Intensive Glycemic Management Is Associated With Reduced Retinal Structure Abnormalities on Ocular Coherence Tomography in the DCCT/EDIC Study.

OBJECTIVE: To investigate quantitative and qualitative changes in retinal structure using optical coherence tomography (OCT) and their associations with systemic or other risk factors in individuals with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, OCT images were obtained during study years 25-28 (2019-2022) in 937 participants; 54% and 46% were from the original intensive (INT) and conventional (CONV) glycemic management treatment groups, respectively. RESULTS: Average age for participants was 61 years old, diabetes duration 39 years, and HbA1c 7.6%. Participants originally in the CONV group were more likely to have disorganization of retinal inner layers (DRIL) (CONV 27.3% vs. INT 18.7%; P = 0.0003), intraretinal fluid (CONV 24.4% vs. INT 19.2%; P = 0.0222), and intraretinal cysts (CONV 20.8% vs. INT 16.6%; P = 0.0471). In multivariable models, sex, age, smoking, mean updated systolic blood pressure, and history of "clinically significant" macular edema (CSME) and of anti-VEGF treatment were independently associated with changes in central subfield thickness, while HbA1c, BMI, and history of CSME and of ocular surgery were associated with DRIL. Visual acuity (VA) decline was associated with significant thinning of all retinal subfields except for the central and inner nasal subfields. CONCLUSIONS: Early intensive glycemic management in T1D is associated with a decreased risk of DRIL. This important morphological abnormality was associated with a history of macular edema, a history of ocular surgery, and worse VA. This study reveals benefits of intensive glycemic management on the retina beyond features detected by fundus photographs and ophthalmoscopy.

Imaging Modalities for Assessing the Vascular Component of Diabetic Retinal Disease: Review and Consensus for an Updated Staging System.

Purpose: To review the evidence for imaging modalities in assessing the vascular component of diabetic retinal disease (DRD), to inform updates to the DRD staging system. Design: Standardized narrative review of the literature by an international expert workgroup, as part of the DRD Staging System Update Effort, a project of the Mary Tyler Moore Vision Initiative. Overall, there were 6 workgroups: Vascular Retina, Neural Retina, Systemic Health, Basic and Cellular Mechanisms, Visual Function, and Quality of Life. Participants: The Vascular Retina workgroup, including 16 participants from 4 countries. Methods: Literature review was conducted using standardized evidence grids for 5 modalities: standard color fundus photography (CFP), widefield color photography (WFCP), standard fluorescein angiography (FA), widefield FA (WFFA), and OCT angiography (OCTA). Summary levels of evidence were determined on a validated scale from I (highest) to V (lowest). Five virtual workshops were held for discussion and consensus. Main Outcome Measures: Level of evidence for each modality. Results: Levels of evidence for standard CFP, WFCP, standard FA, WFFA, and OCTA were I, II, I, I, and II respectively. Traditional vascular lesions on standard CFP should continue to be included in an updated staging system, but more studies are required before they can be used in posttreatment eyes. Widefield color photographs can be used for severity grading within the area covered by standard CFPs, although these gradings may not be directly interchangeable with each other. Evaluation of the peripheral retina on WFCP can be considered, but the method of grading needs to be clarified and validated. Standard FA and WFFA provide independent prognostic value, but the need for dye administration should be considered. OCT angiography has significant potential for inclusion in the DRD staging system, but various barriers need to be addressed first. Conclusions: This study provides evidence-based recommendations on the utility of various imaging modalities for assessment of the vascular component of DRD, which can inform future updates to the DRD staging system. Although new imaging modalities offer a wealth of information, there are still major gaps and unmet research needs that need to be addressed before this potential can be realized. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Report From the 2022 Mary Tyler Moore Vision Initiative Diabetic Retinal Disease Clinical Endpoints Workshop.

