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

描述（由申请人提供）：2型糖尿病是一种严重的代谢性疾病，在世界范围内已达到流行病的程度。与胰腺细胞相关的胰岛素分泌减少是该疾病发展的一个危险因素。这种危险因素发展的一个模型是线粒体功能障碍和活性氧（ROS）的产生增加。该模型的支持来自于鉴定了烟酰胺核苷酸转氢酶（NNT）基因功能缺陷与胰岛素分泌减少之间的遗传联系（Freeman 2006b）。NNT是一种产生NADPH的线粒体膜蛋白，它是还原谷胱甘肽所必需的，谷胱甘肽是ROS清除途径中重要的抗氧化剂。另一个将2型糖尿病与线粒体功能障碍联系起来的因素是细胞内脂质积累。高脂肪饮食的消耗是一个环境因素，与疾病的发病和线粒体损伤有关，通过生成活性氧。确切地说，高脂肪饮食或细胞内脂质积累如何导致线粒体功能障碍或线粒体蛋白如何参与这一过程尚不清楚。因此，饱和脂肪和不饱和脂肪饮食的影响以及线粒体蛋白NNT对线虫线粒体功能的作用将被研究。秀丽隐杆线虫是研究线粒体功能及其生理后果的既定模型。先前的研究表明，nnt-1突变体对氧化应激的敏感性增加，最近的初步数据表明，喂食高饱和脂肪饮食的动物会增加ROS的产生和运动缺陷。测量线粒体功能的全动物研究可以与动物一生中的生理功能一起进行，从而可以直接比较线粒体功能和生物体的整体健康状况。NNT突变和高脂肪饮食结合会通过增加ROS产生和脂质过氧化而加剧线粒体和生理功能障碍的假设将被验证。用线粒体靶向抗氧化剂治疗动物将减少不良反应的预测也将进行测试。这些研究将阐明ROS的起源，并表明是否有必要进一步研究线粒体靶向治疗2型糖尿病患者。

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.