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Abstract:
 
An important mechanism of pathogenesis of type 2 diabetes in obese individual is the elevation of free plasma fatty acids (FFA) and generation of reactive oxygen species (ROS). The objective of the current study is to determine whether the IKK/NF-kB inflammatory pathway also plays a role in liptoxicity. The IKK inhibitor salicylate was used in this study. Study was conducted in vivo using hyperglycemic clamp, ex-vivo with isolated islets, and in vitro.
 
Female Wistar Rats were infused with either a)oleate, b)olive oil+heparin, c)oleate+salicylate, d)olive oil + salicylate, e)salicylate, or f)saline for 48hrs. A two-step hyperglycemic clamp was followed or the islets were isolated. Islets were assayed for insulin and c-peptide.
 
Oleate and olive oil reduce GINF during the two-step hyperglycemic clamp. Oleate impaired insulin secretion when c-peptide was measured. This was prevented by the co-infusion of salicylate. Olive oil decreased insulin sensitivity when the sensitivity index was calculated. The effect of olive oil on insulin sensitivity is prevented by the co-infusion of salicylate. Ex-vivo and in vitro data showed similar result. The data here presented demonstrates the role of IKK/NF-kB in FFA induced liptoxicity and its prevention by salicylate.
 
Introduction:
 
Diabetes mellitus 2 is characterized by a combination of glucotoxicity and lipotoxicity. Evidences supporting glucotoxicity mediated decrease in β-cell function are well documented. However the mechanisms of free fatty acid (FFA) induced liptoxicity is not fully elucidated. FFA is needed acutely for glucose induced insulin secretion (GSIS). However, when chronically exposed to high levels of FFA, β-cell function decreases due to increased insulin resistance or impaired insulin secretion. In vitro results have shown that increased levels of FFA impair GSIS, in vivo results are more controversial with different groups presenting conflict results. Despite this mounting evidence suggest increased levels of FFA in obesity leads to insulin resistance. In vivo a decrease in insulin resistance should be accompanied by a corresponding increase in insulin secretion; this is not seen in individuals pre-disposed to type-2 diabetes, suggesting that other pathway may also be involved. One theory proposes that the release of adipose tissue mass is responsible for intracellular alternations that reduce insulin signaling. Adipose tissues are known to release cytokines such as TNF-α, which causes insulin resistance by serine phosphorylation of the insulin receptor and its substrate (IRS-1). Recently it has been shown that another pathway that elevated FFA may cause β-cell dysfunction is through the generation of reactive oxygen species (ROS).
 
Previous studies have demonstrated that islets cells are especially susceptible to oxidative stress due to inherent low anti-oxidant defense. Proposed pathways of liptoxicity such as activation of JNK, PKC, or IKK/NF-kB pathway are often either upstream or downstream of oxidative stress. Studies conducted in this lab have demonstrated that antioxidants such as taurine, N-Acetylcysteine (NAC), and TEMPOL are able to prevent β-cell dysfunction in rats with elevated FFA levels. Cytosolic superoxide is found to be increased in oleate infused rat while mitochondrial superoxide was not increased.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。