The Role of TNF-\(\alpha\) in Mice with Type 1- and 2- Diabetes

Background: Previously, we have demonstrated that short-term treatment of new onset diabetic Non-obese diabetic (NOD) mice, mice that are afflicted with both type 1 (T1D) and type 2 (T2D) diabetes with either Power Mix (PM) regimen or alpha1 antitrypsin (AAT) permanently restores euglycemia, immune tolerance to self-islets and normal insulin signaling. Methodology and Principal Findings: To search for relevant therapeutic targets, we have applied genome wide transcriptional profiling and systems biology oriented bioinformatics analysis to examine the impact of the PM and AAT regimens upon pancreatic lymph node (PLN) and fat, a crucial tissue for insulin dependent glucose disposal, in new onset diabetic non-obese diabetic (NOD) mice. Systems biology analysis identified tumor necrosis factor alpha (TNF-a) as the top focus gene hub, as determined by the highest degree of connectivity, in both tissues. In PLNs and fat, TNF-a interacted with 53% and 32% of genes, respectively, associated with reversal of diabetes by previous treatments and was thereby selected as a therapeutic target. Short-term anti-TNF-a treatment ablated a T cell-rich islet-invasive and beta cell-destructive process, thereby enhancing beta cell viability. Indeed anti-TNF-a treatment induces immune tolerance selective to syngeneic beta cells. In addition to these curative effects on T1D anti-TNF-a treatment restored in vivo insulin signaling resulting in restoration of insulin sensitivity. Conclusions: In short, our molecular analysis suggested that PM and AAT both may act in part by quenching a detrimental TNF-a dependent effect in both fat and PLNs. Indeed, short-term anti-TNF-a mAb treatment restored enduring euglycemia, self-tolerance, and normal insulin signaling. Citation: Koulmanda M, Bhasin M, Awdeh Z, Qipo A, Fan Z, et al. (2012) The Role of TNF-a in Mice with Type 1and 2Diabetes. PLoS ONE 7(5): e33254. doi:10.1371/journal.pone.0033254 Editor: Matthias G. von Herrath, La Jolla Institute for Allergy and Immunology, United States of America Received November 23, 2011; Accepted February 6, 2012; Published May 11, 2012 Copyright: 2012 Koulmanda et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded both by the Juvenile Diabetes Research Foundation and National Institutes of Health (NIH). Juvenile Diabetes Research Foundation: TS, MK, ZF: JDRF 402004-368 NIH: MK, BH, AQ: NIH RO1 AI54976; MK, TS: NIH RO1 DK067632: TS, PP: NIH PO1 AI041521; JSF, HS: NIH NIH R37 DK 28082: SBW: NIH DK44523 and DK 66056. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Some of the authors are employed by non-commercial shared resource center of the institute (BIDMC Genomics and Proteomics Center). This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: [email protected] (MK); [email protected] (TS)