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Diabetic retinopathy is a vision-threatening complication of diabetes and a leading cause of blindness globally. Complications are a major burden to the healthcare system. This study was carried out to evaluate the real-world treatment outcomes of proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). The first study (I) included 103 patients with type 1 (T1D) or type 2 diabetes and PDR with vitreous hemorrhage (VH). Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agent bevacizumab showed superiority to panretinal photocoagulation, pars plana vitrectomy and observation alone in shortening the time for clearance of VH (p

Diabetic retinopathy is a common diabetes complication that threatens the eyesight and may eventually lead to acquired visual impairment or blindness. While a substantial heritability has been reported for proliferative diabetic retinopathy (PDR), only a few genetic risk factors have been identified. Using genome-wide sib pair linkage analysis including 361 individuals with type 1 diabetes, we found suggestive evidence of linkage with PDR at chromosome 10p12 overlapping the CACNB2 gene (logarithm of odds = 2.73). Evidence of association between variants in CACNB2 and PDR was also found in association analysis of 4,005 individuals with type 1 diabetes with an odds ratio of 0.83 and P value of 8.6 x 10(-4) for rs11014284. Sequencing of CACNB2 revealed two coding variants, R476C/rs202152674 and S502L/rs137886839. CACNB2 is abundantly expressed in retinal cells and encodes the beta 2 subunit of the L-type calcium channel. Blocking vascular endothelial growth factor (VEGF) by intravitreous anti-VEGF injections is a promising clinical therapy to treat PDR. Our data show that L-type calcium channels regulate VEGF expression and secretion from retinal pigment epithelial cells (ARPE19) and support the role of CACNB2 via regulation of VEGF in the pathogenesis of PDR. However, further genetic and functional studies are necessary to consolidate the findings.

In diabetic patients, high blood glucose induces alterations in retinal function and can lead to visual impairment due to diabetic retinopathy. In immortalized retinal pigment epithelial (RPE) cultures, high glucose concentrations are shown to lead to impairment in epithelial barrier properties. For the first time, the induced pluripotent stem-cell-derived retinal pigment epithelium (hiPSC-RPE) cell lines derived from type 2 diabetics and healthy control patients were utilized to assess the effects of glucose concentration on the cellular functionality. We show that both type 2 diabetic and healthy control hiPSC-RPE lines differentiate and mature well, both in high and normal glucose concentrations, express RPE specific genes, secrete pigment epithelium derived factor, and form a polarized cell layer. Here, type 2 diabetic hiPSC-RPE cells had a decreased barrier function compared to controls. Added insulin increased the epithelial cell layer tightness in normal glucose concentrations, and the effect was more evident in type 2 diabetics than in healthy control hiPSC-RPE cells. In addition, the preliminary functionality assessments showed that type 2 diabetic hiPSC-RPE cells had attenuated autophagy detected via ubiquitin-binding protein p62/Sequestosome-1 (p62/SQSTM1) accumulation, and lowered pro- matrix metalloproteinase 2 (proMMP2) as well as increased pro-MMP9 secretion. These results suggest that the cellular ability to tolerate stress is possibly decreased in type 2 diabetic RPE cells. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:20 issue:15 ispartof: location:Switzerland status: published

