Diabetic Eye Disease

Jiang D, Xiao X, Fu T, Mashaghi A, Liu Q, Hong J. Transient Tear Film Dysfunction after Cataract Surgery in Diabetic Patients. PLoS One 2016;11(1):e0146752.Abstract

PURPOSE: Diabetes mellitus is an increasingly common systemic disease. Many diabetic patients seek cataract surgery for a better visual acuity. Unlike in the general population, the influence of cataract surgery on tear film function in diabetic patients remains elusive. The aim of this study was to evaluate the tear function in diabetic and nondiabetic patients following cataract surgery. METHODS: In this prospective, interventional case series, 174 diabetic patients without dry eye syndrome (DES) and 474 age-matched nondiabetic patients as control who underwent phacoemulsification were enrolled at two different eye centers between January 2011 and January 2013. Patients were followed up at baseline and at 7 days, 1 month, and 3 months postoperatively. Ocular symptom scores (Ocular Surface Disease Index, OSDI) and tear film function including tear film stability (tear film break-up time, TBUT), corneal epithelium integrity (corneal fluorescein staining, CFS), and tear secretion (Schirmer's I test, SIT) were evaluated. RESULTS: In total, 83.9% of the diabetic patients (146 cases with 185 eyes) and 89.0% of the nondiabetic patients (422 cases with 463 eyes) completed all check-ups after the interventions (P = 0.095). The incidence of DES was 17.1% in the diabetic patients and 8.1% in the nondiabetic patients at 7 days after cataract surgery. In the diabetic patients, the incidence of DES remained 4.8% at 1 month postoperatively and decreased to zero at 3 months after surgery. No DES was diagnosed in nondiabetic patients at either the 1-month or 3-month follow-up. Compared with the baseline, the diabetic patients had worse symptom scores and lower TBUT values at 7 days and 1 month but not at 3 months postoperatively. In the nondiabetic patients, symptom scores and TBUT values had returned to preoperative levels at 1-month check-up. CFS scores and SIT values did not change significantly postoperatively in either group (P = 0.916 and P = 0.964, respectively). CONCLUSIONS: Diabetic patients undergoing cataract surgery are prone to DES. Ocular symptoms and tear film stability are transiently worsened in diabetic patients and are restored more slowly than those in nondiabetic patients.

Wells JA, Glassman AR, Jampol LM, Aiello LP, Antoszyk AN, Baker CW, Bressler NM, Browning DJ, Connor CG, Elman MJ, Ferris FL, Friedman SM, Melia M, Pieramici DJ, Sun JK, Beck RW, Beck RW. Association of Baseline Visual Acuity and Retinal Thickness With 1-Year Efficacy of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema. JAMA Ophthalmol 2015;:1-8.Abstract

Importance: Comparisons of the relative effect of 3 anti-vascular endothelial growth factor agents to treat diabetic macular edema warrant further assessment. Objective: To provide additional outcomes from a randomized trial evaluating 3 anti-vascular endothelial growth factor agents for diabetic macular edema within subgroups based on baseline visual acuity (VA) and central subfield thickness (CST) as evaluated on optical coherence tomography. Design, Setting, and Participants: Post hoc exploratory analyses were conducted of randomized trial data on 660 adults with diabetic macular edema and decreased VA (Snellen equivalent, approximately 20/32 to 20/320). The original study was conducted between August 22, 2012, and August 28, 2013. Analysis was conducted from January 7 to June 2, 2015. Interventions: Repeated 0.05-mL intravitreous injections of 2.0 mg of aflibercept (224 eyes), 1.25 mg of bevacizumab (218 eyes), or 0.3 mg of ranibizumab (218 eyes) as needed per protocol. Main Outcomes and Measures: One-year VA and CST outcomes within prespecified subgroups based on both baseline VA and CST thresholds, defined as worse (20/50 or worse) or better (20/32 to 20/40) VA and thicker (≥400 µm) or thinner (250 to 399 µm) CST. Results: In the subgroup with worse baseline VA (n = 305), irrespective of baseline CST, aflibercept showed greater improvement than bevacizumab or ranibizumab for several VA outcomes. In the subgroup with better VA and thinner CST at baseline (61-73 eyes across 3 treatment groups), VA outcomes showed little difference between groups; mean change was +7.2, +8.4, and +7.6 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively. However, in the subgroup with better VA and thicker CST at baseline (31-43 eyes), there was a suggestion of worse VA outcomes in the bevacizumab group; mean change from baseline to 1 year was +9.5, +5.4, and +9.5 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively, and VA letter score was greater than 84 (approximately 20/20) in 21 of 33 (64%), 7 of 31 (23%), and 21 of 43 (49%) eyes, respectively. The adjusted differences and 95% CIs were 39% (17% to 60%) for aflibercept vs bevacizumab, 25% (5% to 46%) for ranibizumab vs bevacizumab, and 13% (-8% to 35%) for aflibercept vs ranibizumab. Conclusions and Relevance: These post hoc secondary findings suggest that for eyes with better initial VA and thicker CST, some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups. Given the exploratory nature of these analyses and the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients. Trial Registration: clinicaltrials.gov Identifier: NCT01627249.

