ABSTRACT
The first major breakthrough in understanding type 1 diabetes (T1D) was in 1889 when Von Mering & Minkowski at the University of Strasbourg showed that removing the pancreas of dogs caused diabetes (1). It took 33 years for this knowledge to translate into the isolation of insulin for therapy, thereby changing a fatal disease into a less fatal, chronic disease. It was another 28 years before Bornstein, using a crude insulin bioassay, clearly delineated insulin-dependent (type 1) diabetes and non-insulin-dependent (type 2) diabetes as insulin deficient and noninsulin-deficient, respectively (2). This was soon confirmed with the development of the insulin radioimmunoassay by Berson and Yalow (3). The concept that T1D might be an immune-mediated disease was spurred by the histologic description of immune cells in the islets (insulitis) by Gepts in 1965 (4), and subsequently cemented by a larger analysis of pancreas samples by Foulis in the 1980s (5). Meanwhile, in 1974, Nerup et al. (6) and others (7) reported the association of T1D with specific HLA types and Bottazzo et al. (8) and Irving et al. (9), the association with islet cell antibodies (ICA) detected by indirect immunofluorescence. By the 1980s, autoantibodies to insulin had been identified particularly in younger
patients by Palmer et al. (8,10) and ICA as well as impaired insulin secretion (first phase-insulin response to IV glucose-FPIR) shown by Eisenbarth et al (11-13) to identify at-risk individuals prior to clinical disease. This was the basis, together with further definition of HLA specificities (14), for prediction algorithms for clinical T1D in relatives and subsequently in the general population (15). The immunoserological basis of risk prediction depended on the discovery of specific autoantigens, in addition to insulin, namely glutamic acid decarboxylase molecular weight isoform 65,000 (GAD-65) (16), insulinoma-like antigen-2 (IA-2) (17) and, more recently, zinc transporter 8 (18), and the development of biochemical assays for antibodies to these antigens (19) that have been subjected to quality control in international workshops (20,21). As described in chapter 5, identification of those at risk for T1D using serological and other markers has been a great success story, crossing the first hurdle in prevention, the requirement to identify those who could benefit. Combined with advances in understanding preclinical natural history and immunotherapeutics, clinical trials aimed at primary prevention before initiation of the autoimmune process and secondary prevention during the autoimmune process are now a reality. To date, however, most trials represent tertiary prevention aimed at retarding further -cell destruction in people with clinical T1D (Fig. 1). Primary, secondary, and tertiary prevention trials have been previously reviewed (22-25) and guidelines suggested (26). In this chapter, we describe current and planned clinical trials for T1D prevention, while identifying issues that continue to challenge translational investigators.
