Identification of a Serum-Induced Transcriptional Signature Associated With Type 1 Diabetes in the BioBreeding Rat

Max 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 theHuman and Molecular Genetics Center, Milwaukee, Wisconsin, USA.
Diabetes (Impact Factor: 8.1). 10/2010; 59(10):2375-85. DOI: 10.2337/db10-0372
Source: PubMed


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.
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.
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.
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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Available from: Shuang Jia, Sep 30, 2015
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    • "Gene expression and genetic association studies support an emerging link between the innate immune response and susceptibility to human type 1 diabetes. An interferon regulatory factor 7-driven inflammatory network (IDIN) enriched for viral response genes has been identified in the BB rat [20], and genes from the analogous human IDIN have been shown to associate with susceptibility to type 1 diabetes [21]. In addition, a human genome-wide SNP scan identified the viral RNA receptor gene region IFIH1 (interferon induced with helicase C domain 1) as a type 1 diabetes susceptibility gene. "
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    PLoS ONE 10/2013; 8(10):e78050. DOI:10.1371/journal.pone.0078050 · 3.23 Impact Factor
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    • "Furthermore, there is a high incidence of comorbid or coincident diseases, including Type-2 diabetes and MDD (Katon, 2008), as well as strong associations between MDD and metabolic syndrome (Dunbar et al, 2008). Alterations of serum growth factors and cytokines have also been demonstrated in cardiovascular (Ejiri et al, 2005; Kaplan et al, 2005; von der Thusen et al, 2003), inflammatory (Katsanos et al, 2001; Lee et al, 2010; Lommatzsch et al, 2005a; Schulte- Herbruggen et al, 2005), and metabolic diseases (Dunger et al, 2003; Han et al, 2010; Kaldunski et al, 2010), all of which are more common in depressed patients than the general population (Shelton and Miller, 2010). However, patients with these conditions but without depression (ie, persons with cardiovascular disease or Type-2 diabetes) will have altered levels of the putative biomarkers described above. "
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