Conlin PR, Asefzadeh B, Pasquale LR, Selvin G, Lamkin R, Cavallerano AA. Accuracy of a technology-assisted eye exam in evaluation of referable diabetic retinopathy and concomitant ocular diseases. Br J Ophthalmol 2015;99(12):1622-7.Abstract

BACKGROUND/AIMS: Digital retinal imaging using store-and-forward technology is used to screen for diabetic retinopathy (DR). Its usefulness in detecting non-diabetic eye diseases is uncertain. We determined the level of agreement between teleretinal imaging supplemented with visual acuity and intraocular pressure (IOP) measurements (ie, technology-assisted eye (TAE) exam) and a comprehensive eye exam in evaluation for DR and non-diabetic ocular conditions. METHODS: We conducted a prospective, observational study with two parallel evaluations. Patients with diabetes (n=317) had a TAE exam and a comprehensive eye exam on the same day. A subset of participants with normal baseline exams (n=72) had follow-up exams 1 year later. We measured the level of agreement for referable ocular findings. RESULTS: Agreement for referable ocular findings was moderate (n=389, agreement: 77%; κ: 0.55), due in part to ungradable exams (22%). However, about half of the ungradable exams had findings that warranted referral. There was substantial agreement for follow-up exams (n=72, agreement: 93%; κ: 0.63). Among all gradable exams (n=303), the TAE exam had 86% sensitivity and 84% specificity for referable ocular findings, with high agreement (≥94%) for DR and other major ocular diagnoses. CONCLUSIONS: There was moderate-to-substantial agreement between a TAE exam and a comprehensive eye exam for referable ocular findings in patients with diabetes. Ungradable exams were a frequent marker of ocular pathology. Teleretinal imaging may be a useful evaluation for both diabetic and non-diabetic ocular conditions.

for the Group WTDCCT/EDICR, Gubitosi-Klug RA, Sun W, Cleary PA, Braffett BH, Aiello LP, Das A, Tamborlane W, Klein R. Effects of Prior Intensive Insulin Therapy and Risk Factors on Patient-Reported Visual Function Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort. JAMA Ophthalmol 2015;:1-10.Abstract

