Etiology and pathogenesis of type 1 diabetes

An increasing bulk of evidence suggests that type 1 (insulin-dependent) diabetes mellitus is an autoimmune disease with a strong immunogenetic background. 1st-degree relatives of type 1 diabetic patients, especially HLA-identical individuals, bear an increased risk to develop the disease. The autoimmune reactions are pronounced at the onset of disease where an infiltration of islets with T and B lymphocytes, plasma cells and macrophages can be observed. Autoreactive T lymphocytes play a crucial role among effector mechanisms which finally lead to a selective destruction of pancreatic beta cells. Disease-specific autoantibodies (Ab) include cytoplasmic islet cell Ab (ICA), islet cell surface Ab (ICSA), Ab to the 64KD islet cell protein and Ab to insulin (IAA). As ICA can be detected months or years before the onset of clinical disease, testing of individuals at risk or population screening programs can help to recognize subclinical insulitis. High titers of ICA and high levels of IAA, as measured by radioimmunoassay, indicate a high risk for progression to type 1 diabetes. A blunted first phase insulin response in the i.v. glucose tolerance test is the most sensitive sign of an irreversible metabolic deterioration. It is likely that immunotherapy at a prediabetic state will be more efficacious than its initiation after the clinical manifestation of diabetes. However, the appropriate immunotherapeutical strategies are yet to be worked out.