Fatal Attraction: Interactions between antigen-presenting cells and islets of Langerhans in the pathogenesis of autoimmune diabetes

The onset of diabetes mellitus is characterized by various symptoms, all the result of a disturbed glucose metabolism. The main symptoms are thirst and an excessive production of urine. The disturbed glucose metabolism underlying these symptoms is due to an absolute deficiency of insulin secretion (type 1 diabetes mellitus), a reduction in its biological effectiveness (type 2 diabetes mellitus) or a combination of these factors. Type 1 diabetes mellitus is predominantly manifesting in children, and needs to be treated by life-long exogenous insulin administration to prevent high blood glucose levels. Type 2 diabetes mellitus occurs classically in adults, and is relatively milder in its appearance; usually, exogenous insulin administration is not required. This thesis concerns type 1 (insulin-dependent) diabetes mellitus (type I diabetes). In the Netherlands, the annual incidence of type I diabetes among children younger than 14 years was 14.3 per 100,000 in the period from 1993·1995. Compared to earlier studies, the incidence has increased and the clinical manifestation has shifted to younger ages. Although the possibility of exogenous insulin administration has largely reduced the risk for short-term complications, such as diabetic ketoacidosis and hyperglycaemic coma, over 70% of patients will develop long-tenn complications. These include microangiopathy, that may cause problems with the kidney-function and the vision, and macropangiopathy, that leads to an elevated risk of developing major cardiovascular problems. The quality of life of diabetes patients can be profoundly reduced because of these complications. In addition, the lifeexpectancy of diabetes patients is considerably shorter than that of healthy persons. The risk of developing long-term complications may be signiticantly reduced by normalizing blood glucose levels. However, this requires intensive individual treatment and significant changes in lifestyle. Consequently, the disease has large emotional and social impact on the lifes of patients and their family. In addition, diabetes has serious economic consequences, because of the costs of the treatment and lost productivity due to hospital admission. Therefore, prevention and cure of the disease are major goals of diabetes research. In order to achieve these goals, a thorough knowledge is required about the mechanisms via which diabetes develops. The studies described in this thesis describe such a mechanism.

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