Novel Paradigms in Diabetic Complications

描述（由申请人提供）：糖尿病肾病被认为是导致1型糖尿病患者超额死亡的主要原因。流行的理论是，过量的卡路里通过线粒体处理，导致超氧化物自由基通过电子传递链积累。然而，我们从活体动物成像中获得的令人兴奋的数据显示了完全相反的结论。实际上，在易患糖尿病并发症的组织中，高热量状态会导致超氧自由基的急剧减少。为了确定线粒体功能降低是否也发生在人类中，我们评估了尿液代谢组，发现糖尿病和肾病患者与线粒体功能相关的代谢物减少。在目前的提案中，我们将使用FinnDiane研究和CRIC研究中两个特征良好的大型患者队列来证明这些尿液代谢物在确定未来肾脏疾病中的作用。我们还将确定PGC1a启动子的表观遗传修饰是否可能是患者和动物模型中线粒体功能降低的基础。使用系统生物学和成像方法，我们将线粒体功能的减少与肾脏和尿液中代谢组和表观基因组的改变联系起来。这一应用将为高血糖引起的肾脏疾病的医学挑战提供一种范式转换方法。

DESCRIPTION (provided by applicant): Diabetic kidney disease is recognized as the leading cause of excess mortality in the population with type 1 diabetes. The prevailing theory is that excess calories are processed via the mitochondria resulting in accumulation of superoxide radicals via the electron transfer chain. However, our exciting data generated from live animal imaging demonstrates a completely opposite set of conclusions. There is actually a dramatic reduction of superoxide radicals in response to a high caloric state in tissues prone to diabetic complications. To determine if reduced mitochondrial function also occurs in humans, we evaluated the urine metabolome and found that patients with diabetes and kidney disease had reduced metabolites related to mitochondrial function. In the present proposal we will use two large well characterized cohorts of patients from the FinnDiane Study and the CRIC study to demonstrate the role of these urine metabolites in determining future renal disease. We will also identify if epigenetic modification of the PGC1a promoter may underlie the reduction in mitochondrial function in patients and in animal models. Using a systems biology and imaging approach we will link the reduction in mitochondrial function with alterations in the metabolome and epigenome in the kidney and the urine. This application will be a paradigm shifting approach to the medical challenge of hyperglycemia induced kidney disease. PUBLIC HEALTH RELEVANCE: The renal complications of diabetes are perhaps the number one public health problem facing industrialized nations. By identifying the urine metabolome and epigenome in patients with type 1 diabetes and kidney disease we hope to gain a better understanding of the basis of kidney complications of type 1 diabetes.