Tiam1-Rac1 Signaling Pathway Contributes to the Spontaneous Development of Diabetes in NOD Mice
Presentation Number: LBSat-44
Date of Presentation: April 2nd, 2016
Rajakrishnan Veluthakal, Vaibhav Sidarala* and Anjan Kowluru
Wayne State University, Detroit, MI
Type 1 diabetes (T1D) is characterized by absolute insulin deficiency due to destruction of pancreatic β-cells by the invading T cells and macrophages and secretion of pro-inflammatory cytokines (e.g., IL-1β). The mechanism by which these cytokines induce β-cell dysfunction is still unclear. Recent evidence suggests that excessive generation of reactive oxygen species (ROS) along with significantly low levels of antioxidant capacity of β-cells, drive them toward oxidative damage. One of the sources of ROS in pancreatic β-cell is phagocyte-like NADPH oxidase2 (Nox2). Several components of this enzyme system including Rac1, a small GTP-binding protein, are localized in different cellular compartments of the cell (cytosol and membrane). Upon appropriate stimuli the cytosolic components translocate and assemble in the membrane to form an active holoenzyme and become catalytically active. Recent evidence from our laboratory in in vitro studies has demonstrated that inhibition of Rac1 function mediated by guanine nucleotide exchange factors (GEFs) and/ or post-translational prenylation significantly attenuated cytokine-induced Nox2 activation and ROS generation. To study the role of Rac1-Nox2 signaling pathway in the development of diabetes in an in vivo model, we tested the effects of NSC23766, a known inhibitor of Rac1-Nox2 cascade, on spontaneous development of diabetes in non-obese diabetic mice (NOD), a model for T1D. These mice were divided into two groups with one group treated with NSC23766 (2.5mg/kg/day, i.p) and other group served as untreated NOD controls receiving equal volume of saline. These animals were compared to Balb/c treated without and with NSC23766. The Balb/c and NOD mice were administered NSC23766 daily starting at 8 weeks of age till 32nd week with weekly blood glucose and body weight measurements. The data indicate that administration of NSC23766 significantly prevented the development of overt diabetes in this model. We could demonstrate that NOD control mice developed diabetes around 26 weeks and those treated with NSC23766 were normoglycemic till 32nd week. Furthermore, Rac1 expression and activation and expression of CHOP, an ER stress marker, were significantly lower in NSC23766-treated NOD mice compared to their untreated counterparts. Our findings provide the first in vivo evidence that Tiam1-Rac1-Nox2 axis could be a potential target for therapeutic intervention for the prevention of oxidative damage and development of T1D.
Nothing to Disclose: RV, VS, AK