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Thymic expression of insulin‐related genes in an animal model of autoimmune type 1 diabetes
Author(s) -
KechaKamoun Ouafae,
Achour Imane,
Martens Henri,
Collette Julien,
Lefebvre Pierre J.,
Greiner Dale L.,
Geenen Vincent
Publication year - 2001
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.182
Subject(s) - type 1 diabetes , animal model , gene , insulin , diabetes mellitus , autoimmune disease , gene expression , type 2 diabetes , medicine , biology , immunology , endocrinology , genetics , disease
Background Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self‐reactivity specifically oriented against insulin‐secreting islet β‐cells remains obscure. The primary objective of the present study was to investigate the hypothesis that a defect in thymic central T‐cell self‐tolerance of the insulin hormone family could contribute to the pathophysiology of type 1 diabetes. This hypothesis was investigated in a classic animal model of type 1 diabetes, the Bio‐Breeding (BB) rat. Methods The expression of the mammalian insulin‐related genes ( Ins , Igf1 and Igf2 ) was analysed in the thymus of inbred Wistar Furth rats (WF), diabetes‐resistant BB (BBDR) and diabetes‐prone BB (BBDP) rats. Results RT‐PCR analyses of total RNA from WF, BBDP and BBDR thymi revealed that Igf1 and Ins mRNAs are present in 15/15 thymi from 2‐day‐old, 5‐day‐old and 5‐week‐old WF, BBDR and BBDP rats. In contrast, a complete absence of Igf2 mRNA was observed in more than 80% of BBDP thymi. The absence of detectable Igf2 transcripts in the thymus of BBDP rats is tissue‐specific, since Igf2 mRNAs were detected in all BBDP brains and livers examined. Using a specific immunoradiometric assay, the concentration of thymic IGF‐2 protein was significantly lower in BBDP than in BBDR rats ( p <0.01). Conclusions The present study suggests an association between the emergence of autoimmune diabetes and a defect in Igf2 expression in the thymus of BBDP rats. This tissue‐specific defect in gene expression could contribute both to the lymphopenia of these rats (by impaired T‐cell development) and the absence of central T‐cell self‐tolerance of the insulin hormone family (by defective negative selection of self‐reactive T‐cells). Copyright © 2001 John Wiley & Sons, Ltd.