Lessons on autoimmune diabetes from animal models

TIDM (Type I diabetes mellitus) results from selective destruction of the insulin-producing beta-cells of the pancreas by the immune system, and is characterized by hyperglycaemia and vascular complications arising from suboptimal control of blood glucose levels. The discovery of animal models of TIDM in the late 1970s and early 1980s, particularly the NOD (non-obese diabetic) mouse and the BB (BioBreeding) diabetes-prone rat, had a fundamental impact on our ability to understand the genetics, aetiology and pathogenesis of this disease. NOD and BB diabetes-prone rats spontaneously develop a form of diabetes that closely resembles the human counterpart. Early studies of these animals quickly led to the realization that TIDM is caused by autoreactive T-lymphocytes and revealed that the development of T I D M is controlled by numerous polymorphic genetic elements that are scattered throughout the genome. The development of transgenic and gene-targeting technologies during the 1980s allowed the generation of models of TIDM of reduced genetic and pathogenic complexity, and a more detailed understanding of the immunogenetics of TIDM. In this review, we summarize the contribution of studies in animal models of TIDM to our current understanding of four fundamental aspects of TIDM: (i) the nature of genetic elements affording TIDM susceptibility or resistance; (ii) the mechanisms underlying the development and recruitment of pathogenic autoreactive T-cells; (iii) the identity of islet antigens that contribute to the initiation and/or progression of islet inflammation and beta-cell destruction; and (iv) the design of avenues for therapeutic intervention that are rooted in the knowledge gained from studies of animal models. Development of new animal models will ensure continued progress in these four areas.