Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodies

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Abstract
The prodromal phase of type 1 diabetes is characterised by the appearance of multiple islet‐cell related autoantibodies (Aab). The major target antigens are islet‐cell antigen, glutamic acid decarboxylase (GAD), protein‐tyrosine phosphatase‐2 (IA‐2) and insulin. Insulin autoantibodies (IAA), in contrast to the other autoimmune markers, are the only β‐cell specific antibodies. There is general consensus that the presence of multiple Aab (≥ 3) is associated with a high risk of developing diabetes, where the presence of a single islet‐cell‐related Aab has usually a low predictive value. The most commonly used assay format for the detection of Aab to GAD, IA‐2 and insulin is the fluid‐phase radiobinding assay. The RBA does not identify or measure Aab, but merely detects its presence. However, on the basis of molecular studies, disease‐specific constructs of GAD and IA‐2 have been employed leading to somewhat improved sensitivity and specificity of the RBA. Serological studies have shown epitope restriction of IAA that can differentiate diabetes‐related from unrelated IAA, but current assays do not distinguish between disease‐predictive and non‐predictive IAA or between IAA and insulin antibodies (IA). More recently, phage display technology has been successful in identifying disease‐specific anti‐idiotopes of insulin. In addition, phage display has facilitated the in vitro production of antibodies with high affinity. Identification of disease‐specific anti‐idiotopes of insulin should enable the production of a high affinity reagent against the same anti‐idiotope. Such a development would form the basis of a disease‐specific radioimmunoassay able to identify and measure particular idiotypes, rather than merely detect and titrate IAA. Copyright © 2005 John Wiley & Sons, Ltd.