MITOCHODRIAL DYSFUNCTION IN OBESITY AND DIABETES IN BLOOD

在美国，肥胖是一个公认的公共健康问题，超重的程度是 在土著夏威夷人(NHS)和太平洋人(PPS)等种族/少数民族人口中比例更高。 在夏威夷，2003年报告的超重或肥胖的总体百分比为50%。与之同时 超重和肥胖在美国的流行，是与肥胖相关的疾病的惊人比率，如 糖尿病。NHS和菲律宾(PPS)人群的糖尿病患病率约为8.0%。 最近的证据表明，个体的器官特异性线粒体(Mt)能量变化 被诊断为II型糖尿病和/或肥胖。老年人和父母子女的胰岛素抵抗 II型糖尿病与骨骼肌中三磷酸腺苷的产生减少有关。类似 与非肥胖者相比，肥胖者的肝脏中的ATP水平有所下降。 此外，与肥胖或糖尿病患者相比，肥胖者或糖尿病患者的肌膜下肌肉mt降低。 瘦身的受试者。这与线粒体DNA和氧化磷酸化酶活性的下降相一致。 此外，健康人外周血单个核细胞(Pbmcs)中mtdna的缺失也已被注意到。 胰岛素抵抗的年轻人。此外，II型糖尿病和/或肥胖与 外周血单核细胞和血浆中线粒体氧化应激增加。目前，还没有微创的方法来治疗 研究线粒体功能障碍与糖尿病和/或肥胖的关系。 我们推测，糖尿病和/或肥胖症的线粒体表型可能在 个人。我们还假设在胰岛素的外周血单核细胞中可能检测到糖尿病前期表型。 抵抗力强的个体。在纵向方法中，我们建议研究PBMCs的线粒体功能。 100名肥胖的NHS和PPS在基线水平上立即接受为期16周的减肥干预 干预(第16周)和1年后的随访。我们相信线粒体参数会 由于体重减轻而改善，与糖尿病前期表型的改善相对应。 我们打算在基线、4个月和16个月时评估PBMC线粒体DNA拷贝数/细胞、OXPHOS 利用一种新的免疫学方法检测蛋白质/酶活性和线粒体氧化损伤(8- 氧代脱氧鸟嘌呤)。表型特征将通过评估体重指数(BMI)和 代谢参数(空腹胰岛素、血糖和胆固醇)。 这项拟议的研究的意义在于肥胖和糖尿病是主要的公共健康 特别是在少数群体中的问题。了解导致肥胖的机制和 糖尿病可能为改善发病率和死亡率的干预和治疗提供线索。

Obesity is a well recognized public health problem in the U.S. and the magnitude of excess weight is greater among racial/ethnic minority populations such as Native Hawaiians (NHs) and Pacific Peoples (PPs). In Hawai'i, the overall percentage reported to be overweight or obese was 50% in 2003. Concurrent with the epidemic of overweight and obesity in the U.S., is the alarming rates of obesity-related diseases such as diabetes mellitus. NHs and Filipino (who are PPs) populations have diabetes at rates of ~8.0%. Recent evidence has shown organ specific mitochondrial (mt) energetic alterations in individuals diagnosed with Type II diabetes and/or obesity. Insulin resistance in the elderly and in children of parents with Type II diabetes has been associated with decreased ATP production in skeletal muscle. Similar decreases in ATP levels have been observed in the livers of obese individuals compared to non-obese. Additionally, subsarcolemmal muscle mt are decreased in either obese or diabetic individuals compared to lean subjects. This corresponds with decreases in mtDNA and oxidative phosphorylation enzyme activities. Furthermore, depletion of mtDNA has been noted in peripheral blood mononuclear cells (PBMCs) of healthy insulin resistant young adults. Additionally, Type II diabetes and/or obesity has been associated with increased mt oxidative stress in PBMCs and plasma. Currently, there is no minimally invasive method to study mt dysfunction in diabetes and/or obesity. We hypothesize that a mitochondrial phenotype of diabetes and/or obesity may be studied in PBMCs of individuals. We also hypothesize that a pre-diabetic phenotype may be detectable in PBMCs of insulin resistant individuals. In a longitudinal approach, we propose to study mitochondrial function in PBMCs in 100 obese NHs and PPs undergoing a 16-week weight loss intervention at baseline, immediately following the intervention (week 16) and after 1-year of follow-up. We believe that mitochondrial parameters will improve as a result of weight-loss and correspond to an improvement in the pre-diabetic phenotype. We intend to evaluate at baseline, 4 months, and 16 months PBMC mtDNA copies/cell, OXPHOS protein/enzyme activity using a novel immunological assay, and mitochondrial oxidative damage (8- oxodeoxyguanine). Phenotype characteristics will be obtained by evaluating body mass index (BMI) and metabolic parameters (fasting insulin, glucose, and cholesterol). The significance of the proposed study lies in the fact that obesity and diabetes are major public health issues particularly in minority populations. Understanding the mechanisms contributing to obesity and diabetes may provide clues to intervention and treatment to improve morbidity and mortality.