The stages of type 1A diabetes: 2005

Summary:  Type 1A diabetes is a chronic autoimmune disease usually preceded by a long prodrome during which autoantibodies to islet autoantigens are present. These antibodies are directed to a variety of antigens, but the best characterized are glutamic acid decarboxylase‐65, insulinoma‐associated antigen‐2, and insulin. We hypothesize that the natural history of type 1A diabetes can be represented by several stages, starting from genetic susceptibility and ending in complete β‐cell destruction and overt diabetes. Type 1A diabetes probably results from a balance between genetic susceptibility and environmental influences. In both humans and animal models, the major determinants of the disease are genes within the major histocompatibility complex. The next best‐characterized susceptibility locus is the insulin gene, the variable nucleotide tandem repeat locus. This gene affects the expression of insulin in the thymus and thus may play a role in the modulation of tolerance to this molecule. In a subset of genetically susceptible individuals, the activation of autoimmunity may be triggered by environmental factors such as viruses and/or diet. However, no conclusive association has been established between type 1A diabetes and specific environmental triggers. In this review, we provide evidence that insulin has a fundamental role in anti‐islet autoimmunity.