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

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-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.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

“…Most autoreactive T cell targets are beta cell specific, including glucose-6-phosphatase catalytic subunit 2 (G6PC2, also known as IGRP) and solute carrier family 30 member 8 (SLC30A8 also known as ZNT8); others are not entirely restricted to beta cells, including chromogranin A and PTPRN. Studies in NOD mice have shed some light on the relative roles of individual autoantigens: deletion of either proinsulin gene alters diabetes progression in NOD mice (Moriyama et al 2003, Thébault-Baumont et al 2003, Nakayama et al 2007, whereas deletion of GAD or PTPRN does not alter disease progression (Yamamoto et al 2004, Kubosaki et al 2005.…”

Autoimmunity: Basic Mechanisms and Implications in Endocrine Diseases

“…In mice, two isoforms of pro-insulin exist, and pro-insulin-2 represents the principle isoform targeted during autoimmune reactions. Thébault-Baumont et al [27] demonstrated that NOD mice, which are deficient for pro-insulin-2, develop accelerated insulitis and diabetes. This may be correlated with a lack in the peripheral T cell repertoire, due to the absence of pro-insulin-2 within the thymus.…”

“…This may be correlated with a lack in the peripheral T cell repertoire, due to the absence of pro-insulin-2 within the thymus. Furthermore, allelic variations of pro-insulin correlate with the risk of T1D in humans, while insulin expression within the thymus promotes T cell tolerance to insulin in mice [27]. …”

Immunogenetics of Type 1 Diabetes

“…Mice that were engineered to have a graded thymic insulin deficiency, while pancreatic insulin remained unaltered, exhibited a detectable peripheral T-cell response to proinsulin even against a nondiabetogenic background [36, 37]. Bred against the NOD background, these mice show marked acceleration of insulitis and diabetes [38]. Importantly, enhanced reactivity in these mice was confined to insulin and did not affect autoimmunity against other autoantigens.…”