The Mary Tyler Moore Vision Initiative Diabetic Retinal Disease (DRD) Clinical Endpoints Workshop was held on October 22, 2022 to accelerate progress toward establishment of useful clinical and research endpoints and development of new therapeutics that have important relevance across the full spectrum of DRD pathology. More than 90 patient representatives, clinicians, scientists, funding and regulatory agencies, diagnostic, therapeutic and biotech industry representatives discussed the needs for new diagnostic and therapeutic approaches to prevent and restore retinal neurovascular unit integrity. Phase I of the MTM Vision Initiative plans, notably updating the DRD staging system and severity scale, establishing a human ocular biorepository and resource, and clinical endpoints and biomarker development and validation, was emphasized.

The effect of surgical weight loss on diabetes complications in individuals with class II/III obesity.

AIMS/HYPOTHESIS: The aim of this study was to determine the effect of bariatric surgery on diabetes complications in individuals with class II/III obesity (BMI > 35 kg/m2). METHODS: We performed a prospective cohort study of participants with obesity who underwent bariatric surgery. At baseline and 2 years following surgery, participants underwent metabolic phenotyping and diabetes complication assessments. The primary outcomes for peripheral neuropathy (PN) were a change in intra-epidermal nerve fibre density (IENFD, units = fibres/mm) at the distal leg and proximal thigh, the primary outcome for cardiovascular autonomic neuropathy (CAN) was a change in the expiration/inspiration (E/I) ratio, and the primary outcome for retinopathy was a change in the mean deviation on frequency doubling technology testing. RESULTS: Among 127 baseline participants, 79 completed in-person follow-up (age 46.0 ± 11.3 years [mean ± SD], 73.4% female). Participants lost a mean of 31.0 kg (SD 18.4), and all metabolic risk factors improved except for BP and total cholesterol. Following bariatric surgery, one of the primary PN outcomes improved (IENFD proximal thigh, +3.4 ± 7.8, p<0.01), and CAN (E/I ratio -0.01 ± 0.1, p=0.89) and retinopathy (deviation -0.2 ± 3.0, p=0.52) were stable. Linear regression revealed that a greater reduction in fasting glucose was associated with improvements in retinopathy (mean deviation point estimate -0.7, 95% CI -1.3, -0.1). CONCLUSIONS/INTERPRETATION: Bariatric surgery may be an effective approach to reverse PN in individuals with obesity. The observed stability of CAN and retinopathy may be an improvement compared with the natural progression of these conditions; however, controlled trials are needed.

Frontiers in diabetic retinal disease.

Diabetic retinal disease (DRD) remains a leading cause of vision loss and blindness globally. Although treatments can be effective when given at vision-threatening stages of DRD, there is a lack of knowledge about the earliest mechanisms leading to the development of clinically evident DRD. Recent advances in retinal imaging methods for patients with diabetes allow a more precise and granular characterization of the different stages of DRD than is provided by the classic Diabetic Retinopathy Severity Scale based on fundus photographs. In addition, recent clinical studies have yielded more information on how to adjust blood glucose levels, lipid levels and blood pressure to minimize the risk of DRD. Given the incomplete success of current therapies, there is a critical need for better understanding of the mechanisms underlying DRD and novel treatment targets that address the entire neurovascular retina. Moreover, the causes for interindividual variability in the development of DRD in patients with similar glycemic history and other metabolic factors are not yet clarified either. Finally, greater focus on patients' experience with visual disabilities and treatment effects should be addressed in research in this field.

American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update.

OBJECTIVE: The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS: The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS: This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS: This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.

mTORC1 regulates high levels of protein synthesis in retinal ganglion cells of adult mice.

