetic patients most prone to developing DR might be useful in designing a more individualized treatment. In this regard, there are three main research strategies: candidate gene studies, linkage studies and Genome-Wide Association Studies (GWAS). In the candidate gene approach, several genes encoding proteins closely related to DR development have been analyzed. The linkage studies analyze shared alleles among family members with DR under the assumption that these predispose to a more aggressive development of DR. Finally, Genome-Wide Association Studies (GWAS) are a new tool involving a massive evaluation of single nucleotide polymorphisms (SNP) in large samples. In this review the available information using these three methodologies is critically analyzed. A genetic approach in order to identify new candidates in the pathogenesis of DR would permit us to design more targeted therapeutic strategies in order to decrease this devastating complication of diabetes. Basic researchers, ophthalmologists, diabetologists and geneticists should work together in order to gain new insights into this issue.

Efficacy of Insulin Titration Driven by SMS in Improving Glycemic Control in People with Type 2 Diabetes.

AIM: To evaluate the efficacy of the self-management of insulin titration based on information received by the Short Message Service (SMS). METHODS: A case-control study including 59 subjects in each arm with 16 weeks of follow-up was performed. The inclusion criteria were: (1) Subjects with type 2 diabetes (T2D) under basal insulin treatment; (2) Suboptimal glycemic control: HbA1c ≥ 7.5% and fasting capillary blood glucose (FCBG) > 140 mg/dL (>3 times per week). Subjects were invited to use an insulin titration service based on SMS feedback aimed at optimizing glycemic control depending on fasting blood glucose levels. Psychological aspects were evaluated in the interventional group by means of validated questionnaires (DDS, HADS and SF-12). RESULTS: The intervention group achieved a lower mean FCBG (126 mg/dL ± 34 vs. 149 mg/dL ± 46, p = 0.001) and lower HbA1c (7.5% ± 1.3 vs. 7.9% ± 0.9, p = 0.021) than the control group. In addition, the intervention group showed a significant improvement in psychological aspects related to Emotional Burden (p = 0.031), Regimen Distress (p < 0.001), Depression (p = 0.049) and Mental Health (p < 0.01). CONCLUSIONS: The SMS-guided titration was effective in terms of improving glucometric parameters in comparison with the standard of care and improved significant psychological aspects-mainly, the stress associated with insulin treatment.

Psychometric validation of the MIND Youth Questionnaire (MY-Q) to assess quality of life in Spanish patients with type 1 diabetes between 12 and 25 years old.

AIM: Validate in Spanish the Monitoring Individual Needs in Diabetes Youth Questionnaire (MY-Q), a multi-dimensional self-report HRQoL questionnaire designed for paediatric diabetes care. DESIGN AND METHODS: After translation, 209 patients diagnosed with type 1 diabetes, between 12 and 25 years old were assessed. The patients belonged to 12 hospitals in Spain. RESULTS: Exploratory factor analysis including one-factor up to seven-factor solutions were tested. The three-factor solution (Negative Impact of Diabetes, Empowerment and Control of Diabetes and Worries) was the most parsimonious model with adequate fit: χ2(723)=568.856 (p<0.001), CFI=0.913, RMSEA=0.072 [0.064, 0.080], SRMR=0.075. The three-factor solution and the grouping of the items followed a clear rationale. Cronbach's alpha was 0.816 for Negative Impact, 0.700 for Empowerment and Control and 0.795 for Worries. The study of the relationship between the MY-Q dimensions and socio-demographics variables show a relationship between age and the MY-Q: F(6,410)=10.873 (p<0.001), η2=0.137. Participants younger than 14 years old showed greater scores on Empowerment and Control when compared to participants between 14 and 17 years old (p=0.021); statistically significant differences were found for the participants 18 years old or older, who showed lower levels of Worries than the younger patients. Concurrent validity found that the dimension of Negative Impact of Diabetes was positively related to WHO-5, and the PedsQL Diabetes Module. CONCLUSION: The Spanish version of the MY-Q to measure HRQoL in patients with type 1 diabetes between the ages of 12 and 25, has adequate psychometric properties and conceptual and semantic equivalence with the original version in Dutch.

Switching from treatment with sensor augmented pump to hybrid closed loop system in type 1 diabetes: Impact on glycemic control and neuropsychological tests in the real world.