Importance: Preservation of vision in patients with diabetes mellitus is critical. Interventions to improve glycemic control through early intensive treatment of diabetes reduce rates of severe retinopathy and preserve visual acuity. Objective: To assess the effects of prior intensive insulin treatment and risk factors on patient-reported visual function in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Design, Setting, and Participants: Cohort study of 1184 participants with type 1 diabetes from the DCCT/EDIC study (randomized clinical trial followed by an observational follow-up study) who completed the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) during EDIC years 17 through 20 (September 1, 2009, through April 30, 2014) in 28 institutions across the United States and Canada. Main Outcomes and Measures: The primary outcome was the composite NEI-VFQ-25 score. Secondary outcomes were visual acuity (measured by the Early Treatment Diabetic Retinopathy Study protocol), retinopathy level (determined by masked grading of stereoscopic color fundus photographs), and NEI-VFQ-25 subscale scores. The composite NEI-VFQ-25 scale and its subscales were scored 0 to 100, corresponding to poor to excellent function, respectively. Results: The overall average NEI-VFQ-25 score for 1184 DCCT/EDIC participants (mean [SD] age, 52.3 [6.9] years; 48% female) with a 30-year duration of diabetes was high (all participants: median, 91.7; interquartile range [IQR], 89.7-96.9; intensive treatment [n = 605]: median, 94.7; IQR, 91.0-97.2; conventional treatment [n = 579]: median, 94.0; IQR, 88.4-96.1; P = .006 for intensive vs conventional). After adjustment for sex, age, hemoglobin A1c level, and retinopathy level at DCCT baseline, the former intensive treatment group had a significant, albeit modest, improvement in overall NEI-VFQ-25 score compared with the former conventional diabetes treatment group (median difference, -1.0; 95% CI, -1.7 to -0.3; P = .006). This beneficial treatment effect was fully attributed to the prior glycemic control in DCCT (explained treatment effect: 100%). Those with visual acuity worse than 20/100 reported the largest decline in visual function (median difference, -21.0; 95% CI, -40.5 to -1.6; P = .03). Conclusions and Relevance: In the DCCT/EDIC cohort, patient-reported visual function remains high in both treatment groups, comparable to previous reports of overall health-related quality of life. Intensive diabetes therapy modestly improved NEI-VFQ-25 score 30 years after the start of the DCCT, the benefit underestimated owing to more nonparticipants from the conventional treatment group. Visual acuity had the greatest effect on patient-reported visual function from among all risk factors. Trial Registration: clinicaltrials.gov Identifiers: NCT00360815 and NCT00360893.

Yee KMP, Feener EP, Madigan M, Jackson NJ, Gao B-B, Ross-Cisneros FN, Provis J, Aiello LP, Sadun AA, Sebag J. Proteomic Analysis of Embryonic and Young Human Vitreous. Invest Ophthalmol Vis Sci 2015;56(12):7036-42.Abstract

PURPOSE: The proteomic profile of vitreous from second-trimester human embryos and young adults was characterized using mass spectrometry and analyzed for changes in protein levels that may relate to structural changes occurring during this time. This vitreous proteome was compared to previous reports to confirm proteins already identified and reveal novel ones. METHODS: Vitreous from 17 human embryos aged 14 to 20 weeks gestation (WG) and from a 12-, a 14-, a 15-, and a 28-year-old was individually analyzed using tandem mass spectrometry-based proteomics. Peptide spectral count associations with embryonic age were assessed using a general linear model of fold changes and Spearman's rank correlation. Differences between embryonic and young adult vitreous proteomes were also compared. Immunohistochemistry was used to evaluate three proteins in five additional fetal (10-18 WG) human eyes. RESULTS: There were 1217 proteins identified in fetal and young adult human vitreous, 206 after quantile normalization and variance filtering. In embryos, the peptide counts of 37 proteins changed significantly from 14 to 20 WG: 75.7% increased, 24.3% decreased. Immunohistochemistry confirmed the absence of clusterin and cadherin in 10 and 14 WG eyes and their presence at 18 WG. Comparing embryonic to young adult vitreous, 47 proteins were significantly higher or lower. A total of 768 proteins not previously identified in the literature are presented. CONCLUSIONS: Proteins previously unreported in the human vitreous were identified. The human vitreous proteome undergoes significant changes during embryogenesis and young adulthood. A number of protein levels change considerably during the second trimester, with the majority decreasing.

for the Network WCDRCR, Gross JG, Glassman AR, Jampol LM, Inusah S, Aiello LP, Antoszyk AN, Baker CW, Berger BB, Bressler NM, Browning D, Elman MJ, Ferris FL, Friedman SM, Marcus DM, Melia M, Stockdale CR, Sun JK, Beck RW. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA 2015;314(20):2137-46.Abstract

IMPORTANCE: Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME). OBJECTIVE: To evaluate the noninferiority of intravitreous ranibizumab compared with PRP for visual acuity outcomes in patients with proliferative diabetic retinopathy. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015. INTERVENTIONS: Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n = 203 eyes), or ranibizumab, 0.5 mg, by intravitreous injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n = 191 eyes). Eyes in both treatment groups could receive ranibizumab for DME. MAIN OUTCOMES AND MEASURES: The primary outcome was mean visual acuity change at 2 years (5-letter noninferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization. RESULTS: Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, -0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (-23 dB vs -422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and DME development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, -7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified. CONCLUSIONS AND RELEVANCE: Among eyes with proliferative diabetic retinopathy, treatment with ranibizumab resulted in visual acuity that was noninferior to (not worse than) PRP treatment at 2 years. Although longer-term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01489189.

