Abstract 1124: Increased oxidative stress and mitochondrial dysfunction in Zucker diabetic fatty rat tissues

Abstract The Zucker diabetic fatty (ZDF) rat is a genetic model in which the homozygous (FA/FA) animals develop obesity and type 2 diabetes. Oxidative stress and increased expression of inflammatory signals and cytokines are the hallmarks of type 2 diabetes and cancer. Insulin signaling and IGF receptors are also affected in cancer progression. The precise molecular mechanism of disease progression or protection/prevention is, however, not clear. We, therefore, have investigated molecular and metabolic targets affected in the liver, kidney, brain and pancreas of ZDF (30 weeks old) male rats. Our results have demonstrated that GSH-dependent redox metabolism and mitochondrial respiratory function are affected in ZDF rats when compared to Zucker lean (ZL) control rats (n=6 each). With the exception of brain, cytosolic GSH content in the tissues of ZDF rats was significantly lower than ZL rats. GSH-reductase activity and GSH-conjugation by glutathione S-transferase were also lower in ZDF rat tissues. Although there was no significant increase in the apocynin sensitive- NADPH oxidase -dependent reactive oxygen species (ROS) production in the liver, DCFDA-probed ROS production and reactive nitrogen species (RNS) production were significantly higher in ZDF rat tissues. Higher levels of lipid and protein peroxidation were also observed in ZDF rat tissues. Western blot analysis also confirmed increased expression of iNOS and COX-2 suggesting an increase in oxidative stress and inflammatory markers in ZDF rat tissues. Our results have demonstrated that the increased oxidative stress in ZDF rats was accompanied by lower activities of mitochondrial respiratory complexes and decreased ATP synthesis. Taken together, our results show that ZDF rats are prone to develop complications associated with oxidative stress, inflammation and mitochondrial dysfunction as seen in the pathogenesis of cancer and diabetes. These results might have implications in designing strategies for cancer and diabetes prevention. (Supported by the Terry Fox Cancer Research Fund and a fund from FMHS Research Committee). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1124. doi:1538-7445.AM2012-1124