In vitro inhibition of insulin release mediated by sera with complement-fixing islet cell antibodies belonging to normal first degree relatives of patients with type 1 diabetes

Islet cell antibodies (ICA) are present in the sera of most patients with Type 1 diabetes at diagnosis and in some of their genetically susceptible, but otherwise normal, first degree relatives. In this study we have investigated basal and stimulated insulin release by mouse islets following preincubation with human sera (with or without the addition of guinea pig complement) belonging to: 15 normal first degree relatives of diabetic probands; 7 patients with Type 1 diabetes; 7 control subjects with no history of diabetes. All sera had been previously screened for conventional (IgG), complement fixing (CF) and surface (S) ICA. Basal insulin release was not altered by any of the sera. The response to stimulus after incubation with ICA negative and IgG-ICA positive (but CF-ICA negative) sera was similar whether complement was present or not. Stimulated insulin release was significantly inhibited by complement and sera from 2 relatives and 3 diabetic patients. These sera were CF-ICA positive, the sera of the 2 relatives being also ICSA positive. One relative developed Type 1 diabetes 14 months later. This study demonstrates for the first time that sera containing CF-ICA and belonging to individuals susceptible to Type 1 diabetes, can impair insulin release in vitro. It is therefore likely that antibody-dependent, complement-mediated mechanisms are involved in the pathogenesis of Type 1 diabetes.