title: NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model.
abstract: OBJECTIVE
  Type 1 diabetes (T1D) is characterized by absolute insulin deficiency due to destruction of pancreatic β-cells by cytokines (e.g., interleukin-1β; IL-1β) released by invading immune cells. The mechanisms by which these cytokines induce β-cell dysfunction remain poorly understood. Recent evidence suggests that excessive generation of reactive oxygen species (ROS) by the phagocyte-like NADPH oxidase2 (Nox2), along with significantly low levels of antioxidants in β-cells, drive them toward oxidative damage. Rac1, a small G-protein, is one of the members of Nox2 holoenzyme. We recently reported that NSC23766, a known inhibitor of Rac1, significantly attenuated cytokine-induced Nox2 activation and ROS generation in pancreatic islet β-cells in vitro. Herein, we determined the effects of NSC23766 (2.5 mg/kg/day, i.p/daily) on the development of diabetes in the NOD mouse, a model for T1D.
  
  
  METHODS
  Two groups of experimental animals (Balb/c and NOD mice) received NSC23766, while the two control groups received equal volume of saline. Body weights and blood glucose were measured every week for 34 weeks. Rac1 activation in pancreatic islets was measured by GLISA activation assay. Rac1 and CHOP expression was determined by Western Blotting.
  
  
  RESULTS
  Our findings indicate that administration of NSC23766 significantly prevented the development of spontaneous diabetes in the NOD mice. Furthermore, NSC23766 markedly suppressed Rac1 expression and activity and the endoplasmic reticulum stress (CHOP expression) in NOD islets.
  
  
  CONCLUSIONS
  Our findings provide the first evidence implicating the role of Tiam1-Rac1-Nox2 signaling pathway in the onset of spontaneous diabetes in the NOD mouse model.
authors.affiliation: Department of Molecular and Cellular Endocrinology, Diabetes and Metabolic Research Institute, City of Hope/BRI, Duarte, USA.
authors.forename: Rajakrishnan
authors.initials: R
authors.lastname: Veluthakal
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Sidarala
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Kowluru
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013045:Species Specificity; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D051742:Transcription Factor CHOP / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D001786:Blood Glucose; C497250:Ddit3 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D008562:Membrane Glycoproteins; C487513:NSC 23766; D009479:Neuropeptides; D011743:Pyrimidines; C484602:Rac1 protein, mouse; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; D051742:Transcription Factor CHOP; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein