Diabetic Eye Disease Publications
Fenofibrate, a specific agonist of peroxisome proliferator-activated receptor alpha (PPARα), displays robust therapeutic effects on diabetic retinopathy (DR) in type 2 diabetic patients. Our recent studies have shown that PPARα is down-regulated in the diabetic retina, which contributes to the pathogenesis of DR. However, the mechanism for diabetes-induced down-regulation of PPARα remains unknown. We investigated the role of microRNA-21 (miR-21) in regulating PPARα in DR. MiR-21 was over-expressed, while PPARα levels were decreased in the retina of db/db mice, a type 2 diabetic model. Such alterations were also observed in palmitate-treated retinal endothelial cells. MiR-21 targeted PPARα by inhibiting its mRNA translation. Knockout of miR-21 prevented the decrease of PPARα, alleviated microvascular damage, ameliorated inflammation and reduced cell apoptosis in the retina of db/db mice. Intravitreal injection of miR-21 inhibitor attenuated PPARα down-regulation and ameliorated retinal inflammation in db/db mice. Further, retinal miR-21 levels were increased, while PPARα levels were decreased in oxygen-induced retinopathy (OIR). Knockout of miR-21 prevented PPARα down-regulation and ameliorated retinal neovascularization and inflammation in OIR retinas. In conclusion, diabetes-induced over-expression of miR-21 in the retina is responsible, at least in part, for PPARα down-regulation in DR. Targeting miR-21 may represent a novel therapeutic strategy for DR.
PURPOSE: To compare the choroidal thickness (CT) of diabetic eyes (different stages of disease) with controls, using swept-source optical coherence tomography. METHODS: A multicenter, prospective, cross-sectional study of diabetic and nondiabetic subjects using swept-source optical coherence tomography imaging. Choroidal thickness maps, according to the nine Early Treatment Diabetic Retinopathy Study (ETDRS) subfields, were obtained using automated software. Mean CT was calculated as the mean value within the ETDRS grid, and central CT as the mean in the central 1 mm. Diabetic eyes were divided into four groups: no diabetic retinopathy (No DR), nonproliferative DR (NPDR), NPDR with diabetic macular edema (NPDR + DME), and proliferative DR (PDR). Multilevel mixed linear models were performed for analyses. RESULTS: The authors included 50 control and 160 diabetic eyes (n = 27 No DR, n = 51 NPDR, n = 61 NPDR + DME, and n = 21 PDR). Mean CT (ß = -42.9, P = 0.022) and central CT (ß = -50.2, P = 0.013) were statistically significantly thinner in PDR eyes compared with controls, even after adjusting for confounding factors. Controlling for age, DR eyes presented a significantly decreased central CT than diabetic eyes without retinopathy (β = -36.2, P = 0.009). CONCLUSION: Swept-source optical coherence tomography demonstrates a significant reduction of CT in PDR compared with controls. In the foveal region, the choroid appears to be thinner in DR eyes than in diabetic eyes without retinopathy.
The roles of transforming growth factor (TGF)-β in extracellular matrix production and vascular remodeling, coupled with increased TGF-β expression and signaling in diabetes, suggest TGF-β as an important contributor to the microangiopathy of diabetic retinopathy and nephropathy. To investigate whether increased TGF-β signaling could be a therapeutic target for preventing retinopathy, we used a pharmacologic approach (SM16, a selective inhibitor of the type 1 TGF-β receptor activin receptor-like kinase 5, orally active) to inhibit the increased, but not the basal, Tgf-β signaling in retinal vessels of diabetic rats. At the level of vascular gene expression, 3.5 months' diabetes induced minimal changes. Diabetes + SM16 for 3 weeks caused widespread changes in gene expression poised to enhance vascular inflammation, thrombosis, leakage, and wall instability; these changes were not observed in control rats given SM16. The synergy of diabetes and SM16 in altering gene expression was not observed in the lung. At the level of vascular network morphology, 7 months' diabetes induced no detectable changes. Diabetes + SM16 for 3 weeks caused instead distorted morphology and decreased density. Thus, in diabetes, retinal vessels become dependent on a small increase in TGF-β signaling via activin receptor-like kinase 5 to maintain early integrity. The increased TGF-β signaling may protect against rapid retinopathy progression and should not be a target of inhibitory interventions.
Diabetes mellitus is a chronic disease that affects 415 million people worldwide. Despite treatment advances, diabetic eye disease remains a leading cause of vision loss worldwide. Diabetic macular edema (DME) is a common cause of vision loss in diabetic patients. The pathophysiology is complex and involves multiple pathways that ultimately lead to central retinal thickening and, if untreated, visual loss. First-line treatment of DME has evolved from focal/grid laser established by the Early Treatment of Diabetic Retinopathy Study (ETDRS) to intravitreous pharmacologic therapy. Landmark prospective clinical trials examining the effect of intravitreous injections of vascular endothelial growth factor (VEGF) inhibitors in the treatment of DME have demonstrated improved visual outcomes over focal grid laser. This review focuses on the scientific evidence treatment of DME, disease pathophysiology, clinical disease course, current treatment standards, and emerging novel therapeutic approaches.