Mechanistic target of rapamycin (mTOR) and mTOR complex 1 (mTORC1), linchpins of the nutrient sensing and protein synthesis pathways, are present at relatively high levels in the ganglion cell layer (GCL) and retinal ganglion cells (RGCs) of rodent and human retinas. However, the role of mTORCs in the control of protein synthesis in RGC is unknown. Here, we applied the SUrface SEnsing of Translation (SUnSET) method of nascent protein labeling to localize and quantify protein synthesis in the retinas of adult mice. We also used intravitreal injection of an adeno-associated virus 2 vector encoding Cre recombinase in the eyes of mtor- or rptor-floxed mice to conditionally knockout either both mTORCs or only mTORC1, respectively, in cells within the GCL. A novel vector encoding an inactive Cre mutant (CreΔC) served as control. We found that retinal protein synthesis was highest in the GCL, particularly in RGC. Negation of both complexes or only mTORC1 significantly reduced protein synthesis in RGC. In addition, loss of mTORC1 function caused a significant reduction in the pan-RGC marker, RNA-binding protein with multiple splicing, with little decrease of the total number of cells in the RGC layer, even at 25 weeks after adeno-associated virus-Cre injection. These findings reveal that mTORC1 signaling is necessary for maintaining the high rate of protein synthesis in RGCs of adult rodents, but it may not be essential to maintain RGC viability. These findings may also be relevant to understanding the pathophysiology of RGC disorders, including glaucoma, diabetic retinopathy, and optic neuropathies.

It is time for a moonshot to find "Cures" for diabetic retinal disease.

Diabetic retinal disease (DRD), the most common complication of diabetes and a leading cause of blindness in working age individuals, is now understood to be a form of sensory neuropathy or neurovascular degeneration. Current treatments are focused on advanced vision-threatening disease and a single molecular target, vascular endothelial growth factor, has an approved therapy. We trace the evolution of understanding of DRD pathogenesis, identify new approaches to clinical assessment, trials infrastructure and design, and target identification to accelerate selection and evaluation of new therapeutics that will speed development of potentially curative interventions. Critically, the "Restoring Vision Moonshot" framework will address gaps in knowledge to be filled to achieve the goal of restoring sight and preventing vision loss in persons with diabetes.

A validated analysis pipeline for mass spectrometry-based vitreous proteomics: new insights into proliferative diabetic retinopathy.

BACKGROUND: Vitreous is an accessible, information-rich biofluid that has recently been studied as a source of retinal disease-related proteins and pathways. However, the number of samples required to confidently identify perturbed pathways remains unknown. In order to confidently identify these pathways, power analysis must be performed to determine the number of samples required, and sample preparation and analysis must be rigorously defined. METHODS: Control (n = 27) and proliferative diabetic retinopathy (n = 23) vitreous samples were treated as biologically distinct individuals or pooled together and aliquoted into technical replicates. Quantitative mass spectrometry with tandem mass tag labeling was used to identify proteins in individual or pooled control samples to determine technical and biological variability. To determine effect size and perform power analysis, control and proliferative diabetic retinopathy samples were analyzed across four 10-plexes. Pooled samples were used to normalize the data across plexes and generate a single data matrix for downstream analysis. RESULTS: The total number of unique proteins identified was 1152 in experiment 1, 989 of which were measured in all samples. In experiment 2, 1191 proteins were identified, 727 of which were measured across all samples in all plexes. Data are available via ProteomeXchange with identifier PXD025986. Spearman correlations of protein abundance estimations revealed minimal technical (0.99-1.00) and biological (0.94-0.98) variability. Each plex contained two unique pooled samples: one for normalizing across each 10-plex, and one to internally validate the normalization algorithm. Spearman correlation of the validation pool following normalization was 0.86-0.90. Principal component analysis revealed stratification of samples by disease and not by plex. Subsequent differential expression and pathway analyses demonstrated significant activation of metabolic pathways and inhibition of neuroprotective pathways in proliferative diabetic retinopathy samples relative to controls. CONCLUSIONS: This study demonstrates a feasible, rigorous, and scalable method that can be applied to future proteomic studies of vitreous and identifies previously unrecognized metabolic pathways that advance understanding of diabetic retinopathy.

