Mitochondrial Genetics, Diabetes and Metabolic Syndrome

尽管进行了广泛的生理调查，但2型糖尿病的主要原因仍不清楚。 此外，包括高血压、胰岛素抵抗和血脂异常在内的代谢综合征越来越被认为是一个原因不明的重大公共卫生问题。遗传学和基因组学方法有能力确定这些难以捉摸的主要原因，从而确定这些疾病的病理生理学，并确定新的治疗干预机会。最近的研究表明线粒体功能丧失是导致2型糖尿病的一个因素。在这个项目中，魏将对这一点进行几条不同的调查路线。首先，我们将调查线粒体功能受损不仅可能导致糖尿病，还可能导致代谢综合征的其他组成部分。这将通过对已知功能性线粒体突变的罕见家系的调查以及对线粒体缺陷的代谢综合征患者的调查来实现。其次，我们将研究糖尿病患者年轻后代的基因表达，以确定早期胰岛素抵抗是否与线粒体氧化磷酸化和线粒体拷贝数相关基因的表达改变有关。第三，因为线粒体是 活性氧的主要来源之一胰岛素抵抗时线粒体功能丧失的一个可能的解释是线粒体DNA获得性损伤。我们将通过比较糖尿病父母对胰岛素敏感和抵抗的后代的线粒体损伤来研究这种可能性。最后，通过MRS获得体内线粒体功能的生化表型的能力提供了一个新的机会来定义中间表型，这些中间表型可能与疾病的主要缺陷密切相关。这些都可以显著增加遗传连锁研究的力量。我们将确定项目1中分离极端生化表型的亲缘关系，扩展这些亲缘关系并绘制责任图 通过连锁分析，目的是定位克隆这些新的易感基因。

Despite extensive physiologic investigation, the primary causes of type 2 diabetes mellitus remain unknown. In addition, the metabolic syndrome comprising hypertension, insulin resistance and dyslipidemia has increasingly been recognized as a major public health problem of unknown cause. Genetic and genomic approaches have the capacity to identify these elusive primary causes, thereby defining the pathophysiology of these diseases and identifying new opportunities for therapeutic intervention. Recent studies have implicated loss of mitochondrial function as a factor underlying type 2 diabetes mellitus. In this project, wei will pursue several distinct lines of investigation that bear on this point. First, we will investigate the possibility that impaired mitochondrial function can contribute not only to diabetes but to the other component of the metabolic syndrome. This will be accomplished by the investigation of rare families with known functional mitochondrial mutations, and by the investigation of patients with metabolic syndrome for mitochondrial defects. Second, we will investigate gene expression in the young offspring of diabetics to determine whether early insulin resistance is correlated with altered expression of genes involved in mitochondrial oxidative phosphorylation and mitochondrial copy number. Third, because mitochondria are one of the major sources of reactive oxygen species one possible explanation for loss of mitochondrial function in insulin resistance is acquire damage of mitochondrial DNA. We will investigate this possibility by comparing mitochondrial damage in insulin sensitive and resistant offspring of diabetic parents. Finally, the ability to obtain in vivo biochemical phenotypes of mitochondrial function by MRS provides a new opportunity to define intermediate phenotypes that may be closely related to the primary defect underlying the disease. These can markedly increase the power of genetic linkage studies. We will ascertain kindreds from Project 1 that are segregating extreme biochemical phenotypes, extend these kindreds and map the responsible lenes by analysis of linkage, with an aim to positionally clone these novel susceptibility genes.