title: The role of TNF-α in mice with type 1- and 2- diabetes.
abstract: 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.
  
  
  RESULTS
  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-α) as the top focus gene hub, as determined by the highest degree of connectivity, in both tissues. In PLNs and fat, TNF-α 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-α treatment ablated a T cell-rich islet-invasive and beta cell-destructive process, thereby enhancing beta cell viability. Indeed anti-TNF-α treatment induces immune tolerance selective to syngeneic beta cells. In addition to these curative effects on T1D anti-TNF-α 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-α dependent effect in both fat and PLNs. Indeed, short-term anti-TNF-α mAb treatment restored enduring euglycemia, self-tolerance, and normal insulin signaling.
authors.affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America. mkoulman@bidmc.harvard.edu
authors.forename: Maria
authors.initials: M
authors.lastname: Koulmanda
authors.forename: Manoj
authors.initials: M
authors.lastname: Bhasin
authors.forename: Zuheir
authors.initials: Z
authors.lastname: Awdeh
authors.forename: Andi
authors.initials: A
authors.lastname: Qipo
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Fan
authors.forename: Dusan
authors.initials: D
authors.lastname: Hanidziar
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Putheti
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.forename: Eva
authors.initials: E
authors.lastname: Csizuadia
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D005260:Female; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D007108:Immune Tolerance; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology / Q000502:physiology; D016381:Islets of Langerhans Transplantation; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D049490:Systems Biology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin