This work aimed to assess the maturation of the humoral immune response to insulin in preclinical type 1 diabetes by observing the emergence of various isotypes of insulin autoantibodies (IAA) in children with HLA-DQB1-conferred disease susceptibility. The series was derived from the Finnish Type 1 Diabetes Prediction and Prevention Study and comprised 15 IAA-positive children who presented with type 1 diabetes during prospective observation (progressors) and 30 children who remained nondiabetic (nonprogressors). An isotype-specific radiobinding assay was used to determine isotype-specific IAA (IgG1-4 and IgA) from samples obtained with an interval of 3-12 mo. The progressors had IAA of subclass IgG3 in their first IAA-positive sample more often than did the nonprogressors (13 of 15 versus 12 of 30; p = 0.003). Nine progressors had a dominant IgG1-IAA response initially, and six had a dominant IgG3-IAA response. The corresponding distribution among the nonprogressors was that 20 had a dominant IgG1-IAA response, none had an IgG3-IAA response, and three had a dominant response other than IgG1- or IgG3-IAA (chi(2)(df = 2) = 12.02; p = 0.002). The progressors had higher integrated levels (area under the curve) of IgG1-IAA (p = 0.05) and IgG3-IAA (p = 0.002). Nine progressors had a dominant integrated IgG1-IAA response and six had a dominant IgG3-IAA response over the observation period, whereas 22 nonprogressors had a dominant IgG1-IAA response, six had a dominant IgG2-IAA response, and one an IgG3-IAA response (chi(2)(df = 2) = 11.23; p = 0.004). Genetically susceptible young children who progress rapidly to clinical type 1 diabetes are characterized by strong IgG1 and IgG3 responses to insulin, whereas a weak or absent IgG3 response is associated with relative protection from disease.