High Fat Diet and Deficient Antioxidant Status as Contributing Factors to Mitocho

描述(申请人提供)：2型糖尿病是一种严重的代谢性疾病，已在世界范围内流行。与胰腺2细胞相关的胰岛素分泌减少是该病发生的危险因素。这种危险因素的一个发展模式是线粒体功能障碍和活性氧(ROS)的产生增加。这一模型的支持来自于烟酰胺核苷酸转氢酶(NNT)基因功能缺陷和胰岛素分泌减少之间的遗传联系(Freeman 2006b)。NNT是一种线粒体膜蛋白，能产生NADPH，这是还原谷胱甘肽所必需的，谷胱甘肽是ROS清除途径中的一种重要抗氧化剂。另一个将2型糖尿病与线粒体功能障碍联系在一起的因素是细胞内脂肪堆积。摄入高脂肪饮食是一个环境因素，与疾病的发病和通过产生ROS而造成的线粒体损伤有关。目前尚不清楚高脂饮食或细胞内脂肪堆积是如何导致线粒体功能障碍的，也不清楚线粒体蛋白是如何参与这一过程的。因此，将使用线虫线虫来研究饱和和不饱和脂肪饮食的影响以及线粒体蛋白NNT对线粒体功能的作用。线虫是检测线粒体功能及其生理后果的一个已建立的模型。先前的研究表明，nnt-1突变体增加了对氧化应激的敏感性，最近的初步数据表明，喂养高饱和脂肪饮食的动物增加了ROS的产生和运动缺陷。测量线粒体功能的整个动物研究可以结合动物一生中的生理功能进行，从而可以直接比较线粒体功能和有机体的整体健康。NNT突变和高脂饮食相结合将通过增加ROS产生和脂质过氧化来加剧线粒体和生理功能障碍的假设将得到验证。用线粒体靶向抗氧化剂治疗动物将减少不良影响的预测也将得到检验。这些研究将阐明ROS的来源，并表明是否有必要对2型糖尿病患者的线粒体靶向治疗进行进一步研究。 公共卫生相关性：2型糖尿病是一种严重的疾病，已在全球范围内流行。最近的证据表明，线粒体可能在疾病的发展中发挥关键作用，然而，线粒体功能障碍与生理后果尚未明确联系。这项拟议的工作将解决饮食脂肪和遗传易感性对线粒体和生理功能障碍的潜在影响。结果将阐明线粒体的作用，并表明是否有必要对2型糖尿病患者进行进一步的线粒体靶向治疗研究。

DESCRIPTION (provided by applicant): Type 2 diabetes is a serious metabolic disorder that has reached epidemic proportions worldwide. Decreased insulin secretion associated with the pancreatic 2 cells is a risk factor for the development of the disease. One model for the development of this risk factor is increased mitochondrial dysfunction and reactive oxygen species (ROS) generation. Support of this model comes from identification of a genetic link between defective nicotinamide nucleotide transhydrogenase (NNT) gene function and decreased insulin secretion (Freeman 2006b). NNT is a mitochondrial membrane protein that generates NADPH, which is required for the reduction of glutathione, an important antioxidant in ROS scavenger pathways. Another factor linking type 2 diabetes to mitochondrial dysfunction is intracellular lipid accumulation. Consumption of high- fat diets is an environmental factor that is associated with disease onset and with mitochondrial damage through the generation of ROS. Exactly how high-fat diets or intracellular lipid accumulation lead to mitochondrial dysfunction or how mitochondrial proteins contribute to this process is unclear. Thus, the effects of saturated and unsaturated fat diets and the role of the mitochondrial protein, NNT, on mitochondrial function will be investigated using the nematode, C. elegans. C. elegans is an established model for examining mitochondrial function and its physiological consequences. Previous studies have demonstrated that nnt-1 mutants have increased sensitivity to oxidative stress and recent preliminary data suggests that animals fed a high saturated fat diet have increased ROS production and movement deficits. Whole animal studies measuring mitochondrial function can be performed in conjunction with physiological function over the life span of the animal thus allowing a direct comparison between mitochondrial function and overall health of the organism. The hypothesis that NNT mutations and high-fat diet in combination will exacerbate mitochondrial and physiological dysfunction via increased ROS production and lipid peroxidation will be tested. The prediction that treating animals with mitochondrial-targeted antioxidants will diminish adverse effects will also be tested. These studies will clarify the origin of ROS and indicate whether or not further studies on mitochondrial-targeted therapeutic treatments of patients with type 2 diabetes are warranted. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a serious disease that has reached epidemic proportions worldwide. Recent evidence suggests that mitochondria may play a critical role in the development of the disease, however, mitochondrial dysfunction has not been clearly linked to physiological consequences. The proposed work will address the potential effects of dietary fat and genetic pre-disposition on mitochondrial and physiological dysfunction. Results will clarify the role of mitochondria and indicate whether or not further studies on mitochondrial-targeted therapeutic treatments of patients with type 2 diabetes are warranted.