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

Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease

We studied metabolic progression to IDDM in a cohort of adults who are ICA-positive and have associated autoimmune endocrine disease or circulating organ-specific autoantibodies (the Polyendocrine Study). Of the 186 individuals recruited 27 developed overt diabetes after a median follow-up of 4.5 years (range 0.4-12). Of these, eight patients did not require insulin treatment until at least 6 months after clinical diagnosis, with an interval of 1.8 years (1.2-5.7). An IVGTT was performed in 38 subjects and 23 had sequential studies. Of the initial 38 subjects six developed diabetes and only three showed a loss of FPIR to glucose (below the first percentile of a normal control group) before clinical onset of the disease. An additional three subjects showed a loss of the FPIR, and all still have normal glucose tolerance after median follow-up of 28 months (22-95). A whole or mixed pattern of islet cell staining was found in five of the six patients who developed diabetes and antibodies against an islet 37 k-antigen were detectable in four patients, all of whom required insulin soon after diagnosis. A beta-cell selective ICA staining pattern was seen in 14 of 17 subjects who did not develop diabetes and the mixed pattern in only three. None of this group had detectable 37k-antibodies. We conclude that metabolic deterioration is slow in polyendocrine patients, and that the IVGTT has less prognostic significance in this group than in first degree relatives of patients with IDDM. In contrast, the presence of the whole or mixed ICA staining pattern or of 37k-antibodies can identify a high risk of progression to IDDM within this polyendocrine population and may indicate the rate of metabolic deterioration. © 1994 Springer-Verlag.</p

Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease

We studied metabolic progression to IDDM in a cohort of adults who are ICA-positive and have associated autoimmune endocrine disease or circulating organ-specific autoantibodies (the Polyendocrine Study). Of the 186 individuals recruited 27 developed overt diabetes after a median follow-up of 4.5 years (range 0.4-12). Of these, eight patients did not require insulin treatment until at least 6 months after clinical diagnosis, with an interval of 1.8 years (1.2-5.7). An IVGTT was performed in 38 subjects and 23 had sequential studies. Of the initial 38 subjects six developed diabetes and only three showed a loss of FPIR to glucose (below the first percentile of a normal control group) before clinical onset of the disease. An additional three subjects showed a loss of the FPIR, and all still have normal glucose tolerance after median follow-up of 28 months (22-95). A whole or mixed pattern of islet cell staining was found in five of the six patients who developed diabetes and antibodies against an islet 37 k-antigen were detectable in four patients, all of whom required insulin soon after diagnosis. A beta-cell selective ICA staining pattern was seen in 14 of 17 subjects who did not develop diabetes and the mixed pattern in only three. None of this group had detectable 37k-antibodies. We conclude that metabolic deterioration is slow in polyendocrine patients, and that the IVGTT has less prognostic significance in this group than in first degree relatives of patients with IDDM. In contrast, the presence of the whole or mixed ICA staining pattern or of 37k-antibodies can identify a high risk of progression to IDDM within this polyendocrine population and may indicate the rate of metabolic deterioration. © 1994 Springer-Verlag.</p