Faculty Collaboration Database

Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat. Diabetes 2010 Oct;59(10):2375-85

Date

08/05/2010

Pubmed ID

20682698

Pubmed Central ID

PMC3279523

DOI

10.2337/db10-0372

Scopus ID

2-s2.0-77957549892 (requires institutional sign-in at Scopus site)   26 Citations

Abstract

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.

Author List

Kaldunski M, Jia S, Geoffrey R, Basken J, Prosser S, Kansra S, Mordes JP, Lernmark A, Wang X, Hessner MJ

Author

Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antigens
Diabetes Mellitus, Type 1
Disease Progression
Gene Expression Regulation
Genetic Predisposition to Disease
HLA-DR Antigens
Homeostasis
Humans
Interleukin-1
Interleukin-1beta
Interleukins
Male
Rats
Rats, Inbred BB
Rats, Inbred BN
Signal Transduction
Transcription, Genetic