Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives

Prediction of insulin-dependent diabetes mellitus (IDDM) is still largely based on islet cell antibodies (ICAs), but it may be improved by combined analysis with other humoral markers. We examined autoantibodies to insulin (IAAs), glutamic acid decarboxylase (GAD), and M(r) 37,000 and M(r) 40,000 fragments of islet antigens (37 and 40 kDa) together with ICA subtypes in 101 family members with ICAs â?¥10 Juvenile Diabetes Foundation units (JDF U) followed for up to 14 years, of whom 18 have developed IDDM. Life-table analysis showed a 43 risk of IDDM within 10 years for those with ICAs â?¥10 JDF U, rising to 53 for those with ICAs â?¥20 JDF U. The risk for ICAs â?¥10 JDF U was 62 in the family members in the youngest age quartile (40.7 years of age (P = 0.03). ICAs â?¥10 JDF U combined with IAAs gave a risk of 84 (P = 0.03 compared with IAA-), and ICAs â?¥10 JDF U combined with GAD antibodies gave a risk of 61 (P = 0.018). The risk for ICAs â?¥10 JDF U with antibodies to 37- kDa antigen was 76 (P < 0.0001). Risk increased with the number of autoantibodies, from 8 for ICAs alone to 88 with â?¥3 autoantibodies (14 cases detected) (P < 0.0001). The increased risk associated with multiple antibodies was observed independent of age. The median time to diagnosis in those with antibodies to 37- and/or 40-kDa antigen was 1.5 years, compared with 7.2 years in those with IAAs and GAD antibodies in the absence of antibodies to 37/40 kDa. The intensity and range of the autoantibody response offers better overall prediction of diabetes than any single autoantibody specificity, although antibodies to 37-/40-kDa antigens may prove to be useful markers of early clinical onset. We found that 78 of future cases of IDDM in ICA+ relatives came from the 27 with multiple autoantibodies and estimate that 88 of individuals within this category will need insulin treatment within 10 years. We propose a simple predictive strategy based on these observations.</p

Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives

Prediction of insulin-dependent diabetes mellitus (IDDM) is still largely based on islet cell antibodies (ICAs), but it may be improved by combined analysis with other humoral markers. We examined autoantibodies to insulin (IAAs), glutamic acid decarboxylase (GAD), and M(r) 37,000 and M(r) 40,000 fragments of islet antigens (37 and 40 kDa) together with ICA subtypes in 101 family members with ICAs â?¥10 Juvenile Diabetes Foundation units (JDF U) followed for up to 14 years, of whom 18 have developed IDDM. Life-table analysis showed a 43 risk of IDDM within 10 years for those with ICAs â?¥10 JDF U, rising to 53 for those with ICAs â?¥20 JDF U. The risk for ICAs â?¥10 JDF U was 62 in the family members in the youngest age quartile (40.7 years of age (P = 0.03). ICAs â?¥10 JDF U combined with IAAs gave a risk of 84 (P = 0.03 compared with IAA-), and ICAs â?¥10 JDF U combined with GAD antibodies gave a risk of 61 (P = 0.018). The risk for ICAs â?¥10 JDF U with antibodies to 37- kDa antigen was 76 (P < 0.0001). Risk increased with the number of autoantibodies, from 8 for ICAs alone to 88 with â?¥3 autoantibodies (14 cases detected) (P < 0.0001). The increased risk associated with multiple antibodies was observed independent of age. The median time to diagnosis in those with antibodies to 37- and/or 40-kDa antigen was 1.5 years, compared with 7.2 years in those with IAAs and GAD antibodies in the absence of antibodies to 37/40 kDa. The intensity and range of the autoantibody response offers better overall prediction of diabetes than any single autoantibody specificity, although antibodies to 37-/40-kDa antigens may prove to be useful markers of early clinical onset. We found that 78 of future cases of IDDM in ICA+ relatives came from the 27 with multiple autoantibodies and estimate that 88 of individuals within this category will need insulin treatment within 10 years. We propose a simple predictive strategy based on these observations.</p

Antibodies to GAD and tryptic fragments of islet 64K antigen as distinct markers for development of IDDM: studies with identical twins

Insulin-dependent diabetes mellitus (IDDM) is associated with antibodies to a 64,000-M(r) 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-M(r) and 37,000/40,000-M(r) 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-M(r) 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-M(r) fragments of the 64,000-M(r) antigen or high-titer ICA were the best markers for diabetes development in these twins.</p

Antibodies to GAD and tryptic fragments of islet 64K antigen as distinct markers for development of IDDM: studies with identical twins

Insulin-dependent diabetes mellitus (IDDM) is associated with antibodies to a 64,000-M(r) 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-M(r) and 37,000/40,000-M(r) 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-M(r) 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-M(r) fragments of the 64,000-M(r) antigen or high-titer ICA were the best markers for diabetes development in these twins.</p