The incidence of childhood onset type 1 diabetes in Finland has been the highest in the world for several decades. Optimal management of the disease presents a lifelong challenge to the affected individuals. Related complications are common and include an ocular pathology called diabetic retinopathy. Type 1 diabetes with its ramifications can impact on several facets of a patient’s physical and psychological well-being. This study aimed to assess the ophthalmic findings and to evaluate the characteristics of general well-being of a population-based cohort of paediatric patients with type 1 diabetes and a population-based cohort of young adults with type 1 diabetes since childhood. The prevalence and risk factors of diabetic retinopathy were assessed of the population-based paediatric cohort in the catchment area of the Northern Ostrobothnia Hospital District and these were compared to a similar paediatric cohort studied 18 years previously. There was no significant change in the overall prevalence of diabetic retinopathy (12%) during the study period. Furthermore, glycaemic balance and other risk factors of diabetic retinopathy had remained almost unchanged. A population-based cohort of young adults was evaluated in 2007 for the prevalence and severity of diabetic retinopathy. Most of the cohort subjects (94%) had developed diabetic retinopathy and in every third subject there was evidence of proliferative retinopathy. Health related quality of life was the same as that in the age- and gender-standardised control population. For the most part, the young adults with a long duration of type 1 diabetes fared equally well as the general population in the measured social aspects. However, proliferative diabetic retinopathy was associated with lower educational achievements and poorer health related quality of life as well as with a higher probability of unemployment or being pensioned. Glycaemic balance and prevalence of diabetic retinopathy have remained unchanged in paediatric cohorts for nearly two decades despite concurrent advances in care. Social well-being was mainly restricted in young adults exhibiting signs of proliferative diabetic retinopathy. The negative impact of advanced complications of type 1 diabetes already in these young adults highlights the importance of strict metabolic control to maintain overall well-being. Tiivistelmä Lapsuusiässä alkavan tyypin 1 diabeteksen ilmaantuvuus on ollut Suomessa maailman korkein usean vuosikymmenen ajan. Hyvän hoitotasapainon ylläpitäminen on elinikäinen haaste sairastuneelle. Diabeteksen liitännäissairaudet ovat yleisiä, kuten myös silmänpohjissa todettava diabeettinen retinopatia. Tyypin 1 diabetes voi komplikaatioineen vaikuttaa laajasti potilaan fyysiseen ja psyykkiseen hyvinvointiin. Tässä tutkimuksessa pyrittiin arvioimaan silmien terveydentilaa ja yleiseen hyvinvointiin liittyviä tekijöitä tyypin 1 diabetesta sairastavien lasten sekä lapsena diabetekseen sairastuneiden nuorten aikuisten väestöpohjaisissa potilasaineistoissa. Diabeettisen retinopatian esiintyvyys ja riskitekijät tutkittiin väestöpohjaisessa lapsipotilasaineistossa Pohjois-Pohjanmaan sairaanhoitopiirin alueella ja tuloksia verrattiin vastaavaan 18 vuotta aiemmin tutkittuun potilasaineistoon. Diabeettisen retinopatian esiintyvyys (12 %) ei ollut merkittävästi muuttunut tutkimusaikana. Glykeeminen tasapaino ja muut diabeettisen retinopatian riskitekijät olivat pysyneet kohorttien välillä oleellisilta osin ennallaan. Lapsena sairastuneiden nuorten aikuisten väestöpohjaisesta potilasaineistosta arvioitiin diabeettisen retinopatian esiintyvyys ja vaikeusaste vuonna 2007. Enemmistölle potilaista (94 %) oli kehittynyt diabeettinen retinopatia ja kolmanneksella todettiin proliferatiivinen retinopatia. Terveyteen liittyvä elämänlaatu oli verrattavissa ikä- ja sukupuolivakioituun verrokkiväestöön. Sosiaalista hyvinvointia mittaavat tulokset olivat pääosin yhtäläiset muuhun väestöön verrattuna. Proliferatiivisella diabeettisella retinopatialla havaittiin kuitenkin yhteys huonompaan terveyteen liittyvään elämänlaatuun ja koulutustasoon sekä korkeampiin työttömyys- ja eläköitymislukuihin. Tutkitussa aineistossa lapsipotilaiden glykeeminen tasapaino sekä diabeettisen retinopatian esiintyvyys pysyivät ennallaan lähes kahden vuosikymmenen ajan hoitojen kehittymisestä huolimatta. Nuorten aikuisten sosiaalisessa hyvinvoinnissa esiintyi poikkeavuuksia lähinnä proliferatiivista diabeettista retinopatiaa sairastavilla. Tyypin 1 diabeteksen pitkälle edenneiden komplikaatioiden negatiivinen vaikutus jo nuorella aikuisiällä korostaa hyvän hoitotasapainon tärkeyttä yleisen elämänlaadun ylläpitämisessä.

PURPOSE. The role of R-Ras in retinal angiogenesis and vascular permeability was evaluated in an oxygen-induced retinopathy (OIR) model using R-Ras knockout (KO) mice and in human diabetic neovascular membranes. METHODS. Mice deficient for R-Ras and their wild-type (WT) littermates were subjected to 75% oxygen from postnatal day 7 (P7) to P12 and then returned to room air. At P17 retinal vascularization was examined from whole mounts, and retinal vascular permeability was studied using Miles assay. Real-time RT-PCR, Western blotting, and immunohistochemistry were used to assess the expression of R-Ras in retina during development or in the OIR model. The degree of pericyte coverage and vascular endothelial (VE)-cadherin expression on WT and R-Ras KO retinal blood vessels was quantified using confocal microscopy. The correlation of R-Ras with vascular endothelial growth factor receptor 2 (VEGFR2) and human serum albumin on human proliferative diabetic retinopathy membranes was assessed using immunohistochemistry. RESULTS. In retina, R-Ras expression was mostly restricted to the vasculature. Retinal vessels in the R-Ras KO mice were significantly more permeable than WT controls in the OIR model. A significant reduction in the direct physical contact between pericytes and blood vessel endothelium as well as reduced VE-cadherin immunostaining was found in R-Ras–deficient mice. In human proliferative diabetic retinopathy neovascular membranes, R-Ras expression negatively correlated with increased vascular leakage and expression of VEGFR2, a marker of blood vessel immaturity. CONCLUSIONS. Our results suggest that R-Ras has a role in controlling retinal vessel maturation and stabilization in ischemic retinopathy and provides a potential target for pharmacologic manipulation to treat diabetic retinopathy. peerReviewed