Silva PS, Dela Cruz AJ, Ledesma MG, van Hemert J, Radwan A, Cavallerano JD, Aiello LM, Sun JK, Aiello LP. Diabetic Retinopathy Severity and Peripheral Lesions Are Associated with Nonperfusion on Ultrawide Field Angiography. Ophthalmology 2015;122(12):2465-72.Abstract

PURPOSE: To assess whether the presence of peripheral nonperfusion on ultrawide field (UWF) fluorescein angiography (FA) is associated with diabetic retinopathy (DR) severity and the presence of predominantly peripheral lesions (PPLs). DESIGN: Single-site, cross-sectional, retrospective study. PARTICIPANTS: Sixty-eight eyes of 37 diabetic subjects with or without DR and no history of prior panretinal laser photocoagulation. METHODS: Both 200° UWF images and UWF FA images were acquired at the same visit. Early Treatment Diabetic Retinopathy Study (ETDRS) templates were overlaid digitally based on disc and macula location onto stereographically projected UWF images. Images were evaluated for the presence of PPLs, defined as more than 50% of the graded lesion located outside the ETDRS field in each of the 5 extended fields. The UWF-FA images were evaluated by 2 masked, independent graders for extent of retinal nonperfusion area (NPA) and nonperfusion index (NPI; nonperfused/total gradable area). MAIN OUTCOME MEASURES: Association of NPA and NPI with DR severity and presence of PPLs. RESULTS: Distribution of DR severity was as follows: no DR, 8.8% eyes; mild nonproliferative DR (NPDR), 17.6%; moderate NPDR, 32.4%; severe NPDR, 17.6%; proliferative DR (PDR), 19.1%; and high-risk PDR, 4.4%; with PPL present in 61.8%. There was strong intragrader (r = 0.95) and intergrader (r = 0.86) agreement for NPA. Presence of PPLs was associated with increased NPA (191.8 mm(2) vs. 306.1 mm(2); P = 0.0019) and NPI (0.25 vs. 0.43; P = 0.0003). These relationships remained significant after adjusting for DR severity and diabetes duration. In eyes without PDR (n = 52), increasing NPA and NPI was associated with worsening DR (NPA, P = 0.001; NPI, P = 0.0003). NPA and NPI were not associated with clinically significant macular edema (NPA, P = 0.99; NPI, P = 0.67), nor correlated with visual acuity (NPA, r = 0.14, P = 0.23; NPI, r = 0.24, P = 0.05). CONCLUSIONS: Following a standardized protocol, the evaluation of UWF FA for NPA and NPI is reproducible. Both parameters are correlated highly with the presence of PPLs and DR severity. Given that the presence and extent of PPLs have been associated with increased risks of DR progression, the clinical identification of PPLs may reflect closely the extent of nonperfusion and ischemia, thus accounting for the increased risk of progression.

Kim LA, Wong LL, Amarnani DS, Bigger-Allen AA, Hu Y, Marko CK, Eliott D, Shah VA, McGuone D, Stemmer-Rachamimov AO, Gai X, D'Amore PA, Arboleda-Velasquez JF. Characterization of cells from patient-derived fibrovascular membranes in proliferative diabetic retinopathy. Mol Vis 2015;21:673-87.Abstract

