The importance of immunological, genetic and clinical factors for beta cell function in childhood diabetes

Abstract: Type I diabetes is caused by environmentally initiated, progressive autoimmune destruction of pancreatic beta cells in genetically susceptible individuals, which results in insulin deficiency and hyperglycemia. At diagnosis, about 10-20 % of beta cells remain, but after insulin therapy is started, a period with regained secretive capacity follows. This period, called the clinical remission, offers an opportunity to arrest beta cell destruction by intervention with immune-modulation, antioxidant treatment and beta cell rest. Diabetes risk is strongly influenced by age-related genetic factors, and diabetes-specific autoantibodies can be found already before diagnosis. Although, extensive data on genetic and immunological factors which influence the process exist, uncertainty remains concerning the complicated combined effect, of genetic, immunological and clinical influences, that befall the growing child who develops type I diabetes. The aims of our studies were: To investigate prevalence of GAD65Ab with a new radioimmunoassay; to study immunological, genetic and clinical factors which influence the duration of the clinical remission and rate of progression of beta cell destruction in newly onset childhood diabetes; to study evolution and species-specificity of GAD65Ab; and to evaluate the effect of initial diazoxide treatment on residual endogenous insulin secretion. We have studied, in total, 330 children, with newly diagnosed type 1 diabetes, and a reference group of 119 healthy children. 56 children were randomized to either diazoxide or placebo for the first 3 months of diabetes and followed for two years. Insulin secretion was evaluated indirect as duration of clinical remission, or as fasting- and breakfast-stimulated C-peptide. Autoantibodies were analyzed by radioimmunoassay (GAD65Ab, GAD65Ab epitopes and IA-2Ab) and indirect immunofluorescence (ICA) and HLA-DQ and -DR haplotypes were analyzed by PCR-techniques. In conclusion we have found: Higher prevalence and index levels of GAD65Ab in female than male patients and a positive age-correlation of GAD65Ab in boys; Age- and gender-dependent divergence in the duration of the clinical remission and also dependence on ICA; HLA-DQ- and GAD65Ab-influences on the rate of change in beta cell function, with the fastest loss of endogenous insulin secretion in DQ2-positive individuals with GAD65Ab; Maturation of the humoral immunity towards GAD65, with a change from preference for rodent GAD65 to human GAD65 during the first year after diagnosis; and, although a 50% reduction in C-peptide secretion was achieved during treatment with diazoxide, the subsequent effect on residual insulin secretion was of shorter duration in children than in adults. We propose, that the increased risk for a faster reduction in beta cell function in HLA-DQ2 positive patients, with GAD65Ab, should be taken into consideration when new intervention protocols are planned. The fact, that male and female patients differ in their physiological response to growth also needs to be accounted for. The high rate of adverse effects for diazoxide and the short term effect achieved, prompt the development of new beta cell-specific inhibiting drugs, which may also be tried in pre-diabetic individuals. The time, when autoimmune markers have revealed that a process involving beta cell destruction is started, and during the first months of clinical disease (when preservation of remaining beta cells may be possible), is an important window of opportunity for intervention. Still, many questions remain to be answered until we find the optimal screening procedures and intervention strategies that are safe and effective in large groups of children.