Primary prevention of type 1A diabetes: are we there yet?

Type 1A diabetes (immune-mediated diabetes) is one of the most intensively studied autoimmune disorders. Tools for the prediction of diabetes have revolutionized the field, and with our current state of knowledge, the disease can be predicted’ in man and prevented in animal models. Despite large studies and commitment on the part of the research and lay communities, at present, the disease is not preventable in man (1). Type 1A diabetes is hypothesized to be a chronic autoimmune disease that passes through a series of stages prior to manifesting clinically as hyperglycemia (2). In models of diabetes development, individuals at genetic risk for type 1A diabetes experience an insult that initiates the autoimmune attack against the beta cell. Markers of the autoimmune process including diabetes-related antibodies have been extensively studied in long-term prospective studies of the natural history of type 1A diabetes, and the markers may be present for years prior to the diagnosis of diabetes (3, 4). As beta-cell destruction progresses, insulin production begins to fail and abnormalities of glucose metabolism first identified as decreased first-phase insulin response on intravenous glucose tolerance test progress to impaired glucose tolerance and culminate in frank hyperglycemia and clinical symptoms. Studies on the prevention of type 1A diabetes have generally targeted subjects already expressing diabetes-related autoimmunity and follow them for the development of diabetes (5, 6). These studies target subjects who may have an immune response against the beta cell that is firmly entrenched and difficult to alter. Evaluation of the best studied animal model, the spontaneous diabetes of the non-obese diabetic (NOD) mouse, has amassed a body of evidence suggesting that insulin/proinsulin may be the primary autoantigen. The evidence includes studies where the immune response to other specificities (e.g., islet glucose-related phosphatase) have been shown to be downstream of the immune response to insulin, and not essential for disease development, and where complete prevention of diabetes by altering a single amino acid of insulin is possible (changing B16 tyrosine of insulin to an alanine of the B:9–23 insulin peptide target). Diabetes is relatively easy to prevent in animal models of the disease, and an array of therapies are effective (7). However, the mechanism of prevention is usually poorly defined, and there is a lack of surrogate assays of the immune response to define which therapies are likely to prevent diabetes in man. Inability to define surrogate assays probably results from a subtle fine balance of the immune system such that even with inbred strains of animals, only a subset progress to diabetes, and thus, relatively small changes in immune function may prevent disease. It is possible to develop more robust animal models where essentially 100% progress to diabetes (e.g., insulin 2 knockout NOD mice; recurrent disease in islet transplants). Preventing diabetes in these models may present too high a hurdle to identify methods of prevention that would be effective in man, while not being able to prevent in such robust models may predict failure in man. These observations have led to the hypothesis that identifying children at a very high genetic risk for diabetes, prior to development of measurable beta-cell autoimmunity, and treating them may be a more effective means of diabetes prevention. Proposed interventions are largely based upon animal models of type 1A diabetes, studies of the natural history of type 1A diabetes, and pilot studies in humans. Studies for the primary prevention of type 1A diabetes, i.e., prior to the expression of islet autoantibodies, are currently being designed and implemented. These studies target young children at a very high genetic risk for type 1A diabetes and propose treatments that are very safe. These studies are large undertakings requiring large-scale screening to identify these highest risk subjects and follow-up over a long period of time for the outcome of anti-islet autoimmunity and diabetes, as we have no surrogate marker for the disease. The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) described in this issue of the journal is on the forefront of such studies. As reviewed in the manuscript by the TRIGR Study Group, dietary manipulation has been shown to delay diabetes in animal models. There are conflicting data