Human Studies on Blood Levels of Glycated CD59 as a Biomarker in Diabetes

描述（由申请人提供）：本提案的目的是验证人血液中的糖化CD 59（GCD 59）作为识别糖尿病前期个体的筛选试验，以及糖尿病并发症的早期生物标志物，重点是糖尿病神经病变。这项提案是高度转化的，并解决了主要的公共卫生优先事项，因为1）糖尿病影响2500万美国人，2）糖尿病并发症是美国发病率和死亡率的主要原因，以及3）这些并发症的治疗花费惊人的2450亿美元/年（预计到2034年将上升到> 3000亿美元）。HbA 1c是糖尿病患者管理的临床金标准，不能识别出发生某些并发症的高风险个体，也不足以敏感地区分糖尿病前期个体。慢性高血糖症是人类糖尿病并发症的最终原因，但高血糖症引起组织损伤的细胞和分子机制仍然知之甚少。申请人已经1）发现人CD 59通过糖化而失活，2）提供了补体系统与糖尿病并发症的发病机制之间的联系的证据，以及3）开发了允许定量血液和组织中的GCD 59的关键试剂。具体而言，我们已经证明：1）GCD 59存在于糖尿病并发症的靶器官中; 2）GCD 59可以在正常血浆或血清中容易地测量。此外，我们的初步数据显示，GCD 59 a）在糖尿病或糖尿病前期个体以及妊娠期糖尿病孕妇的血液中显著增加，B）是通过标准2小时口服葡萄糖耐量试验确定的葡萄糖耐量的强且独立的预测因子，和c）似乎比HbA 1c更快地响应个体内血糖负荷的变化。在申请人和专家合作者的实验室中可以获得实现我们的目标的所有必要工具和专业知识，包括GCD 59特异性单克隆抗体和测定校准品，获得大量不同的糖尿病患者和非糖尿病患者，以及进行申请中提议的所有研究所需的诊断工具、设备和专业知识。我们的目标的成功实现将代表着在诊断、治疗和预防葡萄糖代谢异常和糖尿病的毁灭性并发症方面的重大进步，并应有助于降低糖尿病及其并发症带来的极高成本。

DESCRIPTION (provided by applicant): The goal of this proposal is to validate glycated CD59 in human blood (GCD59) as a screening test to identify individuals with pre-diabetes, and an early bio-marker of diabetes complications focusing on diabetic neuropathy. This proposal is highly translational and addresses major Public Health priorities because 1) diabetes affects H 25 million Americans, 2) diabetes complications are a major cause of morbidity and mortality in the U.S., and 3) treatment of these complications costs a staggering 245 billion dollars/year (expected to rise to >300 billion by 2034). HbA1c, the clinical gold standard for management of patients with diabetes, does not identify individuals at higher risk of developing some complications and is not sensitive enough to clearly discriminate individuals with pre-diabetes. Chronic hyperglycemia is ultimately responsible for the complications of human diabetes but the cellular and molecular mechanism(s) by which hyperglycemia causes tissue damage are still poorly understood. The applicants have 1) discovered that human CD59 is inactivated by glycation, 2) provided evidence for a link between the complement system and the pathogenesis of the complications of diabetes, and 3) developed key reagents that allow quantification of GCD59 in blood and tissues. Specifically, we have demonstrated that 1) GCD59 is present in target organs of diabetic complications, and 2) GCD59 can be readily measured in normal plasma or serum. Furthermore, our preliminary data show that GCD59 is a) significantly increased in the blood of individuals with diabetes or pre-diabetes as well as in pregnant women with gestational diabetes mellitus, b) is a strong and independent predictor of glucose tolerance determined by standard 2hr oral glucose tolerance test, and c) seems to respond faster than HbA1c to changes in glycemic load within an individual All necessary tools and expertise to accomplish our aims are available in the laboratory of the applicant and expert collaborators, including monoclonal antibodies specific for GCD59 and assay calibrators, access to large and diverse population of individuals with and without diabetes, and diagnostic tools, equipment and expertise necessary to conduct all studies proposed in the application. Successful accomplishment of our aims would represent a major advancement in diagnosis, treatment and prevention of the devastating complications of glucose dysmetabolism and diabetes, and should help lower the extremely high costs derived from diabetes and its complications.