David T. Robles

Insulin autoimmunity: prediction/precipitation/prevention type 1A diabetes

Type 1 diabetes of both the NOD mouse and man is associated with autoimmunity directed against insulin which is the only beta cell specific autoantigen identified to date. One can use autoantibodies to insulin to predict diabetes, use insulin peptides to create insulin autoantibodies, insulitis and diabetes, and use insulin or its peptides in animal models to prevent diabetes. An expanding set of resources are now available for the development and testing in man of therapies to prevent type 1 diabetes, and a number of trials utilizing insulin peptides are now underway.

Homozygosity for premature stop codon of the MHC class I chain-related gene A (MIC-A) is associated with early activation of islet autoimmunity of DR3/4-DQ2/8 high risk DAISY relatives.

We hypothesized that homozygosity for the major histocompatibility complex (MHC) class I chain-related gene A (MIC-A)5.1 allele with premature stop codon would increase diabetes risk of individuals followed from infancy in the DAISY study (Diabetes Autoimmunity Study in the young). Forty five percent (10/22) of relatives (siblings and offspring cohort, SOC) who developed anti-islet autoantibodies were MIC-A5.1/5.1 homozygous. Of SOC individuals without autoantibodies, 12/58 (19%, p = 0.02) were MIC-A5.1 homozygous. By life table analysis of expression of autoantibodies, DR3-DQ2/ DR4-DQ8 more than 50% of MIC-A5.1 homozygous children became autoantibody positive by 7 years of age, compared to delayed development of autoantibodies for non-MIC-A5.1/5.1 DR3-DQ2/ DR4-DQ8 children (p = 0.005). For DR3-DQ2/DR4-DQ8 nonrelatives, the risk of activating anti-islet autoimmunity remained low even with MIC-A5.1 homozygosity suggesting that there are additional factors contributing to the marked risk of relatives compared to the general population with the DR3-DQ2/DR4-DQ8 genotype.