Type 1 diabetes results from autoimmune destruction of insulin-producing beta cells. There is a genetic predisposition to the disease, with the greatest contribution conferred by alleles present within the major histocompatibility complex (MHC; known as the human leukocyte antigen [HLA] region) on the short arm of chromosome 6. Whether the initiation of this immune response results from environmental triggers remains to be determined. Over years, immune infiltration into pancreatic islets leads to beta cell damage, impairment of cell function, and destruction of beta cells. This notion has led to clinical trials to arrest the progression of disease and potentially prevent or reverse the clinical syndrome.
Clinical trials using various immunologic agents have been conducted at multiple stages of the disease process. Primary prevention trials have been conducted in individuals with genetic predisposition who have not yet developed immunologic markers. Secondary prevention trials have been conducted in individuals with two or more type 1 diabetes-related autoantibodies, either during Stage 1 (normal metabolic function) or Stage 2 (abnormal metabolic function). Intervention trials, also referred to as tertiary prevention trials, have been conducted after diagnosis of hyperglycemia (Stage 3), mostly shortly after clinical onset of disease.
This article provides brief summaries of randomized controlled clinical trials that have been performed and mentions some nonrandomized pilot studies. Success has been limited in primary and secondary prevention trials, with one recent and notable exception (teplizumab). Some tertiary intervention trials have demonstrated improved beta cell function, but these studies have not permanently prevented the decline in beta cell function (eventually declining in parallel to controls). Future interventions with combinations of agents that can target multiple immunologic mechanisms may be needed, including strategies to improve regulatory immunity, as well as to replace and restore beta cell function.