Novel Paradigms in Diabetic Complications

描述(申请人提供)：糖尿病肾病被认为是1型糖尿病患者死亡率过高的主要原因。流行的理论是，过量的卡路里是通过线粒体处理的，导致超氧阴离子通过电子转移链积累。然而，我们从活体动物成像中产生的令人兴奋的数据证明了一套完全相反的结论。事实上，在容易发生糖尿病并发症的组织中，由于高热量状态，超氧阴离子自由基显著减少。为了确定线粒体功能降低是否也发生在人类身上，我们评估了尿代谢组，发现糖尿病和肾脏疾病患者与线粒体功能相关的代谢物减少。在目前的提案中，我们将使用来自FinnDiane研究和CRIC研究的两个具有良好特征的大型患者队列来证明这些尿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线粒体功能降低的基础。利用系统生物学和成像方法，我们将把线粒体功能的降低与肾脏和尿液中代谢组和表观基因组的变化联系起来。这一应用将是应对高血糖引起的肾脏疾病这一医学挑战的一种范式转换方法。 公共卫生相关性：糖尿病的肾脏并发症可能是工业化国家面临的头号公共卫生问题。通过对1型糖尿病合并肾脏疾病患者尿液代谢组和表观基因组的鉴定，以期对1型糖尿病肾脏并发症的基础有更好的认识。

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.