Genetic modification of risk assessment based on staging of preclinical type 1 diabetes in siblings of affected children.

We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P < 0.001 for DQB1 genotypes according to the first classification), whereas there was a higher proportion of siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P < 0.001 according to the first classification). Autoantibodies alone were more sensitive in the prediction of future diabetes in siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P < 0.001 according to the first classification) and whether overt type 1 diabetes became manifest or not. Genetic susceptibility has an impact on both the initiation and progression of the autoimmune process leading to clinical diabetes in siblings of affected children.

Natural course of preclinical type 1 diabetes in siblings of affected children.

AIM: To define the dynamics of preclinical type 1 diabetes in siblings of affected children and to characterize the siblings experiencing a progressive process. METHODS: From 801 families taking part in the "Childhood Diabetes in Finland" (DiMe) Study, 715 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case, while another classification system covering 641 of the siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to intravenous glucose. RESULTS: Based on the first classification, there was a total of 95 siblings with initial signs of prediabetes, out of whom 34 (36%) progressed, 26 (27%) remained stable and 35 (37%) regressed during prospective observation for a median of 3.6 y (range 0.01-9.8 y). The siblings who progressed were younger, had a higher initial number of detectable autoantibodies, higher initial levels of various antibodies, with the exception of insulin autoantibodies, lower FPIR and a retarded glucose elimination rate in the first intravenous glucose tolerance test as compared with those that regressed. According to the second classification there were 41 siblings with initial signs of prediabetes, among whom 23 (56%) progressed, 14 (34%) remained stable and 4 (10%) regressed during the observation period. CONCLUSION: These data show that almost half of the siblings with signs of prediabetes at the time of diagnosis of the index case progressed further in their preclinical disease process during prospective observation. Young age, a strong humoral immune response to beta-cell antigens and reduced insulin secretory capacity appeared to be characteristic of those with a progressive process. Advanced and late prediabetes seem to represent a point of no return, as regression from these stages to no prediabetes was extremely rare.

Staging of preclinical type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group.

OBJECTIVES: To assess whether it is clinically relevant to classify siblings of children with recent-onset type 1 diabetes mellitus (T1DM) into various stages of preclinical diabetes, and to compare the risk of developing clinical disease and the time to diagnosis between these stages. STUDY DESIGN: From a total of 801 families taking part in the Childhood Diabetes in Finland Study, 758 initially unaffected siblings were graded into four stages of preclinical T1DM based on the number of disease-associated autoantibodies detectable close to the time of diagnosis in the index case: no (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (more than three antibodies). Another classification system, used with 712 siblings, was based on a combination of the number of antibodies and the first-phase insulin response (FPIR) to intravenous glucose: no (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (one or more antibodies, reduced FPIR). RESULTS: Six out of 661 siblings who initially presented no signs of prediabetes (0.9%; 95% confidence interval [CI], 0.3%-2.0%) progressed to clinical T1DM. Based on the first set of criteria, 3 out of 49 individuals (6.1%; CI, 1.3%-16. 9%; odds ratio [OR], 7.1; CI, 1.7-29.4) from the early prediabetes category, 3 out of 13 with advanced prediabetes (23.1%; CI, 5.0%-53. 8%; OR, 32.8; CI, 7.2-150), and 23 out of 35 with late prediabetes (65.7%; CI, 47.8%-80.9%; OR, 209; CI, 72.2-607) presented with clinical signs of T1DM. According to the second set of criteria 1 out of 15 siblings with early prediabetes (6.7%; CI, 0.2%-32.0%; OR, 7.8; CI, 0.9-69.1), 6 out of 23 with advanced prediabetes (26.1%; CI, 10.2%-48.4%; OR, 38.5; CI, 11.3-132), and 12 out of 13 with late prediabetes (92.3%; CI, 64.0%-99.8%; OR, 1310; CI, 146-11 737) presented with clinical signs of T1DM. The time to diagnosis was significantly shorter in those with late prediabetes initially than in those with no signs of prediabetes. CONCLUSIONS: Our observations indicate that it is possible to grade siblings of children with newly diagnosed T1DM into categories with significant differences in the subsequent risk of clinical T1DM and time to diagnosis. Such a classification will become clinically relevant as soon as effective measures are available for preventing or delaying the manifestation of overt T1DM.autoantibodies, classification, prospective, first-phase insulin response.