Diabetic retinopathy (DR) is the most frequent microvascular complication from diabetes and requires annual screening and at least annual follow-up. A systemic approach to optimize blood glucose and blood pressure may halt progression to severe stages of DR and obviate the need for ocular treatment. Although there is evidence of benefit from fenofibrate or intravitreous antiVEGF treatment for eyes with nonproliferative DR (NPDR), these therapies are not standard care for NPDR at this time. Some patients with severe NPDR, especially those with type 2 diabetes, benefit from early panretinal photocoagulation (PRP). Once DR progresses to proliferative DR (PDR), treatment is often necessary to prevent visual loss. PRP remains mainstay treatment for PDR with high-risk characteristics. However, intravitreous antiVEGF injections appear to be a safe and effective treatment alternative for PDR through at least two years. Vitreoretinal surgery is indicated for PDR cases with non-clearing vitreous hemorrhage and/or tractional retinal detachment.
According to current projections, the number of Americans with diabetes mellitus will increase from 27.8 million in 2007 to 60.7 million in 2030. With the increasing gap between demand for eye care and supply of ophthalmologists and optometrists, and the non-uniform distribution of eye care providers in US counties, barriers to eye examinations will likely increase. Telemedicine assessment of diabetic retinal disease through remote retinal imaging and diagnosis has the potential to meet these growing demands. To establish evidence for a telemedicine program as an effective modality for diabetic retinopathy (DR) assessment, the interpretation of teleretinal images should compare favorably with Early Treatment Diabetic Retinopathy Study film or digital photographs. We review the current evidence on the critical features and characteristics of ocular telehealth programs for DR in the following categories: image gradability, mydriasis, sensitivity and specificity, cost-effectiveness, long-term effectiveness, patient comfort and satisfaction, and improvement of patient related outcomes.
PURPOSE: To investigate the association between sleep duration and diabetic retinopathy (DR). METHODS: A population-based cross-sectional study using a nation-wide, systemically stratified, multistage, clustered sampling method included a total of 1670 subjects aged ≥40 years with diabetes who participated in the Korean National Health and Nutrition Examination Survey during 2008-2012. All participants performed standardized interviews, including self-reported sleep duration, and comprehensive ophthalmic examinations. Seven standard retinal fundus photographs were obtained from both eyes after pupil dilatation. Diabetic retinopathy (DR) was graded and classified as any DR and vision-threatening DR. Participants were stratified into men and women. RESULTS: The mean sleep duration was 6.71 hr/day. In men, adjusted OR of any DR was 1.88 [95% confidence interval (OR), 1.01-3.59] in those with ≤5 hr sleep, and 2.19 (95% CI, 1.01-4.89) in those with ≥9 hr sleep, compared to in subjects with 6-8 hr sleep, after adjusting for potential confounders including age, body mass index (BMI), diabetes duration, fasting glucose level, haemoglobin A1c levels and hypertension. In women, however, no significant association between sleep duration and DR was found. The vision-threatening DR was not significantly associated with sleep duration in either men or women. CONCLUSIONS: Short and long sleep was associated with high prevalence of DR in men. Sleep deprivation may be involved in the pathogenesis of DR development.
Purpose: To determine whether cone density, spacing, or regularity in eyes with and without diabetes (DM) as assessed by high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) correlates with presence of diabetes, diabetic retinopathy (DR) severity, or presence of diabetic macular edema (DME). Methods: Participants with type 1 or 2 DM and healthy controls underwent AOSLO imaging of four macular regions. Cone assessment was performed by independent graders for cone density, packing factor (PF), nearest neighbor distance (NND), and Voronoi tile area (VTA). Regularity indices (mean/SD) of NND (RI-NND) and VTA (RI-VTA) were calculated. Results: Fifty-three eyes (53 subjects) were assessed. Mean ± SD age was 44 ± 12 years; 81% had DM (duration: 22 ± 13 years; glycated hemoglobin [HbA1c]: 8.0 ± 1.7%; DM type 1: 72%). No significant relationship was found between DM, HbA1c, or DR severity and cone density or spacing parameters. However, decreased regularity of cone arrangement in the macular quadrants was correlated with presence of DM (RI-NND: P = 0.04; RI-VTA: P = 0.04), increasing DR severity (RI-NND: P = 0.04), and presence of DME (RI-VTA: P = 0.04). Eyes with DME were associated with decreased density (P = 0.04), PF (P = 0.03), and RI-VTA (0.04). Conclusions: Although absolute cone density and spacing don't appear to change substantially in DM, decreased regularity of the cone arrangement is consistently associated with the presence of DM, increasing DR severity, and DME. Future AOSLO evaluation of cone regularity is warranted to determine whether these changes are correlated with, or predict, anatomic or functional deficits in patients with DM.
Diabetic retinopathy is a leading cause of new-onset vision loss worldwide. Treatments supported by large clinical trials are effective in preserving vision, but many persons do not receive timely diagnosis and treatment of diabetic retinopathy, which is typically asymptomatic when most treatable. Telemedicine evaluation to identify diabetic retinopathy has the potential to improve access to care, but there are no universal standards regarding camera choice or protocol for ocular telemedicine. We review the literature regarding the impact of imaging device, number and size of retinal images, pupil dilation, type of image grader, and diagnostic accuracy on telemedicine assessment for diabetic retinopathy. Telemedicine assessment of diabetic retinopathy has the potential to preserve vision, but further development of telemedicine specific technology and standardization of operations are needed to better realize its potential.