Prediabetes in children: natural history, diagnosis, and preventive strategies

The clinical manifestation of type 1 diabetes mellitus is preceded by an asymptomatic prodromal period called prediabetes or preclinical diabetes. It may last from a few months to several years, during which the autoimmune destruction of the insulin-producing beta-cells in the pancreas progresses. The genes on the human leukocyte antigen (HLA) and insulin gene region are major genetic determinants for genetic disease susceptibility, while dietary compounds and viral infections are the most likely environmental factors contributing to the etiopathogenesis. T cells are thought to be the effector cells for the beta-cell destruction, and glutamic acid decarboxylase, insulinoma-associated protein 2 and insulin represent the three major autoantigens. Autoantibodies are early detectable markers of an ongoing disease process and are used to diagnose prediabetes. Among first-degree relatives of patients with type 1 diabetes, the risk for clinical disease can be graded from <5% in those with one or no antibodies to >90% in individuals who carry the HLA-DQB1*02/0302 risk genotype and are positive for multiple autoantibodies. beta-Cell function may also be tested in autoantibody-positive individuals and low first-phase insulin response is highly predictive for rapid progression to the clinical disease. However, dynamic course and individual variation of the disease process complicates the disease prediction, and it is not known whether all individuals with signs of prediabetes will inevitably progress to clinical type 1 diabetes. Until clinically applicable prevention for the condition exists, the screening for the risk markers of type 1 diabetes should actively be undertaken only in the context of research projects. Several major national and international multicenter studies are ongoing to test the potential of various agents (e.g. insulin and nicotinamide) or early elimination of dietary compounds (e.g. cow's milk proteins) to delay or prevent the onset of clinical type 1 diabetes.