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The cytoplasmic islet cell antibody patterns of sera from islet cell antibody positive non-diabetic and diabetic endocrine autoimmune patients, and newly-diagnosed Type 1 (insulin-dependent) diabetic patients were characterised using four layer immunofluorescence with monoclonal anti-proinsulin or anti-glucagon antibodies. Two distinct islet cell antibody types were identified. One gave a diffuse cytoplasmic staining in both Beta and Alpha cells ('whole' islet pattern), and was not affected by pre-incubation with rat brain homogenate. The other had a granular appearance with staining restricted predominantly to Beta cells ('selective' islet pattern) and was completely inhibited by pre-incubation with rat brain homogenate. Some sera appeared to have a 'mixed' islet pattern, in which glucagon-positive cells gave a weaker cytoplasmic staining than proinsulin-positive cells. The granular 'selective' pattern was found in sera from 19 (79%) of 24 non-diabetic endocrine autoimmune patients, in two (22%) endocrine autoimmune patients who developed Type 1 diabetes (p less than 0.0001 vs non-diabetic endocrine autoimmune patients), and in none of 19 newly-diagnosed diabetic patients. The 'whole' islet pattern was found only in sera from patients who had, or who subsequently progressed to, Type 1 diabetes. This study has identified a novel islet cell antibody specificity and demonstrates that in islet cell antibody positive endocrine autoimmune patients, only islet cell antibodies which stain both Beta and Alpha cells are associated with progression to Type 1 diabetes.

IgG and IgM class insulin autoantibodies were measured by an enzyme-linked immunosorbent assay in sera from members of the Barts-Windsor-Middlesex prospective family study for Type 1 (insulin-dependent) diabetes. One hundred and twelve individuals from 28 families were selected for study on the basis of a clearly defined islet cell antibody status. IgG insulin autoantibodies were found to be significantly associated with islet cell antibody positive (n = 30) versus islet cell antibody negative (n = 57) first degree family relatives (p = 0.002), with increased significance (p = 0.0003) if complement-fixing (CF)-islet cell antibody individuals (n = 20) only were considered. In addition, a significant association of IgG insulin autoantibodies with subsequent development of diabetes was observed within the CF-islet cell antibody positive group (p less than 0.0003). No such associations were found for IgM insulin autoantibodies, but a higher prevalence of these autoantibodies was observed in islet cell antibody negative first degree relatives (n = 57) compared with a control group of 73 Blood Bank donors (p = 0.00007), and they were significantly associated with siblings (n = 48) rather than parents (n = 39), (p = 0.001). We conclude that the presence of IgG insulin autoantibodies and CF-islet cell antibodies confer more risk for future development of diabetes than the presence of either marker alone.