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The antioxidants NAC and taurine does not decrease superoxide suggesting other ROS also play important role in lipotoxicity. These other reactive oxygen species can be detected by H2DCF-DA. The ability of reactive oxygen species to activate transcription factor NF-kB and the inflammatory pathway are well established. The next logical step would be to investigate whether FFA also induce activation of NF-kB by generating ROS.
 
The transcription factor NF-kB is activated downstream of ROS generated by elevated FFA. NF-kB is responsible for the transcription of various cytokines and chemokines that mediates inflammatory response. However, its close association with ROS would suggest that NF-kB also plays a role in lipotoxicity. Nuclear localization of NF-kB is dependent upon activation by IKKβ. Yuan and colleagues were able to demonstrate that by using salicylate (a weak inhibitor of IKKβ), diet induced hyperglycemia and dyslipidemia could be reversed. The paper demonstrated that by inhibiting the IKK/NF-kB pathway insulin resistance could be reversed. Studies have also shown the ability of salicylate to prevent hepatic and peripheral insulin resistance in rat models. Liptoxicity is a combination of insulin resistance and dysfunction in insulin secretion. A decrease in insulin sensitivity should be compensated by an increase in insulin secretion, but this is not seen in models of lipotoxicity. Hence it is also possible that the NF-kB pathway is involved in insulin resistance and decreased insulin secretion at the β-cell level. The aim of the study presented here is to determine whether FFA induced oxidative stress also activate NF-kB within islets to cause defect in insulin sensitivity and insulin secretion. An in vivo, ex-vivo, and in vitro models are presented here. The IKKβ inhibitor salicylate will be used to investigate the possibility of NF-kB activation within this pathway. This study will help to further elucidate mechanisms of liptoxicity and present possible therapeutic options.
 
Design and Methods:
 
Surgery: Female Wistar rats were cannulated 2-3 days prior infusion. During surgery rats were anesthetized with isofluorane. Catheters were injected into right jugular vein for infusion and left carotid artery for sampling. All procedures are approved by the University of Toronto Animal Care facility.
 
Intravenous Infusion: Rats were infused for 48 hours with 1)saline; 2)oleate; 3)olive oil; 4)oleate and salicylate; 5)olive oil and salicylate; 6)salicylate, followed by a two step hyperglycemic clamp. Same infusion protocol was followed for ex-vivo study. Olive oil was prepared from a triglyceride mixture containing 20% olive oil infused at 5µl/min and heparin at 50u/ml. Olive oil with salicylate was infused at a rate of 5µl/min. Oleate was infused at 5µl/min. Oleate with salicylate was infused at 5µl/min. Salicylate was infused at 10µl/min and saline was used as control with an infusion rate of 5µl/min.
 
Hyperglycemic clamps: A two-step hyperglycemic clamp (13mmol/l and 22mmol/l) was used to determine plasma insulin and c-peptide content. An infusion of 37.5% glucose was started at time zero minute. Plasma glucose was maintained at 13mmol/l by adjusting the rate of glucose infusion every 10 minutes. After two hours the plasma glucose level was raised to 22mmol/l and maintained until 本论文由英语论文网提供整理，提供论文代写，英语论文代写，代写论文，代写英语论文，代写留学生论文，代写英文论文，留学生论文代写相关核心关键词搜索。