GLYCATION OF PROTEIN IN DIABETES

糖尿病慢性高血糖的化学后果之一是 糖化(非酶糖化)增加身体负担 蛋白质。糖基化被认为是一系列复杂的 葡萄糖和蛋白质之间的美拉德反应或褐变反应，导致 在体外，对蛋白质的变性、交联性和不溶性。 据推测，这些相同的反应也可能在体内发生， 蛋白质结构的变化可能会加速发育 糖尿病和正常衰老过程中组织的病理变化。事实上， 老年人眼、肾和血管慢性并发症的研究进展 糖尿病与增加的交联度和不溶化有关 晶状体、基底膜和结缔组织蛋白。伴随而来的 糖基化、褐变和荧光的增加这些长寿 胞外蛋白提示可能参与了美拉德反应。 在这些过程中。 这项研究计划的主要目标是继续研究 蛋白质的糖基化及其在褐变反应中的作用 糖尿病和衰老的病理生理学中的蛋白质。具体目标 包括：(1)形成的美拉德产物的结构表征 模型氨基酸-葡萄糖褐变体系；(2)影响褐变因素的研究 指导蛋白质糖基化的体外和体内特异性； (3)荧光物质的结构和形成机理的研究 模型美拉德反应中产生的交联物 蛋白质的体外研究；以及(4)方法的开发和应用 体内美拉德反应产物及其分解代谢产物的测定。 我们希望更好地了解梅拉德在多大程度上 在正常和病理条件下，体内会发生反应 增加我们对它们在糖尿病并发症中的作用的了解。 这些知识应该为设计和评估提供更好的基础 管理糖尿病的治疗方法。

One of the chemical consequences of chronic hyperglycemia in diabetes is an increased body burden of glycated (nonenzymatically glycosylated) proteins. Glycation is recognized as the first step in a complex series of Maillard or browning reactions between glucose and protein which lead, in vitro, to the denaturation, crosslinking and insolubilization of protein. It is hypothesized that these same reactions may also occur in vivo, and that the alterations in protein structure may precipitate the development of pathology in tissues in diabetes and during normal aging. Indeed, the development of chronic complications in the eye, kidney and vasculature in diabetes is associated with increased crosslinking ahd insolubilization of lens, basement membrane and connective tissue proteins. Concomitant increases in glycation, browning and fluorescence of these long-lived extracellular proteins suggest that the Maillard reaction may be involved in these processes. The major objective of this research proposal is to continue studies on the glycation of protein and the role of the browning reaction of glycated proteins in the pathophysiology of diabetes and aging. Specific aims include: (1) structural characterization of Maillard products formed in model amino acid-glucose browning systems; (2) studies of factors which direct the specificity of glycation of protein in vitro and in vivo; (3)\studies on the structure and mechanism of formation of fluorescent and crosslinking compounds generated during Maillard reactions of model proteins in vitro; and (4) development and application of methods for measurement of Maillard reaction products and their catabolites in vivo. We expect that a better understanding of the extent to which Maillard reactions occur in vivo under normal and pathological conditions will increase our understanding of their role in the complications of diabetes. This knowledge should provide a better basis for the design and evaluation of therapeutic approaches to the management of diabetes.