Acceleration of type 1 diabetes mellitus in proinsulin 2–deficient NOD mice

Accumulating evidence favors a role for proinsulin as a key autoantigen in diabetes.In the mouse, two proinsulin isoforms coexist.Most studies point to proinsulin 2 as the major isoform recognized by T cells in the NOD mouse.We studied mice in which a null proinsulin 2 mutation was transferred from proinsulin 2-deficient 129 mice onto the NOD background along with 16 genetic markers (including I-A g7 MHC molecule) associated with diabetes.Intercross mice from the fourth backcross generation showed that proinsulin 2 -/-mice develop accelerated insulitis and diabetes.The high prevalence of anti-insulin autoantibodies in proinsulin 2 -/-mice indicates that diabetes acceleration relates to altered recognition of proinsulin.The prevalence of anti-glutamic acid decarboxylase autoantibodies and of sialitis is not increased in proinsulin 2 -/-mice.We give evidence that proinsulin 2 expression leads to silencing of T cells specific for an epitope shared by proinsulin 1 and proinsulin 2. In the human, alleles located in the VNTR region flanking the insulin gene control β cell response to glucose and proinsulin expression in the thymus and are key determinants of diabetes susceptibility.Proinsulin 2 -/-NOD mice provide a model to study the role of thymic expression of insulin in susceptibility to diabetes.