Awareness of Diabetic Retinopathy: Insight From the National Health and Nutrition Examination Survey.

INTRODUCTION: This study determines the prevalence and associated correlates of people unaware of their diabetic retinopathy diagnosis in the U.S. METHODS: Participants unaware of diabetic retinopathy from the National Health and Nutrition Examination Survey from 2005 to 2008 were identified. The prevalence of those unaware of their diabetic retinopathy diagnosis was determined. Descriptive statistics and logistic regression were used to determine correlates associated with being unaware of one's diabetic retinopathy diagnosis (completed in 2018‒2020). RESULTS: Among 5,563 participants aged ≥40 years who underwent fundus photography, the prevalence of those unaware of their diabetic retinopathy diagnosis was 10.6% (9.8 million). This included 23.1% of those with self-reported diabetes (2.9 million) and 6.8% of those who reported not having diabetes (6.9 million). Among participants reporting diabetes with photographic evidence of retinopathy, 70.1% were unaware. Among individuals with self-reported diabetes, correlates of being unaware of one's diabetic retinopathy diagnosis included diabetes diaganosis for ≥10 years (OR=3.15, 95% CI=1.78, 5.56), HbA1c ≥6.5% (OR=2.92, 95% CI=1.65, 5.18), and treatment with insulin only (OR=4.04, 95% CI=1.43, 11.39). Self-reported hypertension was associated with decreased odds of undiagnosed diabetic retinopathy (OR=0.48, 95% CI=0.28, 0.82). Among those without self-reported diabetes, correlates of being unaware of diabetic retinopathy included older age (OR=1.02, 95% CI=1.01, 1.04), male sex (OR=1.83, 95% CI=1.31, 2.56), Black race (OR=1.81, 95% CI=1.12, 2.92), Hispanic race/ethnicity (OR=1.60, 95% CI=1.14, 2.25), elevated blood pressure (OR=1.54, 95% CI=1.23, 1.93), current smoking (OR=1.74, 95% CI=1.21, 2.51), and history of stroke (OR=2.20, 95% CI=1.06, 4.58). CONCLUSIONS: A substantial proportion of individuals with diabetic retinopathy are unaware of the diagnosis. These data provide a path toward refining efforts to diagnose and treat diabetic retinopathy to decrease the burden of preventable blindness.

Diminished retinal complex lipid synthesis and impaired fatty acid ß-oxidation associated with human diabetic retinopathy.

BACKGROUNDThis study systematically investigated circulating and retinal tissue lipid determinants of human diabetic retinopathy (DR) to identify underlying lipid alterations associated with severity of DR.METHODSRetinal tissues were retrieved from postmortem human eyes, including 19 individuals without diabetes, 20 with diabetes but without DR, and 20 with diabetes and DR, for lipidomic study. In a parallel study, serum samples from 28 American Indians with type 2 diabetes from the Gila River Indian Community, including 12 without DR, 7 with mild nonproliferative DR (NPDR), and 9 with moderate NPDR, were selected. A mass-spectrometry-based lipidomic platform was used to measure serum and tissue lipids.RESULTSIn the postmortem retinas, we found a graded decrease of long-chain acylcarnitines and longer-chain fatty acid ester of hydroxyl fatty acids, diacylglycerols, triacylglycerols, phosphatidylcholines, and ceramide(NS) in central retina from individuals with no diabetes to those with diabetes with DR. The American Indians' sera also exhibited a graded decrease in circulating long-chain acylcarnitines and a graded increase in the intermediate-length saturated and monounsaturated triacylglycerols from no DR to moderate NPDR.CONCLUSIONThese findings suggest diminished synthesis of complex lipids and impaired mitochondrial ß-oxidation of fatty acids in retinal DR, with parallel changes in circulating lipids.TRIAL REGISTRATIONClinicalTrials.gov NCT00340678.FUNDINGThis work was supported by NIH grants R24 DK082841, K08DK106523, R03DK121941, P30DK089503, P30DK081943, P30DK020572, P30 EY007003; The Thomas Beatson Foundation; and JDRF Center for Excellence (5-COE-2019-861-S-B).

