Diabetic neuropathy, nephropathy, and retinopathy cause significant morbidity in patients with type 1 diabetes, even though improvements in treatment modalities delay the appearance and reduce the severity of these complications. To prevent or further delay the onset, it is necessary to better understand common underlying pathogenesis and to discover preclinical biomarkers of these complications. Retinal vessel calibers have been associated with the presence of microvascular complications, but their long-term predictive value has only been sparsely investigated. We examined retinal vessel calibers as 16-year predictors of diabetic nephropathy, neuropathy, and proliferative retinopathy in a young population-based Danish cohort with type 1 diabetes. We used semiautomated computer software to analyze vessel diameters on baseline retinal photos. Calibers of all vessels coursing through a zone 0.5-1 disc diameter from the disc margin were measured and summarized as the central artery and vein equivalents. In multiple regression analyses, we found wider venular diameters and smaller arteriolar diameters were both predictive of the 16-year development of nephropathy, neuropathy, and proliferative retinopathy. Early retinal vessel caliber changes are seemingly early markers of microvascular processes, precede the development of microvascular complications, and are a potential noninvasive predictive test on future risk of diabetic retinopathy, neuropathy, and nephropathy.Diabetic microvascular complications, namely diabetic peripheral neuropathy (DPN), diabetic nephropathy (DN), and diabetic retinopathy (DR), are common in type 1 diabetes (1) despite advances in metabolic care. Identifying new predictors of microvascular disease could be helpful for early individual risk stratification, which may provide better opportunity for timely implementation of effective interventions. For this purpose, the retinal vasculature provides a unique opportunity to assess vascular health directly and noninvasively in vivo.Studies have investigated how retinal vessel calibers are associated with microvascular complications in both type 1 and type 2 diabetes (2-14). The evidence to date suggests that wider retinal venular diameters are associated with presence of both DN and severe levels of DR in several cross-sectional studies (3,(8)(9)(10) and with incident DN (4,5) and progression to severe

Aims/hypothesis Fractal analysis of the retinal vasculature provides a global measure of the complexity and density of retinal vessels summarised as a single variable: the fractal dimension. We investigated fractal dimensions as long-term predictors of microvasculopathy in type 1 diabetes. Methods We included 180 patients with type 1 diabetes in a 16 year follow-up study. In baseline retinal photographs (from 1995), all vessels in a zone 0.5-2.0 disc diameters from the disc margin were traced using Singapore Institute Vessel Assessment-Fractal image analysis software. Artefacts were removed by a certified grader, and fractal dimensions were calculated using the box-counting method. At follow-up (in 2011), diabetic neuropathy, nephropathy and proliferative retinopathy were assessed and related to baseline fractal dimensions in multiple regressions adjusted for sex and baseline age, diabetes duration, HbA 1c , BP, BMI, vibration perception threshold, albuminuria, retinopathy and vessel diameters. Results Mean baseline age and diabetes duration were 21.0 and 13.4 years, respectively, and of patients 50.0% were males. The mean fractal dimension was 1.3817. The 16 year incidences of neuropathy, nephropathy and proliferative retinopathy were 10.8%, 8.0% and 27.9%, respectively. Multiple regression analyses showed a lower fractal dimension to significantly predict incident neuropathy (OR 1.17 per 0.01 fractal dimension decrease [95% CI 1.01, 1.36]), nephropathy (OR 1.40 per 0.01 fractal dimension decrease [95% CI 1.10, 1.79]) and proliferative retinopathy (OR 1.22 per 0.01 fractal dimension decrease [95% CI 1.09, 1.37]). Conclusions/interpretation The retinal vascular fractal dimension is a shared biomarker of diabetic microvasculopathy, thus indicating a possible common pathogenic pathway. Retinal fractal analysis therefore is a potential tool for risk stratification in type 1 diabetes.

The aim was to investigate the long-term incidence of proliferative diabetic retinopathy (PDR), and progression and regression of diabetic retinopathy (DR) and associated risk factors in young Danish patients with Type 1 diabetes mellitus. In 1987-89, a pediatric cohort involving approximately 75 % of all children with Type 1 diabetes in Denmark <19 years of age was identified (n = 720). In 1995, 339 (47.1 %) were re-studied with retinopathy graded and all relevant diabetic parameters assessed. Of those, 185 (54.6 %) were evaluated again in 2011 for the same clinical parameters. All retinal images were graded using modified early treatment of DR study for 1995 and 2011. In 1995, mean age was 21.0 years and mean diabetes duration 13.5 years. The 16-year incidence of proliferative retinopathy, 2-step progression and 2-step regression of DR was 31.0, 64.4 and 0.0 %, respectively, while the incidence of DR was 95.1 %. In a multivariate logistic regression model, progression to PDR was significantly associated with 1995 HbA1c (OR 2.61 per 1 % increase, 95 % CI 1.85-3.68) and 1995 diastolic blood pressure (OR 1.79 per 10 mmHg increase, 95 % CI 1.04-3.07). Two-step progression of DR was associated with male gender (OR 2.37 vs. female, 95 % CI 1.07-5.27), 1995 HbA1c (OR 3.02 per 1 % increase, 95 % CI 2.04-4.48) and 1995 vibration perception threshold (OR 1.19 per 1 Volt increase, 95 % CI 1.02-1.40). In conclusion, one in three progressed to PDR and two in three had 2-step progression despite young age and increased awareness of the importance of metabolic control. After 30 years duration of diabetes, the presence of DR is almost universal.