NEW METABOLITES & PATHWAYS IN DIABETIC HUMAN ERTHROCYTES

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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.