PURPOSE: Epiretinal fibrovascular membranes (FVMs) are a hallmark of proliferative diabetic retinopathy (PDR). Surgical removal of FVMs is often indicated to treat tractional retinal detachment. This potentially informative pathological tissue is usually disposed of after surgery without further examination. We developed a method for isolating and characterizing cells derived from FVMs and correlated their expression of specific markers in culture with that in tissue. METHODS: FVMs were obtained from 11 patients with PDR during diabetic vitrectomy surgery and were analyzed with electron microscopy (EM), comparative genomic hybridization (CGH), immunohistochemistry, and/or digested with collagenase II for cell isolation and culture. Antibody arrays and enzyme-linked immunosorbent assay (ELISA) were used to profile secreted angiogenesis-related proteins in cell culture supernatants. RESULTS: EM analysis of the FVMs showed abnormal vessels composed of endothelial cells with large nuclei and plasma membrane infoldings, loosely attached perivascular cells, and stromal cells. The cellular constituents of the FVMs lacked major chromosomal aberrations as shown with CGH. Cells derived from FVMs (C-FVMs) could be isolated and maintained in culture. The C-FVMs retained the expression of markers of cell identity in primary culture, which define specific cell populations including CD31-positive, alpha-smooth muscle actin-positive (SMA), and glial fibrillary acidic protein-positive (GFAP) cells. In primary culture, secretion of angiopoietin-1 and thrombospondin-1 was significantly decreased in culture conditions that resemble a diabetic environment in SMA-positive C-FVMs compared to human retinal pericytes derived from a non-diabetic donor. CONCLUSIONS: C-FVMs obtained from individuals with PDR can be isolated, cultured, and profiled in vitro and may constitute a unique resource for the discovery of cell signaling mechanisms underlying PDR that extends beyond current animal and cell culture models.

Silva PS, Cavallerano JD, Tolson AM, Rodriguez J, Rodriguez S, Ajlan R, Tolls D, Patel B, Sehizadeh M, Thakore K, Sun JK, Aiello LP. Real-Time Ultrawide Field Image Evaluation of Retinopathy in a Diabetes Telemedicine Program. Diabetes Care 2015;38(9):1643-9.Abstract

OBJECTIVE: To evaluate the ability of trained nonphysician retinal imagers to perform diabetic retinopathy (DR) evaluation at the time of ultrawide field retinal (UWF) imaging in a teleophthalmology program. RESEARCH DESIGN AND METHODS: Clinic patients with diabetes received Joslin Vision Network protocol retinal imaging as part of their standard medical care. Retinal imagers evaluated UWF images for referable DR at the time of image capture. Training of the imagers included 4 h of standardized didactic lectures and 12 h of guided image review. Real-time evaluations were compared with standard masked gradings performed at a centralized reading center. RESULTS: A total of 3,978 eyes of 1,989 consecutive patients were imaged and evaluated. By reading center evaluation, 3,769 eyes (94.7%) were gradable for DR, 1,376 (36.5%) had DR, and 580 (15.3%) had referable DR. Compared with the reading center, real-time image evaluation had a sensitivity and specificity for identifying more than minimal DR of 0.95 (95% CI 0.94-0.97) and 0.84 (0.82-0.85), respectively, and 0.99 (0.97-1.00) and 0.76 (0.75-0.78), respectively, for detecting referable DR. Only three patients with referable DR were not identified by imager evaluation. CONCLUSIONS: Point-of-care evaluation of UWF images by nonphysician imagers following standardized acquisition and evaluation protocols within an established teleophthalmology program had good sensitivity and specificity for detection of DR and for identification of referable retinal disease. With immediate image evaluation, <0.1% of patients with referable DR would be missed, reading center image grading burden would be reduced by 60%, and patient feedback would be expedited.

Tandon A, Chen CJ, Penman A, Hancock H, James M, Husain D, Andreoli C, Li X, Kuo JZ, Idowu O, Riche D, Papavasilieou E, Brauner S, Smith SO, Hoadley S, Richardson C, Kieser T, Vazquez V, Chi C, Fernandez M, Harden M, Cotch MF, Siscovick D, Taylor HA, Wilson JG, Reich D, Wong TY, Klein R, Klein BEK, Rotter JI, Patterson N, Sobrin L. African Ancestry Analysis and Admixture Genetic Mapping for Proliferative Diabetic Retinopathy in African Americans. Invest Ophthalmol Vis Sci 2015;56(6):3999-4005.Abstract

