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 beta 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.
Thébault-Baumont
Karine
K
Institut National de la Santé et de la Recherche Médicale (INSERM) U561, Hôpital Cochin-Saint Vincent de Paul, Paris, France.
Dubois-Laforgue
Danielle
D
Krief
Patricia
P
Briand
Jean-Paul
JP
Halbout
Philippe
P
Vallon-Geoffroy
Karine
K
Morin
Joëlle
J
Laloux
Véronique
V
Lehuen
Agnès
A
Carel
Jean-Claude
JC
Jami
Jacques
J
Muller
Sylviane
S
Boitard
Christian
C
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000276:immunology; D007330:Insulin Antibodies / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D011384:Proinsulin / Q000172:deficiency / Q000502:physiology*
D007330:Insulin Antibodies; D011384:Proinsulin; D005968:Glutamate Decarboxylase