Novel Pathways of AGE Formation in Diabetes

描述（由申请人提供）：美拉德反应，羰基化合物与氨基在蛋白质上的反应，在糖尿病中以加速的速度发生。这种反应产生的产物被称为晚期糖基化终产物或AGEs，对蛋白质和细胞功能有害。AGEs与糖尿病的所有主要并发症都有关系。已经测试了几种抑制AGE合成的抑制剂，其中一些在抑制糖尿病并发症方面显示出有希望的结果。然而，这些抑制剂似乎没有高度特异性，可能不会抑制细胞内AGEs。为了开发更具体和更有效的抑制剂，对AGE化学的全面了解是必不可少的。最近，一种新的AGE合成途径被发现。在这一途径中，Amadori产物，即美拉德反应的初始缩合产物，经过自发的远距离羰基转移，产生蛋白质结合的二脱氧酮。二脱氧索酮可能在蛋白质中产生大量的AGEs。这种AGEs可能包括赖氨酸-精氨酸和赖氨酸-赖氨酸交联结构。在本研究中，我们计划首先利用一种新的免疫学方法在体内建立二脱氧糖酮介导的AGE合成的发生，然后推断二脱氧糖酮特异性产生的主要AGE的化学结构，开发其在组织中检测的方法，评估该途径对糖尿病AGE合成的重要性。我们的研究有望为糖尿病中AGE的形成提供新的见解，并可能导致新的药物来预防糖尿病中AGE的形成和并发症。

DESCRIPTION (provided by applicant): The Maillard reaction, the reaction of carbonyl compounds with amino group on proteins occurs at an accelerated rate in diabetes. This reaction produces products known as, advanced glycation end products or AGEs that are detrimental to proteins and cell functions. AGEs have been implicated in all major complications of diabetes. Several inhibitors against AGE synthesis have been tested and a few of them have shown promising results in inhibiting diabetic complications. However, these inhibitors do not appear to be highly specific and may not inhibit intracellular AGEs. In order to develop more specific and potent inhibitors, a thorough knowledge of AGE chemistry is essential. Recently, a new pathway for AGE synthesis has been uncovered. In this pathway, the Amadori products, the initial condensation products of the Maillard reaction undergo spontaneous long-range carbonyl shift to produce protein-bound dideoxyosones. The dideoxyosones can potentially produce significant amounts of AGEs in proteins. Such AGEs may include lysine-arginine and lysine-lysine cross linking structures. In this proposal, we plan to first establish occurrence of dideoxyosone-mediated AGE synthesis in vivo using a novel immunological method and then deduce chemical structure of major AGE specifically arising from dideoxyosone, develop methods for their detection in tissues, assess importance of this pathway for AGE synthesis in diabetes. Our study is expected to provide novel insights into AGE formation in diabetes and may lead to new pharmacological agents to prevent AGE formation and complications in diabetes.