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Physiol. Genomics 21: 201-211, 2005. First published January 25, 2005; doi:10.1152/physiolgenomics.00173.2004
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Dynamic interaction between T cell-mediated ß-cell damage and ß-cell repair in the run up to autoimmune diabetes of the NOD mouse

¹ Diabetes Research Center, Division of Endocrinology
² Division of Pediatric Informatics
³ Division of Developmental Biology
⁴ Divison of Molecular Immunology, Cincinnati Children’s Hospital Research Foundation and College of Medicine, University of Cincinnati, Cincinnati, Ohio

In type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, the pathogenic destruction of the insulin-producing pancreatic ß-cells is under the control of and influenced by distinct subsets of T lymphocytes. To identify the critical genes expressed by autoimmune T cells, antigen presenting cells, and pancreatic ß-cells during the evolution of T1DM in the nonobese diabetic (NOD) mouse, and the genetically-altered NOD mouse (BDC/N), we used functional genomics. Microarray analysis revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin (IL)-17, and islet cell regenerating genes, Reg3, Reg3ß, and Reg3. Our data indicate that progression to insulitis was connected to marked changes in islet antigen expression, ß-cell differentiation, and T cell activation and signaling, all associated with tumor necrosis factor- and IL-6 expression. Overt diabetes saw a clear shift in cytokine, chemokine, and T cell differentiation factor expression, consistent with a focused Th1 response, as well as a significant upregulation in genes associated with cellular adhesion, homing, and apoptosis. Importantly, the temporal pattern of expression of key verified genes suggested that T1DM develops in a relapsing/remitting as opposed to a continuous fashion, with insulitis linked to hypoxia-regulated gene control and diabetes with C/EBP and Nkx2 gene control.

type 1 diabetes; nonobese diabetic mouse; pancreas; microarray; gene expression profile

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