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Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat

Kaldunski, Mary L.; Jia, Shuang; Geoffrey, Rhonda; Basken, Joel; Prosser, Simon; Kansra, Sanjay; Mordes, John P.; Lernmark, Åke LU ; Wang, Xujing and Hessner, Martin J (2010) In Diabetes 59(10). p.2375-2385
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... (More)

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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author
publishing date
type
Contribution to journal
publication status
published
in
Diabetes
volume
59
issue
10
pages
11 pages
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:77957549892
ISSN
0012-1797
DOI
10.2337/db10-0372
language
English
LU publication?
no
id
e354f835-eede-4569-9071-97a656f07f2c
date added to LUP
2017-09-07 11:54:57
date last changed
2018-05-29 11:42:53
@article{e354f835-eede-4569-9071-97a656f07f2c,
  abstract     = {<p>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 &lt; 10<sup>-6</sup>), 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.</p>},
  author       = {Kaldunski, Mary L. and Jia, Shuang and Geoffrey, Rhonda and Basken, Joel and Prosser, Simon and Kansra, Sanjay and Mordes, John P. and Lernmark, Åke and Wang, Xujing and Hessner, Martin J},
  issn         = {0012-1797},
  language     = {eng},
  number       = {10},
  pages        = {2375--2385},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat},
  url          = {http://dx.doi.org/10.2337/db10-0372},
  volume       = {59},
  year         = {2010},
}