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

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Abstract

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-Ag7 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.

Authors

Karine Thébault-Baumont, Danielle Dubois-Laforgue, Patricia Krief, Jean-Paul Briand, Philippe Halbout, Karine Vallon-Geoffroy, Joëlle Morin, Véronique Laloux, Agnès Lehuen, Jean-Claude Carel, Jacques Jami, Sylviane Muller, Christian Boitard