PURPOSE: To examine the relationship between proportion of African ancestry (PAA) and proliferative diabetic retinopathy (PDR) and to identify genetic loci associated with PDR using admixture mapping in African Americans with type 2 diabetes (T2D). METHODS: Between 1993 and 2013, 1440 participants enrolled in four different studies had fundus photographs graded using the Early Treatment Diabetic Retinopathy Study scale. Cases (n = 305) had PDR while controls (n = 1135) had nonproliferative diabetic retinopathy (DR) or no DR. Covariates included diabetes duration, hemoglobin A1C, systolic blood pressure, income, and education. Genotyping was performed on the Affymetrix platform. The association between PAA and PDR was evaluated using logistic regression. Genome-wide admixture scanning was performed using ANCESTRYMAP software. RESULTS: In the univariate analysis, PDR was associated with increased PAA (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.16-1.59, P = 0.0002). In multivariate regression adjusting for traditional DR risk factors, income and education, the association between PAA and PDR was attenuated and no longer significant (OR = 1.21, 95% CI = 0.59-2.47, P = 0.61). For the admixture analyses, the maximum genome-wide score was 1.44 on chromosome 1. CONCLUSIONS: In this largest study of PDR in African Americans with T2D to date, an association between PAA and PDR is not present after adjustment for clinical, demographic, and socioeconomic factors. No genome-wide significant locus (defined as having a locus-genome statistic > 5) was identified with admixture analysis. Further analyses with even larger sample sizes are needed to definitively assess if any admixture signal for DR is present.

Aiello LP, Ayala AR, Antoszyk AN, Arnold-Bush B, Baker C, Bressler NM, Elman MJ, Glassman AR, Jampol LM, Melia M, Nielsen J, Wolpert HA, Wolpert HA. Assessing the Effect of Personalized Diabetes Risk Assessments During Ophthalmologic Visits on Glycemic Control: A Randomized Clinical Trial. JAMA Ophthalmol 2015;133(8):888-96.Abstract

IMPORTANCE: Optimization of glycemic control is critical to reduce the number of diabetes mellitus-related complications, but long-term success is challenging. Although vision loss is among the greatest fears of individuals with diabetes, comprehensive personalized diabetes education and risk assessments are not consistently used in ophthalmologic settings. OBJECTIVE: To determine whether the point-of-care measurement of hemoglobin A1c (HbA1c) and personalized diabetes risk assessments performed during retinal ophthalmologic visits improve glycemic control as assessed by HbA1c level. DESIGN, SETTING, AND PARTICIPANTS: Ophthalmologist office-based randomized, multicenter clinical trial in which investigators from 42 sites were randomly assigned to provide either a study-prescribed augmented diabetes assessment and education or the usual care. Adults with type 1 or 2 diabetes enrolled into 2 cohorts: those with a more-frequent-than-annual follow-up (502 control participants and 488 intervention participants) and those with an annual follow-up (368 control participants and 388 intervention participants). Enrollment was from April 2011 through January 2013. INTERVENTIONS: Point-of-care measurements of HbA1c, blood pressure, and retinopathy severity; an individualized estimate of the risk of retinopathy progression derived from the findings from ophthalmologic visits; structured comparison and review of past and current clinical findings; and structured education with immediate assessment and feedback regarding participant's understanding. These interventions were performed at enrollment and at routine ophthalmic follow-up visits scheduled at least 12 weeks apart. MAIN OUTCOMES AND MEASURES: Mean change in HbA1c level from baseline to 1-year follow-up. Secondary outcomes included body mass index, blood pressure, and responses to diabetes self-management practices and attitudes surveys. RESULTS: In the cohort with more-frequent-than-annual follow-ups, the mean (SD) change in HbA1c level at 1 year was -0.1% (1.5%) in the control group and -0.3% (1.4%) in the intervention group (adjusted mean difference, -0.09% [95% CI, -0.29% to 0.12%]; P = .35). In the cohort with annual follow-ups, the mean (SD) change in HbA1c level was 0.0% (1.1%) in the control group and -0.1% (1.6%) in the intervention group (mean difference, -0.05% [95% CI, -0.27% to 0.18%]; P = .63). Results were similar for all secondary outcomes. CONCLUSIONS AND RELEVANCE: Long-term optimization of glycemic control is not achieved by a majority of individuals with diabetes. The addition of personalized education and risk assessment during retinal ophthalmologic visits did not result in a reduction in HbA1c level compared with usual care over 1 year. These data suggest that optimizing glycemic control remains a substantive challenge requiring interventional paradigms other than those examined in our study. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01323348.

