Friedman E A
Department of Medicine, State University of New York, Health Science Center at Brooklyn, NY 11203, USA.
Diabetes Care. 1999 Mar;22 Suppl 2:B65-71.
Protein alteration resulting from a nonenzymatic reaction between ambient glucose and primary amino groups on proteins to form glycated residues called Amadori products is termed the Maillard reaction. By dehydration and fragmentation reactions, Amadori products are transformed to stable covalent adducts called advanced glycosylation end products (AGEs). In diabetes, accelerated synthesis and tissue deposition of AGEs is proposed as a contributing mechanism in the pathogenesis of clinical complications. Uremia in diabetes is associated with both a high serum level of AGEs and accelerated macro- and microvasculopathy. Diabetic uremic patients accumulate advanced glycosylated end products in "toxic" amounts that are not decreased to normal by hemodialysis or peritoneal dialysis but fall sharply to within the normal range within 8 h of restoration of half-normal glomerular filtration by renal transplantation. It follows that the higher mortality of hemodialysis-treated diabetic patients compared with those given a renal transplant may relate, in part, to persistent AGE toxicity. Pharmacologic prevention of AGE formation is an attractive means of preempting diabetic microvascular complications because it bypasses the necessity of having to attain euglycemia, an often unattainable goal. Pimagidine (aminoguanidine) interferes with nonenzymatic glycosylation and reduces measured AGE levels leading to its investigation as a potential treatment. The mechanism by which pimagidine prevents renal, eye, nerve, and other microvascular complications in animal models of diabetes is under investigation. Separate multicenter clinical trials of pimagidine in type 1 and type 2 diabetes, where proteinuria is attributable to diabetic nephropathy, are in progress. The effect of treatment on the amount of proteinuria, progression of renal insufficiency, and the course of retinopathy will be monitored.
环境中的葡萄糖与蛋白质上的伯氨基发生非酶促反应，形成称为阿马多里产物的糖化残基，由此导致的蛋白质改变被称为美拉德反应。通过脱水和裂解反应，阿马多里产物转变为稳定的共价加合物，即晚期糖基化终产物（AGEs）。在糖尿病中，AGEs合成加速和组织沉积被认为是临床并发症发病机制中的一个促成因素。糖尿病中的尿毒症与血清中高水平的AGEs以及大血管和微血管病变加速有关。糖尿病尿毒症患者会累积“毒性”量的晚期糖基化终产物，这些产物不会通过血液透析或腹膜透析降至正常水平，但在肾移植使肾小球滤过恢复至半正常水平8小时内会急剧降至正常范围内。由此可见，与接受肾移植的糖尿病患者相比，接受血液透析治疗的糖尿病患者死亡率较高，这可能部分与AGEs的持续毒性有关。药理学预防AGEs形成是预防糖尿病微血管并发症的一种有吸引力的方法，因为它无需达到血糖正常这一往往难以实现的目标。匹马吉定（氨基胍）可干扰非酶糖基化并降低测得的AGEs水平，因此被作为一种潜在治疗方法进行研究。匹马吉定在糖尿病动物模型中预防肾脏、眼睛、神经和其他微血管并发症的机制正在研究中。针对1型和2型糖尿病（蛋白尿由糖尿病肾病引起）的匹马吉定多中心临床试验正在进行。将监测治疗对蛋白尿水平、肾功能不全进展以及视网膜病变病程的影响。
