NEW METABOLITES & PATHWAYS IN DIABETIC HUMAN ERTHROCYTES

通过使用31 p NMR光谱， 在人红细胞中观察到磷酸单酯， 以前未知的代谢途径可能在这些疾病中起作用， 细胞 这五种代谢物中有两种已被鉴定为 山梨糖醇-3-磷酸（S3 P）和果糖-3-磷酸（F3 P）。 他们 这两种都是先前在糖尿病大鼠的透镜中检测到的， 其浓度急剧增加之前的发展， 白内障 抑制这些化合物的积累， 醛糖还原酶抑制剂Sorbinil（TM）延迟了 白内障形成 因为果糖-3-磷酸是一种有效的糖化剂 这些数据表明，该化合物可能与 该组织中蛋白质的糖基化增加和白内障发生。 在镜片中检测到S3 P和/或F3 P后，在 受糖尿病并发症影响的其他组织，包括外周 神经、视网膜和红细胞。 由于这些代谢物之间的明显关联， 糖尿病，对S3 P浓度进行了初步调查， F3 P和其他三种未鉴定的代谢产物在糖尿病患者中的作用， 正常对照者 作为这项研究的结果，确定其中一个 未鉴定的代谢物（化合物B）显示出有趣的 与糖尿病肾病的相关性 31 P NMR分析 对从10名糖尿病患者和10名非糖尿病患者中获得的红细胞进行了检测。 糖尿病血液透析患者。 第二次调查结果显示， 与先前观察到的相关性一致， 代谢物B的浓度升高（相对于正常 在几乎所有的尿毒症个体中。 这些升高 从非糖尿病患者的10倍增加到 在糖尿病患者中增加了20倍。 在这项研究中，我们建议通过识别这些发现来跟进这些发现。 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 生产这些不寻常的磷酸单酯，并确定其 影响细胞功能。 最后，我们打算进行一次更大规模的调查 正常人、尿毒症和糖尿病患者，以确定 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.