Insulin-dependent diabetes mellitus (IDDM) is associated with antibodies to a 64,000-Mr islet cell protein, at least part of which is identified as glutamic acid decarboxylase (GAD). These antibodies are detected as two distinct antibody specificities to 50,000-Mr and 37,000/40,000-Mr tryptic fragments of the autoantigen (50K and 37K antibodies, respectively). We determined the frequencies of antibodies to intact GAD, tryptic fragments of islet 64,000-Mr antigen, islet cell antibodies (ICAs), and insulin autoantibodies (IAAs) in sera from 58 nondiabetic identical twins of patients with IDDM, of whom 12 subsequently developed diabetes. ICA, antibodies to intact GAD, and those to tryptic fragments were detected at similar frequencies in prediabetic twins (67–75%), but only 25% had IAA. Of 46 twins who remain nondiabetic, GAD antibodies, 50K antibodies, and ICA were detected in 6 (13%), 7 (15%), and 5 (11%), respectively, whereas only 1 (2%) possessed 37K antibodies and 2 (4%) had IAA. Eight of 9 twins with 37K antibodies and all 6 twins with ICA > 20 Juvenile Diabetes Foundation U have developed diabetes. Antibodies to GAD are sensitive markers for diabetes development but may also be present in genetically susceptible individuals who are unlikely to develop disease. Antibodies to 37,000/40,000-Mr fragments of the 64,000-Mr antigen or high-titer ICA were the best markers for diabetes development in these twins.

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