Only multiple autoantibodies to islet cells (ICA), insulin, GAD65, IA-2 and IA-2 beta predict immune-mediated (type 1) diabetes in relatives

We report here our prospective,study of 15,224 non-diabetic, first-degree r elatives of probands with immune-mediated (type 1) diabetes (IMD), of which 135 were found to eventually develop diabetes. We determined,islet cell, i nsulin, GAD65, insulinoma-associated antigen-2 and 2 beta autoantibodies (I CA, IAA, GAD65A, LA-2A and IA-2 beta A), on the first available serum sampl es. The latter three autoantibodies were-however assayed on subsets of the relatives with and without ICA, IAA and/or GAD65A, plus most of the relativ es who developed diabetes. Of the relatives who progressed to diabetes, 94% had at least one of these autoantibodies on the first screening, while ICA proved to be the most sensitive single marker (sensitivity 74%). Risk of d iabetes was however negligible when ICA was found in the absence of the oth ers (5-year risk=5.3%), but increased dramatically whenever two or more aut oantibodies were present (5-year risk=28.2% and 66.2%, respectively). The m ost predictive combination of markers was ICA plus IA-2A and/or IA-2 beta A . Loss of first phase insulin release to IVGTT also occurred only in those ICA-positive relatives who had one or more of the other autoantibodies. The data suggests that significant beta-cell damage is seen only when the unde rlying autoimmunity has spread to multiple antigenic islet cell determinant s. Combinations of the autoantibodies occurred most often in relatives with the highest risk HLA-DR/DQ phenotypes. These data document that only relat ives positive for at least two or more of these five autoantibodies are at significant risk of diabetes themselves. Intervention trials for the preven tion of type 1 diabetes could be designed based on testing for these autoan tibodies alone, without the need for HLA typing and IVGTT testing. (C) 1999 Academic Press.