GLYCATION OF PROTEIN IN DIABETES

糖尿病高血糖的一个后果是增加非酶 糖基化的蛋白质在整个身体。糖基化被认为是 这是一系列复杂的美拉德反应的第一步， 蛋白质的布朗宁、交联、变性和不溶 还原糖 这些反应有助于结构和功能 随着年龄的增长自然发生的蛋白质变化。的加快 糖尿病高血糖时的美拉德反应和 蛋白质中的晚期糖基化终产物，特别是在长寿命的 透镜晶体蛋白和基底膜及结缔组织胶原蛋白， 被认为有助于长期并发症的发展， 糖尿病，如失明、肾衰竭和血管疾病。 我们 最近的研究表明，糖化和氧化反应都是 参与蛋白质的不可逆修饰和交联， 葡萄糖，产生称为糖氧化产物的产物。 的 建议研究的重点是之间的关系 糖氧化、交联和糖尿病并发症。主要 目的包括：（1）确定的结构和机制， 糖-氨基中主要美拉德反应产物的形成 酸和糖蛋白质模型系统;（2）表征的路线， 在生理条件下糖的氧化降解， 糖降解反应主要产物的鉴定 蛋白质产品;（3）分离新技术的应用 美拉德反应产物的鉴定和分析 组织蛋白中的浓度，包括使用免疫亲和性和 免疫测定技术，液相色谱法和毛细管 电泳-质谱（4）产物表征 在氨基胍抑制美拉德反应过程中形成， 鉴定和比较氨基胍捕获的活性中间体 体外和体内;（5）评估变化的影响 对照组和糖尿病大鼠的氧化应激状态对 组织蛋白中糖基氧化产物的形成及其发展 糖尿病肾病的研究;（6）糖尿病肾病患者脂质糖化的研究。 血浆脂蛋白和细胞膜。更好地了解 美拉德反应的机理和产物，以及 糖对蛋白质的化学修饰中的氧化应激， 将有可能评估这种反应在发展中的作用， 糖尿病的病理生理学，然后开发更好的治疗方法 治疗糖尿病的方法。

One consequence of high blood sugar in diabetes is increased non-enzymatic glycation of proteins throughout the body. Glycation is recognized as the first step in a complex series of Maillard reactions, which lead to the browning, crosslinking, denaturation and insolubilization of proteins by reducing sugars. These reactions contribute to structural and functional changes in proteins which occur naturally with age. The acceleration of Maillard reactions during hyperglycemia in diabetes and accumulation of advanced glycation end products in proteins, particularly in long-lived lens crystallins and basement membrane and connective tissue collagens, is thought to contribute to the development of long-term complications of diabetes, such as blindness, renal failure and vascular disease. Our recent work indicates that both glycation and oxidation reactions are involved in the irreversible modification and crosslinking of proteins by glucose, yielding products which have termed glycoxidation products. The focus of the proposed research is on the relationship between glycoxidation, crosslinking and complications in diabetes. Major objectives include: (1) determination of the structure and mechanism of formation of the predominant Maillard reaction products in sugar-amino acid and sugar-protein model systems; (2) characterization of routes of oxidative degradation of sugars under physiological conditions and identification of major products formed on reaction of sugar degradation products with protein; (3) application of novel techniques for isolation and identification of Maillard reaction products and assaying their concentrations in tissue proteins, including the use of immunoaffinity and immunoassay techniques, liquid chromatography - and capillary electrophoresis - mass spectrometry (4) characterization of products formed during inhibition of the Maillard by aminoguanidine, in order to identify and compare the reactive intermediates trapped by aminoguanidine in vitro and in vivo; (5) assessment of the effects of changes in the status of oxidative stress in control and diabetic rats on the rates of formation of glycoxidation products in tissue proteins and the development of diabetic nephropathy; and (6) studies on the glycation of lipids in plasma lipoproteins and cell membranes. With a better understanding of mechanisms and products of the Maillard reaction, and the role of oxidative stress in the chemical modification of proteins by sugars, it will be possible to assess the role of this reaction in the development of pathophysiology in diabetes and then to develop better therapeutic approaches for the treatment of diabetes.