Huang T, Zheng Y, Qi Q, Xu M, Ley SH, Li Y, Kang JH, Wiggs J, Pasquale LR, Chan AT, Rimm EB, Hunter DJ, Manson JAE, Willett WC, Hu FB, Qi L. DNA Methylation Variants at HIF3A Locus, B-Vitamin Intake, and Long-term Weight Change: Gene-Diet Interactions in Two U.S. Cohorts. Diabetes 2015;64(9):3146-54.Abstract

The first epigenome-wide association study of BMI identified DNA methylation at an HIF3A locus associated with BMI. We tested the hypothesis that DNA methylation variants are associated with BMI according to intake of B vitamins. In two large cohorts, we found significant interactions between the DNA methylation-associated HIF3A single nucleotide polymorphism (SNP) rs3826795 and intake of B vitamins on 10-year changes in BMI. The association between rs3826795 and BMI changes consistently increased across the tertiles of total vitamin B2 and B12 intake (all P for interaction <0.01). The differences in the BMI changes per increment of minor allele were -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.12 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B2 intake and -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.10 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B12 intake. In two independent cohorts, a DNA methylation variant in HIF3A was associated with BMI changes through interactions with total or supplemental vitamin B2, vitamin B12, and folate. These findings suggest a potential causal relation between DNA methylation and adiposity.

Kita T, Clermont AC, Murugesan N, Zhou Q, Fujisawa K, Ishibashi T, Aiello LP, Feener EP. Plasma Kallikrein-Kinin System as a VEGF-Independent Mediator of Diabetic Macular Edema. Diabetes 2015;64(10):3588-99.Abstract

This study characterizes the kallikrein-kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma prekallikrein (PPK) and plasma kallikrein (PKal) were increased twofold and 11.0-fold (both P < 0.0001), respectively, in vitreous from subjects with DME compared with those with a macular hole (MH). While the vascular endothelial growth factor (VEGF) level was also increased in DME vitreous, PKal and VEGF concentrations do not correlate (r = 0.266, P = 0.112). Using mass spectrometry-based proteomics, we identified 167 vitreous proteins, including 30 that were increased in DME (fourfold or more, P < 0.001 vs. MH). The majority of proteins associated with DME displayed a higher correlation with PPK than with VEGF concentrations. DME vitreous containing relatively high levels of PKal and low VEGF induced RVP when injected into the vitreous of diabetic rats, a response blocked by bradykinin receptor antagonism but not by bevacizumab. Bradykinin-induced retinal thickening in mice was not affected by blockade of VEGF receptor 2. Diabetes-induced RVP was decreased by up to 78% (P < 0.001) in Klkb1 (PPK)-deficient mice compared with wild-type controls. B2- and B1 receptor-induced RVP in diabetic mice was blocked by endothelial nitric oxide synthase (NOS) and inducible NOS deficiency, respectively. These findings implicate the PKal pathway as a VEGF-independent mediator of DME.

Chronopoulos A, Roy S, Beglova E, Mansfield K, Wachtman L, Roy S. Hyperhexosemia-induced retinal vascular pathology in a novel primate model of diabetic retinopathy. Diabetes 2015;Abstract

The paucity of animal models exhibiting full pathology of diabetic retinopathy (DR) has impeded understanding of the pathogenesis of DR and the development of therapeutic interventions. Here we investigated if hyperhexosemic marmosets (Callithrix jacchus) develop characteristic retinal vascular lesions including macular edema (ME), a leading cause of vision loss in DR. Marmosets maintained on 30% galactose (gal)-rich diet for two years were monitored for retinal vascular permeability, development of ME, and morphological characteristics including acellular capillaries (AC) and pericyte loss (PL), vessel tortuosity, and capillary basement membrane (BM) thickness. Excess vascular permeability, increased number of AC and PL, vascular BM thickening, and increased vessel tortuosity were observed in the retinas of gal-fed marmosets. Optical coherence tomography (OCT) images revealed significant thickening of the retinal foveal and the juxtafoveal area, and histological analysis showed incipient microaneurysms in retinas of gal-fed marmosets. Findings from this study indicate that hyperhexosemia can trigger retinal vascular changes similar to those seen in human DR including ME and microaneurysms. The striking similarities between the marmoset retina and the human retina, and the exceptionally small size of the monkey, offer significant advantages to this primate model of DR.

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