Proteomic Analyses of Vitreous in Proliferative Diabetic Retinopathy: Prior Studies and Future Outlook.

Vitreous fluid is becoming an increasingly popular medium for the study of retinal disease. Numerous studies have demonstrated that proteomic analysis of the vitreous from patients with proliferative diabetic retinopathy yields valuable molecular information regarding known and novel proteins and pathways involved in this disease. However, there is no standardized methodology for vitreous proteomic studies. Here, we share a suggested protocol for such studies and outline the various experimental and analytic methods that are currently available. We also review prior mass spectrometry-based proteomic studies of the vitreous from patients with proliferative diabetic retinopathy, discuss common pitfalls of these studies, and propose next steps for moving the field forward.

Integrative Biology of Diabetic Retinal Disease: Lessons from Diabetic Kidney Disease.

Diabetic retinal disease (DRD) remains the most common cause of vision loss in adults of working age. Progress on the development of new therapies for DRD has been limited by the complexity of the human eye, which constrains the utility of traditional research techniques, including animal and tissue culture models-a problem shared by those in the field of kidney disease research. By contrast, significant progress in the study of diabetic kidney disease (DKD) has resulted from the successful employment of systems biology approaches. Systems biology is widely used to comprehensively understand complex human diseases through the unbiased integration of genetic, environmental, and phenotypic aspects of the disease with the functional and structural manifestations of the disease. The application of a systems biology approach to DRD may help to clarify the molecular basis of the disease and its progression. Acquiring this type of information might enable the development of personalized treatment approaches, with the goal of discovering new therapies targeted to an individual's specific DRD pathophysiology and phenotype. Furthermore, recent efforts have revealed shared and distinct pathways and molecular targets of DRD and DKD, highlighting the complex pathophysiology of these diseases and raising the possibility of therapeutics beneficial to both organs. The objective of this review is to survey the current understanding of DRD pathophysiology and to demonstrate the investigative approaches currently applied to DKD that could promote a more thorough understanding of the structure, function, and progression of DRD.

Insulin-like growth factor-2 regulates basal retinal insulin receptor activity.

The retinal insulin receptor (IR) exhibits basal kinase activity equivalent to that of the liver of fed animals, but unlike the liver, does not fluctuate with feeding and fasting; it also declines rapidly after the onset of insulin-deficient diabetes. The ligand(s) that determine basal IR activity in the retina has not been identified. Using a highly sensitive insulin assay, we found that retinal insulin concentrations remain constant in fed versus fasted rats and in diabetic versus control rats; vitreous fluid insulin levels were undetectable. Neutralizing antibodies against insulin-like growth factor 2 (IGF-2), but not insulin-like growth factor 1 (IGF-1) or insulin, decreased IR kinase activity in normal rat retinas, and depletion of IGF-2 from serum specifically reduced IR phosphorylation in retinal cells. Immunoprecipitation studies demonstrated that IGF-2 induced greater phosphorylation of the retinal IR than the IGF-1 receptor. Retinal IGF-2 mRNA content was 10-fold higher in adults than pups and orders of magnitude higher than in liver. Diabetes reduced retinal IGF-2, but not IGF-1 or IR, mRNA levels, and reduced IGF-2 and IGF-1 content in vitreous fluid. Finally, intravitreal administration of IGF-2 (mature and pro-forms) increased retinal IR and Akt kinase activity in diabetic rats. Collectively, these data reveal that IGF-2 is the primary ligand that defines basal retinal IR activity and suggest that reduced ocular IGF-2 may contribute to reduced IR activity in response to diabetes. These findings may have importance for understanding the regulation of metabolic and prosurvival signaling in the retina.

A critical review: Psychophysical assessments of diabetic retinopathy.

