PATHOGENESIS OF DIABETIC MICROVASCULAR COMPLICATIONS

两个因素构成了这个方案项目的主要基础。首先，越来越明显的是，目前我们不能仅仅依靠改善的血糖控制来预防糖尿病的微血管并发症，这既是因为我们无法保持良好的血糖控制，以预防糖尿病的微血管并发症，这既是因为我们无法在许多患者中保持良好的血糖控制，也是因为有证据表明，尽管血糖控制良好，一些患者仍会发展成视网膜病变和其他并发症；其次，氧化应激是高血糖的一种常见后遗症，我们和其他人正在寻找证据表明氧化应激可能在组织病理学的发展中发挥作用。这项提案汇集了四个项目和四个核心，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说。这一中心假设提出了两个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将在最容易发生并发症的患者中表现出更高的水平，因此将独立于血糖控制措施来预测哪些患者将发生并发症，从而将独立于血糖控制措施来预测哪些患者将发生并发症，以及(2)沿着该代谢方案的几个步骤可能是发生并发症的治疗目标，以及(2)沿着该代谢方案的几个步骤可能是发生并发症的治疗目标，这些代谢方案中的几个步骤可能成为抑制并发症发展的治疗靶点。项目1研究二羰基应激、晚期糖基化终末产物(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的发展的关系。项目2研究了在细胞培养和糖尿病大鼠体内形成的氧化应激不同于在糖尿病人类中形成的氧化应激的假设，并使用一种新的强大的探针来测试这一假设，以使用19F-核磁共振波谱在患者和动物身上评估体内的氧化应激。项目3假定，暴露于AGEs和高血糖引起的肾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的凋亡来发挥这一作用。项目1、2和3还寻求确定特定的氧化应激化学产物，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.