Insulin-dependent diabetes mellitus (IDDM) is associated with the formation of autoantibodies against different antigens in the islets of Langerhans, so-called islet cell antibodies (ICA). The expression of a major autoantigen, the beta-cell specific enzyme glutamic acid decarboxylase (GAD), is glucose-dependentin vitroand correlated to insulin releasein vitro.In this study the expression of islet autoantigens was examinedin vivoand the relationship between beta-cell function and islet cell surface antibody (ICSA) reactivity was tested.Rats were fed for 10 days with glipizide or diazoxide, in order to stimulate or inhibit insulin release, respectively. Frozen sections of pancreata were incubated with ten ICA-positive IDDM sera and analyzed by indirect immunofluorescence. Two sera with a“beta-cell restricted”staining, five with an“all-islet cell”staining and three with a“mixed”pattern were employed. In all three groups, the highest end-point litres were obtained when pancreata of rats treated with glipizide were used. Intermediate litres were seen in control animals and the lowest litres were observed on pancreata from diazoxide-treated rats, regardless of the serum used. In contrast to these observations, no correlation between ICSA reactivily and islet cell activity could be demonstrated. Conflicting results concerning ICSA in previous reports and our failure to show a glucose regulation of ICSA reactivity, indicate that ICSA is a phenomenon with a low degree of specificity.The observation that the recognition of islet cells by autoantibodies is influenced by the melabolic state of the islelsin vivosuggests that the level of autoantigen expression could be of importance in determining the intensity of the autoimmune destructive process present at the onset of IDDM.