Diabetic retinal disease remains a leading cause of vision loss despite currently available screening methods, ocular treatments, and efforts to control metabolic dysfunction. It is now understood that diabetes damages the entire retina and the cellular components of the neurovascular unit. Multiple studies have demonstrated impairment of various aspects of retinal function across the spectrum of retinopathy severity. Here we review these tests, the principles underlying their use, clinical data from multiple publications, the strengths and limitations of the studies, and prospects for their application to understand the pathophysiology of diabetic retinal disease and monitor its response to therapy. We focus on visual acuity, contrast sensitivity, color vision, visual field, and dark adaptation and their use to understand the pathophysiology of diabetic retinopathy and as potential endpoints for clinical trials.

Density-based classification in diabetic retinopathy through thickness of retinal layers from optical coherence tomography.

Diabetic retinopathy (DR) is a severe retinal disorder that can lead to vision loss, however, its underlying mechanism has not been fully understood. Previous studies have taken advantage of Optical Coherence Tomography (OCT) and shown that the thickness of individual retinal layers are affected in patients with DR. However, most studies analyzed the thickness by calculating summary statistics from retinal thickness maps of the macula region. This study aims to apply a density function-based statistical framework to the thickness data obtained through OCT, and to compare the predictive power of various retinal layers to assess the severity of DR. We used a prototype data set of 107 subjects which are comprised of 38 non-proliferative DR (NPDR), 28 without DR (NoDR), and 41 controls. Based on the thickness profiles, we constructed novel features which capture the variation in the distribution of the pixel-wise retinal layer thicknesses from OCT. We quantified the predictive power of each of the retinal layers to distinguish between all three pairwise comparisons of the severity in DR (NoDR vs NPDR, controls vs NPDR, and controls vs NoDR). When applied to this preliminary DR data set, our density-based method demonstrated better predictive results compared with simple summary statistics. Furthermore, our results indicate considerable differences in retinal layer structuring based on the severity of DR. We found that: (a) the outer plexiform layer is the most discriminative layer for classifying NoDR vs NPDR; (b) the outer plexiform, inner nuclear and ganglion cell layers are the strongest biomarkers for discriminating controls from NPDR; and (c) the inner nuclear layer distinguishes best between controls and NoDR.

Treated PDR Reveals Age-Appropriate Vision Deterioration But Distorted Retinal Organization.

Purpose: We determined the progression of visual function, macular structure, and quality of life in patients with regressed proliferative diabetic retinopathy (PDR) after panretinal photocoagulation (PRP). Methods: In this prospective study, 22 patients who underwent PRP for PDR and 11 age-matched control participants underwent examinations at baseline and after 5 years. Visual acuity, contrast sensitivity, reading acuity, frequency doubling perimetry, Humphrey field analyzer, and dark adaptation were measured. The Low Luminance Questionnaire and National Eye Institute Vision Function Questionnaire-25 were administered. Macular spectral-domain optical coherence tomography was taken. Results: After 5 years, patients who had previously undergone PRP for PDR (18.4 ± 7.9 years previously) showed significant deterioration in contrast sensitivity, reading acuity, frequency doubling perimetry 24-2 pattern standard deviation, and Humphrey field analyzer 10-2 foveal sensitivity, which were equivalent to age-related decreases in control participants. They revealed no further impairment in vision-related activities on questionnaires. In contrast with controls, their maculas showed pathologic disorganization of the retinal layers, especially the nerve fiber layer, which were thicker and constituted a greater proportion of the overall retinal thickness than the norm and associated with impaired vision. Conclusions: Patients with treated PDR had age-related decreases in vision, but stable quality of life. Prior injuries from the diabetes and, possibly, laser treatment led to substantial disruption in the retinal structure, which may explain the loss of vision. Translational Relevance: Despite PRP treatment, patients with regressed PDR had pathologic progression of the nerve fiber layer; further investigation may identify a new therapeutic target to reverse the visual deficits.