NEW METABOLITES & PATHWAYS IN DIABETIC HUMAN ERTHROCYTES

通过使用31P核磁共振波谱，有五个以前未知的 在人类红细胞中观察到了磷酸单酯，这表明 以前未知的代谢途径可能在这些 细胞。这五种代谢物中有两种已被鉴定为 山梨醇-3-磷酸(S3P)和果糖-3-磷酸(F3P)。它们是 之前在糖尿病大鼠的晶状体中检测到这两种情况，其中 在它们的浓度急剧增加之前， 白内障。一种抑制这些化合物积累的方法 醛糖还原酶抑制剂Sorbinil(Tm)延缓 白内障的发生。因为3-磷酸果糖是一种有效的糖化作用 探员，这些数据表明这种化合物可能与 这种组织中蛋白质糖基化的增加和白内障的发生。 在晶状体中检测到S3P和/或F3P后，在 其他受糖尿病并发症影响的组织，包括外周 神经、视网膜和红细胞。 因为这些代谢物和 糖尿病，对S3P浓度进行了初步调查， F3P和其他三种未知代谢物在糖尿病患者和 正常对照组。作为这项研究的结果，确定了其中一个 未知的代谢物(化合物b)显示出一种有趣的 与糖尿病肾病的相关性。因此，31P核磁共振分析 对10名糖尿病患者和10名非糖尿病患者的红细胞进行了检测。 糖尿病血液透析患者。第二次调查的结果显示 这与之前观察到的相关性一致 代谢物b浓度升高(相对于正常 在几乎所有的尿毒症患者中)。这些高程 范围从非糖尿病患者增加10倍到超过 糖尿病患者的发病率增加了20倍。 在这项研究中，我们建议通过确定 其余三种未知代谢物，特别强调 代谢物b。我们还计划研究导致 这些不寻常的磷单酯的生产并确定它们的 对细胞功能的影响。最后，我们打算进行一项更大规模的调查 对正常人、尿毒症患者和糖尿病患者的判断意义 之前观察到的相关性。

Through the use of 31p NMR spectroscopy, five previously unknown phosphomonoesters have been observed in human erythrocytes suggesting that previously unknown metabolic pathways may be operative in these cells. Two of these five metabolites have been identified as sorbitol-3-phosphate (S3P) and fructose-3-phosphate (F3P). They were both previously detected in the lens of the diabetic rat wherein a dramatic increase in their concentrations precedes the development of cataracts. Inhibition of the accumulation of these compounds by an aldose reductase inhibitor Sorbinil (tm) delays the process of cataractogenesis. Because fructose-3-phosphate is a potent glycating agent, these data suggest that this compound may by causally related to the increased glycation of proteins and cataractogenesis in this tissue. Subsequent to their detection in lenses S3P and/or F3P were observed in other tissues affected by diabetic complications including peripheral nerves, retina and erythrocytes. Because of the apparent association between these metabolites and diabetes, a preliminary survey was conducted on the concentration of S3P, F3P and the other three unidentified metabolites in diabetic patients and normal controls. As a result of this study it was determined that one of the unidentified metabolites (compound b) showed an interesting correlation with diabetic nephropathy. Consequently, 31P NMR analysis was performed on erythrocytes obtained from 10 diabetic and 10 non- diabetic hemodialysis patients. Results of this second survey showed that, consistent with the previously observed correlation the concentrations of metabolite b were elevated (relative to normal controls) in almost all of the uremic individuals. These elevations ranged from a ten-fold increase in the non-diabetic patients to over twenty-fold increase in the diabetic individuals. In this study we propose to follow up on these findings by identifying the remaining three unknown metabolites, with particular emphasis on metabolite b. We also plan to study the metabolic pathways leading to the production of these unusual phosphomonoesters and to determine their effect on cell function. Finally, we intend to conduct a larger survey of normal, uremic and diabetic individuals to determine the significance of the previously observed correlations.