Early risk stratification in pediatric type 1 diabetes.

Abstract

In the late 1980s all Danish children with type 1 diabetes were invited for a nationwide evaluation of glycemic control. Approximately 75% (n = 720) participated and have later been referred to as The Danish Cohort of Pediatric Diabetes 1987 (DCPD1987). The results were surprisingly poor glycemic control among these young patients which lead to a great emphasis on glycemic control in the Danish Pediatric Departments. In 1995 the participants were invited for yet another evaluation but this time with main focus on early signs of microvascular complications - 339 participated. The mean HbA1c had remained at high levels (9.6%) and 60% of the participants had some level of Diabetic Retinopathy (DR). However, as the patients with DR mostly had the very milder forms it was believed that stricter glycemic control would reverse or at least stop progression of the disease in accordance with results from the large intervention study DCCT. This was investigated further at follow-up in 2011. The first study in the present thesis aimed to describe the 16-year incidence, progression and regression of DR in 185 participants from the DCPD1987 cohort. The 16-year incidence of proliferative retinopathy (PDR), 2-step progression and regression of DR was 31.0, 64.4, and 0.0%, respectively. As expected, the participants with PDR at follow-up had significantly higher HbA1c-values at both baseline and follow-up than those without PDR. However; a significantly larger decrease in HbA1c was also observed in the group with PDR over the study period, which in accordance with DCCT should have prevented the development of PDR to some extent. A surprisingly high incidence of proliferative retinopathy amongst young patients with type 1 diabetes in Denmark was found despite improvements in HbA1c over time. The improvement in HbA1c was either too small or happened too late. This study highlights that sight-threatening diabetic retinopathy remain a major concern in type 1 diabetes and the importance of early glycemic control. Identifying high-risk patients at a very early stage is not only desired for prevention of diabetic retinopathy - neuropathy and nephropathy similarly remain frequent in type 1 diabetes. Early risk stratification will allow for timely implementation of effective interventions and for individualized screening and diabetes care. The second and third studies of this thesis provide the longest prospective studies to date on both retinal vessel calibers and retinal fractal dimensions and their predictive value on diabetic microvascular complications. Semi-automated computer software has been developed to measure smaller changes in the retinal vessels on retinal photographs. Two of the first parameters to be reliably estimated by these programs were retinal vessel calibers and retinal vascular fractal dimensions (a quantitative measure on vascular complexity). There is very limited knowledge on their predictive value on diabetic complications thus far. In the second and third study, a consistent relation between narrower retinal arteriolar calibers, wider retinal venular calibers, lower fractal dimensions and the 16-year incidences of diabetic neuropathy, nephropathy and proliferative retinopathy was found. This has never been shown before. The results on vessel analyzes provides indications of a common pathogenic pathway for diabetic microvascular complications and therefore a possibility of universal risk estimation for development of neuropathy, nephropathy and retinopathy in type 1 diabetes.