Glutamic acid decarboxylase (GAD65) and insulin are implicated as target antigens in the pathogenesis of human diabetes through correlative measurements of humoral and cellular reactivity to them in diabetics and at-risk diabetic individuals. Recently, an age-dependent loss of tolerance to one of several naturally processed epitopes of GAD65 (555-567) has been observed to precede diabetes in diabetes-prone mice transgenic for diabetes-correlated human class II genes. Extended studies in these mice (RIP-B7/DR0404) now show that tolerance is maintained to another DR4-restricted naturally processed region within GAD65. While tolerance is lost to GAD65 (555-567) in B7/DR0404 mice prior to diabetes, these mice remain T cell-tolerant to GAD65 (273-286). Prediabetes loss of tolerance to GAD65 (555-567) has now been shown to correlate with an impaired response to exogenous glucose in an intraperitoneal (i.p.) glucose tolerance test. In addition, these mice exhibit a T cell response to insulin A(6-21) at the hyperglycemic state. Investigating a possible cause-and-effect relationship between T cell reactivity to GAD65 and diabetes pathogenesis, GAD65 (555-567) T cell receptor (TcR) transgenic mice have been generated and future work is aimed at understanding the importance of T cell GAD65 reactivity and its role in diabetes progression.