Mitochondrial Diabetes & Manganic Porphyrin Treatment

自从我们最初证明线粒体DNA（mtDNA）突变可导致II型糖尿病以来， 越来越多的证据支持II型糖尿病是遗传性部分性糖尿病的产物这一假设。 线粒体氧化磷酸化（OXPHOS）缺乏， 卡路里和增加线粒体产生的活性氧（ROS）。氧化应激形成ROS 进一步侵蚀靶组织和胰腺P细胞中的线粒体功能，导致胰岛素抵抗、丧失 胰岛素分泌的影响;为了进一步阐明mtDNA突变在II型糖尿病中的作用，我们 我建议在一些母系遗传的糖尿病中鉴定导致糖尿病的遗传mtDNA突变 血统然后我们将使用cybrid转移技术将这些突变置于肝和胰腺细胞上 核背景，然后表征这些胞质杂种细胞系的生化缺陷， mtDNA突变然后用金属卟啉超氧化物歧化酶（SOD）处理这些相同的细胞系。 模拟物来确定与这些催化抗氧化剂可以减少和改善所造成的生化缺陷， mtDNA突变此外，我们将研究线粒体抗氧化防御（Sod 2）遗传缺陷的小鼠。 和OXPHOS ATP产生（Ant 1和Ant 2），以将糖尿病的发展与年龄相关的 线粒体功能和体细胞线粒体DNA突变的积累在胰岛素靶向和胰岛素分泌中的作用 组织中这些小鼠也将接受金属卟啉模拟物治疗，以确定这些药物是否会延迟 症状的发展和体细胞mtDNA突变的积累。

Since our initial demonstration that mitochondrial DNA (mtDNA) mutations can result in Type II diabetes, considerable evidence has accumulated supporting the hypothesis that Type II diabetes is the product of inherited partial mitochondrial oxidative phosphorylation (OXPHOS) deficiency which inhibitsthe mitochondrial metabolism of calories and increases mitochondrial production of reactive oxygen species (ROS). The oxidative stress form the ROS further erodes mitochondrial function in both target tissues and in pancreatic p cells, leading to insulin resistance, loss of insulin secretion, and (3 cells apoptosis. To further clarify the role of mtDNA mutations in Type II diabetes, we propose to identify the inherited mtDNA mutations causing diabetes in a number of maternally inherited diabetes pedigrees. We will then use the cybrid transfer technique to place these mutations onto hepatic and pancreatic cell nuclear backgrounds and then the characterize these cybrid cell lines for the biochemical defects assoiated with the mtDNA mutations. These same cell lines with then be treated with metallopophyrin superoxide dismutase (SOD) mimetics to determine with these catalytic antioxidants can reduce ameliorate the biochemical defect caused by the mtDNA mutation. In addition, we will study mice with inherited defects in mitochondrial antioxidant defenses (Sod2) and in OXPHOS ATP production (Antl & Ant2) to correlate the development of diabetes with the age-related decline in mitochondrial function and the accumulation of somatic mtDNA mutations in both insulin target and insulin secreting tissues. These mice will also be treated with the metalloporphyrinmimetics to determine if these drugs will then delay the development of the symptoms and the accumulation of the somatic mtDNA mutations.