Prediction of type-1 diabetes : evaluation of assays for ß-cell antibodies

Type·1 diabetes mellitus is an autoimmune disease. The clinical manifestation is the end-point of a subclinical process that destroys the insulin producing B·cells in the islets of Langerhans (prediabetes). Prediabetes may last months to years and theoretically gives the unique opportunity for prevention of the disease. This requires the availability of an effective therapy and the possibility to reliably identify individuals who are eligible for such a therapy. In order to develop intervention strategies, studies on the pathogenesis of Type-1 diabetes are required. At the clinical manifestation of the disease B-cell autoimmunity has been present for years. As a consequence disease-initiating events will have disappeared and the immune response and pathophysiology of the B-cells may have changed due to the ongoing destruction process. Thus, studies of the prediabetic phase are a prerequisite. The identification of those who are at high risk to develop the disease is therefore an important key to further studies on the pathogenesis of Type-1 diabetes. In addition, clinical trials of potential prevention strategies require the development of reliable techniques to identify such individuals. Using a combination of genetic markers and autoantibodies against B-cell antigens, prediction is possible in first·degree relatives of patients with Type-1 diabetes. For relatives baring high genetic risk markers and being positive for more than one B-cell autoantibody the risk to proceed to diabetes exceeds 60%. However, the majority of new cases of Type-1 diabetes occur in the general population and it is not clear whether prediction in the general population is as efficient as in first degree relatives. This thesis aims to: • Decipher the natural course of B-cell autoantibodies and their relation to disease progression in established diabetes and prediabetes • Improve knowledge on the applicability of antibodies for the prediction of Type-1 diabetes in the general population • Improve the performance of screening by technical evaluation of assays to detect GAD· and IA2·antibodies in serum

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