Identification of a Serum-Induced Transcriptional Signature Associated With Type 1 Diabetes in the BioBreeding Rat
- Mary Kaldunski1,
- Shuang Jia1,
- Rhonda Geoffrey1,
- Joel Basken1,
- Simon Prosser1,
- Sanjay Kansra1,
- John P. Mordes2,
- Åke Lernmark3,
- Xujing Wang4 and
- Martin J. Hessner1
- 1Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics at the Medical College of Wisconsin, the Children's Research Institute of Children's Hospital of Wisconsin, and the Human and Molecular Genetics Center, Milwaukee, Wisconsin;
- 2Division of Endocrinology and Metabolism, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts;
- 3Robert H. Williams Laboratory, Department of Medicine, University of Washington, Seattle, Washington;
- 4Department of Physics and the Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, Alabama.
- Corresponding author: Martin J. Hessner, .
OBJECTIVE Inflammatory mediators associated with type 1 diabetes are dilute and difficult to measure in the periphery, necessitating development of more sensitive and informative biomarkers for studying diabetogenic mechanisms, assessing preonset risk, and monitoring therapeutic interventions.
RESEARCH DESIGN AND METHODS We previously utilized a novel bioassay in which human type 1 diabetes sera were used to induce a disease-specific transcriptional signature in unrelated, healthy peripheral blood mononuclear cells (PBMCs). Here, we apply this strategy to investigate the inflammatory state associated with type 1 diabetes in biobreeding (BB) rats.
RESULTS Consistent with their common susceptibility, sera of both spontaneously diabetic BB DRlyp/lyp and diabetes inducible BB DR+/+ rats induced transcription of cytokines, immune receptors, and signaling molecules in PBMCs of healthy donor rats compared with control sera. Like the human type 1 diabetes signature, the DRlyp/lyp signature, which is associated with progression to diabetes, was differentiated from that of the DR+/+ by induction of many interleukin (IL)-1–regulated genes. Supplementing cultures with an IL-1 receptor antagonist (IL-1Ra) modulated the DRlyp/lyp signature (P < 10−6), while administration of IL-1Ra to DRlyp/lyp rats delayed onset (P = 0.007), and sera of treated animals did not induce the characteristic signature. Consistent with the presence of immunoregulatory cells in DR+/+ rats was induction of a signature possessing negative regulators of transcription and inflammation.
CONCLUSIONS Paralleling our human studies, serum signatures in BB rats reflect processes associated with progression to type 1 diabetes. Furthermore, these studies support the potential utility of this approach to detect changes in the inflammatory state during therapeutic intervention.
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- Received March 17, 2010.
- Accepted July 12, 2010.
- © 2010 by the American Diabetes Association.
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