ABSTRACT
Diabetes mellitus results from multiple genetic and pathologic processes in human and animal models. The current nomenclature from the American Diabetes Association Expert Committee classifies diabetes into broad groups on the basis of the etiological causes of diabetes. This review focuses on type 1A diabetes, which is caused by the immune-mediated destruction of b cells. Type 1A diabetes is a genetically heterogeneous disorder with certain well-defined rare syndromes. In particular, both the neonatal diabetes of the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome and the diabetes of approximately 15% of patients with autoimmune polyendocrine syndrome type 1 (APS-1) are determined by major ‘‘monogenic’’ mutations (IPEX: FOXP3 gene and APS-1: AIRE gene) (1-3). In contrast, type 1A diabetes is more typically associated with a polygenic pattern of inheritance (typical type 1A diabetes), with risk predominantly determined by genes within or linked to the major histocompatibility complex (MHC) on chromosome 6. The rare monogenic syndromes provide important and precise information as to the pathologic processes that can cause immune-mediated diabetes when mechanisms of self-tolerance fail. It is likely that mutations of the FOXP3 gene lead to diabetes by eliminating a major class of regulatory T lymphocytes (CD4+CD25+), while mutations of the AIRE gene contribute to diabetes by decreasing the expression of ‘‘peripheral’’ antigens within the thymus, such as insulin, and thereby reduce the negative selection of T cells within the thymus (4).