AIMS: The aim of this study is to assess in the real world the impact of initiating hybrid closed loop (HCL) on glycemic control and quality of life in patients using sensor-augmented pump (SAP). METHODS: In this prospective study, patients using SAP changed to an HCL system in a specialized hospital. HCL devices used were Medtronic 780G®, Tandem Control-IQ® and Diabeloop® system. Glucometric data and hypoglycemia and neuropsychological tests were assessed at baseline and 3 months after initiating HCL. RESULTS: A total of 66 consecutive patients were included (74% women, mean age 44 ± 11 years, diabetes duration 27.2 ± 11 years). Significant improvements were observed in coefficient of variation (from 35.6% to 33.1%), time in range (from 62.2 % to 73.8%), time above 180 mg/dl (from 26.9% to 18%), time below 70 mg/dl (from 3.3% to 2.1%) and time below 55 mg/dl (from 0.7% to 0.3%). In addition, significant improvements were observed in fear of hypoglycemia and grade of distress associated to treatment and to interpersonal sphere. CONCLUSIONS: Switching from SAP to HCL system improves time in range and reduces time in hypoglycemia and glycemic variability at 3 months. These changes are accompanied by significant reduction of neuropsychological burden related to diabetes.

Serum glial fibrillary acidic protein and neurofilament light chain as biomarkers of retinal neurodysfunction in early diabetic retinopathy: results of the EUROCONDOR study.

AIMS: Neurodegeneration and glial activation are primary events in the pathogenesis of diabetic retinopathy. Serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are biomarkers of underlying neuroinflammatory and neurodegenerative disease processes. The aim of the present study was to assess the usefulness of these serum biomarkers for the identification and monitoring of retinal neurodysfunction in subjects with type 2 diabetes. METHODS: A case-control study was designed including 38 patients from the placebo arm of the EUROCONDOR clinical trial: 19 with and 19 without retinal neurodysfunction assessed by multifocal electroretinography. GFAP and NfL were measured by Simoa. RESULTS: Serum levels of GFAP and NfL directly correlated with age (r = 0.37, p = 0.023 and r = 0.54, p < 0.001, respectively). In addition, a direct correlation between GFAP and NfL was observed (r = 0.495, p = 0.002). Serum levels of GFAP were significantly higher at baseline in those subjects in whom neurodysfunction progressed after the 2 years of follow-up (139.1 ± 52.5 pg/mL vs. 100.2 ± 54.6 pg/mL; p = 0.04). CONCLUSIONS: GFAP could be a useful serum biomarker for retinal neurodysfunction. Monitoring retinal neurodysfunction using blood samples would be of benefit in clinical decision-making. However, further research is needed to validate this result as well as to establish the best cutoff values.

Usefulness of the vitreous fluid analysis in the translational research of diabetic retinopathy.

Diabetic retinopathy (DR) is the major cause of acquired blindness in working-age adults. Current treatments for DR (laser photocoagulation, intravitreal corticosteroids, intravitreal antivascular endothelial growth factor (VEGF) agents, and vitreo-retinal surgery) are applicable only at advanced stages of the disease and are associated with significant adverse effects. Therefore, new pharmacological treatments for the early stages of the disease are needed. Vitreous fluid obtained from diabetic patients undergoing vitreoretinal surgery is currently used to explore the events that are taking place in the retina for clinical research. However, several confounding factors such as vitreous haemorrhage and concentration of vitreous proteins should be considered in the analysis of the results. In this paper we will focus on the vitreous fluid as a tool for exploring the mediators of DR and in particular the molecules related to inflammatory pathways. In addition, their role in the pathogenesis of DR will be discussed. The usefulness of new technologies such as flow cytometry and proteomics in identifying new candidates involved in the inflammatory process that occurs in DR will be overviewed. Finally, a more personalized treatment based on vitreous fluid analysis aiming to reduce the burden associated with DR is suggested.

Diabetic Retinopathy: Role of Neurodegeneration and Therapeutic Perspectives.

ABSTRACT: Retinal neurodegeneration plays a significant role in the pathogenesis of diabetic retinopathy, the leading cause of preventable blindness. The hallmarks of diabetes-induced neurodegeneration are neural cell apoptosis and glial activation, which seem even before vascular lesions can be detected by ophthalmoscopic examination. The molecular mediators of retinal neurodegeneration include proinflamma- tory cytokines, oxidative stress, mitochondrial dysfunction, and the molecular pathways closely related to chronic hyperglycemia. In this article, an overview of the main components of neurodegeneration, its key underlying mechanisms, and the more useful experimental models for investigative purposes will be given. In addition, the results of most relevant treatments based on neuroprotection, and the research gaps that should be filled will be critically reviewed.