The goal is to determine the effect of diabetes on myo-inositol metabolism in the peripheral nerve. The theory is that reduced myo-inositol levels be responsible for some diabetic neuropathy. Presumably elevated glucose or sorbitol levels cause a reduction in myo-inositol uptake and subsequently inositol phospholipid levels. Because of the difficulty in conducting studies with the present in vivo systems, this theory has not been thoroughly investigated. To overcome this problem I have developed a tissue culture system to selectively study the effects of certain diabetic circulatory conditions on myo-inositol metabolism and neural cell functions. The first goal is to thoroughly characterize the effect of elevated glucose and sorbitol levels on myo-inositol uptake and incorporation into phospholipids. These studies will be done with neuroblastoma cells grown in normal media or medium supplemented with elevated levels of glucose, fructose, sorbitol or other polyols to mimic diabetic circulation. Preliminary studies with the system indicate a decrease in myoinositol uptake and incorporation into lipid by cells exposed to elevated levels of glucose or sorbitol. In these studies special emphasis will be placed on determining the effect of diabetes on metabolism of the inositol phospholipids. This has been largely overlooked in previous studies eventhough the inositol phospholipids are intrinsic to neural cell function. A second goal of this project is to thoroughly examine some of the neural cell functions which may be altered in diabetes. Except for Na+/K+ ATPase activity, the specific biological changes which occur in the diabetic nerve are unknown. At first the defined tissue culture system will be used for these studies and then when possible an animal model. The neuroblastoma cells offer a distinct advantage because of the many highly characterized neural cell functions they possess. The final goal of this project is to correlate inositol phospholipid levels with altered nerve conduction velocity and Na+/K+ ATPase activity in diabetic rats. In addition, studies will be conducted to determine if improvement of peripheral nerve activity by dietetic treatment or drug therapy correlates with improved myo-inositol metabolism. Previous studies have concentrated on measuring free intracellular myoinositol levels and not the inositol phospholipids which are an essential membrane component. These investigations will answer many of the remaining questions regarding the effect of diabetes on myo-inositol metabolism in peripheral nerve which could result in a protocol for improved treatment of diabetic neuropathy.
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