Antigen-specific islet antibodies: prediction of beta cell failure and differentiation between Type 1 and Type 2 diabetes

Abstract: Autoantibodies against glutamic acid decarboxylase (GADA), protein tyrosine-phosphatase-like protein (IAÐ2A), and/or pancreatic islet cells (ICA) are autoimmune markers usually present at diagnosis of Type 1 diabetes. Type 1 diabetes is therefore in general believed to be caused by an immune-mediated beta cell destruction. In children this destruction is fast, whereas in adult patients Type 1 diabetes is sometimes slowly-progressive, with preserved insulin production, and is therefore clinically often considered as Type 2 diabetes. The aims of this thesis were to develop GADA and IA-2A assays and study the value of these antigen-specific islet antibodies in the prediction of beta cell failure and differentiation between Type 1 and Type 2 diabetes. In children (<15 years) with recently diagnosed diabetes, GADA and/or IA-2A were detected as frequently as ICA (89% and 87%, respectively). Development of complete beta cell failure (fasting P-C-peptide <0.10 nmol/l) within 12 years after diagnosis of adult-onset diabetes (>20 years of age) was always associated with presence of GADA and/or IA-2A at diagnosis. The antibody patterns differed between rapid (2-3 antibodies and high antibody levels) and slow development (only GADA or ICA). In the Diabetes Incidence Study in Sweden (DISS) (15-34 years of age), islet antibodies were found in 83% of patients with clinical Type 1, but also in 24% of patients with clinical Type 2 and 51% of patients with unclassifiable diabetes. Hence, measurements of islet antibodies are necessary for a correct classification of diabetes (Type 1 versus Type 2). In 13% of antibody negative cases, low fasting P-C-peptide levels (<0.25 nmol/l) identified idiopathic non-autoimmune Type 1 diabetes. Most children and adults remained GADA and/or IA-2A positive many years after diagnosis. In conclusion, the antigen-specific islet antibodies predicted beta cell failure. To differentiate between classical Type 1 diabetes, slowly-progressive Type 1 diabetes, idiopathic Type 1 diabetes, and Type 2 diabetes, a classification into seropositive (islet antibody positive) or negative diabetes, with or without preserved beta cell function, is proposed.