Immunological and genetic markers can be used to assess risk of developing type 1 diabetes prior to the onset of clinical symptoms. Autoantibody-positive relatives of patients with type 1 diabetes are at increased risk for disease, while the presence of HLA DQA1*0102/DQB1*0602 is thought to confer protection. Using the unique population identified by the Diabetes Prevention Trial--Type Diabetes (DPT-1), our aim was to determine if these individuals were protected from type 1 diabetes.We described metabolic and immunological characteristics of islet cell cytoplasmic autoantibodies-positive relatives with DQB1*0602 identified as part of DPT-1.We found that 32% of DQB1*0602-positive relatives identified through the DPT-1 had abnormalities of glucose tolerance despite the fact that only 19% had multiple type 1 diabetes-associated autoantibodies and only 13% had abnormal insulin secretion, markers typically associated with the disease. In addition, these markers were not associated with abnormal glucose tolerance. In contrast, the DQB1*0602-positive relatives had elevated fasting insulin (117+/-10 pmol/l) and homeostasis model assessment of insulin resistance (HOMA-R) (4.90+/-0.5) values, which are more commonly associated with type 2 diabetes. The later marker of insulin resistance was associated with glucose tolerance status.Our data indicate that DQA1*0102/DQB1*0602 relatives identified through DPT-1 have a high frequency of abnormal glucose tolerance and a disease phenotype with characteristics of type 1 and type 2 diabetes. Thus, multiple pathways to abnormal glucose tolerance are present within families of these type 1 patients.