PATHOGENESIS OF DIABETIC MICROVASCULAR COMPLICATIONS

两个因素构成了这个项目的主要基础。首先，越来越清楚的是，目前我们不能仅仅依靠改善血糖控制来预防糖尿病的微血管并发症，一方面是因为我们无法维持良好的血糖控制来预防两种糖尿病的微血管并发症，另一方面是因为我们无法在许多患者中维持良好的血糖控制，另一方面是因为有证据表明，尽管血糖控制良好，一些患者仍会出现视网膜病变和其他并发症。氧化应激是高血糖的常见后遗症，我们和其他人正在研究氧化应激可能在组织病理学发展中起作用的证据。本研究将四个项目和四个核心组合在一起，以协调的方式研究高血糖导致细胞外和细胞内氧化应激，从而导致视网膜和肾脏功能和结构改变的假设。这一中心假设提出了两种具有潜在临床意义的结果：(1)我们预测氧化应激的特定化学产物在最容易发生并发症的患者中会表现出更高的水平，因此可以独立于血糖控制措施来预测哪些患者会发生并发症，因此可以独立于血糖控制措施来预测哪些患者会发生并发症；(2)沿着这个代谢方案的几个步骤可能是发生并发症的治疗目标。(2)代谢方案中的几个步骤可能是并发症发生的治疗靶点，(2)代谢方案中的几个步骤可能是并发症发生被抑制的治疗靶点。项目1研究二羰基应激、晚期糖基化终产物（AGEs）和氧化应激之间的相互关系，以及二羰基与微血管并发症发生的关系。项目2研究了在细胞培养和糖尿病大鼠中发生的氧化应激与糖尿病人不同的假设，并使用一种新颖而强大的探针在患者和动物体内使用19F-NMR波谱来评估氧化应激。项目3假设暴露于AGEs和高血糖引起的小管氧化应激导致肾小球改变。项目4研究了氧化应激是糖尿病视网膜病变的主要原因的假设，通过刺激视网膜细胞凋亡来发挥这一作用。项目1、2和3还寻求确定氧化应激的特定化学产物，这些化学产物可以作为替代标记物，以确定哪些患者特别容易患上糖尿病并发症。

Two factors form the major basis for this program project. First, it is becoming clear that we cannot at present rely solely on improved glycemic control to prevent microvascular complications of diabetes, both because of our inability to maintain good glycemic control to prevent microvascular complications of both diabetes, both because of our inability to maintain good glycemic control in many patients, and because evidence indicates that some patients develop retinopathy and other complications despite good glycemic control, Second, oxidative stress is a commonly reported sequelae of hyperglycemia, and we and others der developing evidence that the oxidative stress might play a role in the development of histopathology. This proposal assembles four projects and four cores to investigate, in a coordinated manner, the hypothesis that hyperglycemia leads to extra- and intracellular oxidative stress, which subsequently causes altered function and structure in the retina and kidney. This central hypothesis suggests two outcomes that have potential clinical significance: (1) we predict that specific chemical products of oxidative stress will exhibit higher levels in patients most prone to develop complications, and thus will predict, independently of measures of glycemic control, which patients will develop complications, and thus will predict independently of measures of glycemic control, which patients will develop complications, and (2) several steps along this metabolic scheme might be therapeutic targets where the develop complications, and (2) several steps along this metabolic scheme might be therapeutic targets where the development of complications, and (2) several steps among this metabolic schemes might be therapeutic targets where the development of complications could be inhibited. Project 1 investigates the inter-relationship between dicarbonyl stress, advanced glycation endproducts (AGEs) and oxidative stress and the relation of dicarbonyls to the development of microvascular complications. Project 2 investigates the postulate that the oxidative stress which develops in cell culture and in diabetic rats differs from that which develops in diabetic humans, and tests the hypothesis using a novel and powerful probe to assess oxidative stress in vivo using 19F-NMR spectroscopy in patients and animals. Project 3 postulates that tubular oxidative stress caused by exposure to AGEs and hyperglycemia leads to glomerular changes. Project 4 investigates the hypothesis that oxidative stress is a major cause of diabetic retinopathy, exerting this effect via stimulation of apoptosis of retinal cells. Projects 1,2 and 3 additionally seek to identify specific chemical products of oxidative stress which can act as surrogate markers to identify which patients are particularly susceptible to develop complications of diabetes.