With the development of deoxyglucose autoradiography and its adaptation to positron emission tomography, non-invasive studies of local cerebral glucose utilization became possible. However, technical limitations still preclude non-invasive studies to observe actual glucose metabolism in its various metabolic pathways in brain. Recently, a non-invasive method to observe in vivo metabolism of 2-fluoro-2-deoxy-D-glucose (FDG) in the pentose monophosphate shunt (PMS) and aldose reductase sorbitol (ARS) pathways has been developed in our laboratory using 19-fluorine nuclear magnetic resonance (NMR) spectroscopy. This proposal is focused on the application of this technique to the quantitative analysis of cerebral glucose metabolism in the PMS and ARS under various physiologic conditions and two common major pathologic conditions affecting carbohydrate metabolism, diabetes and alcohol consumption, using FDG metabolism as a model of glucose metabolism in the PMS and ARS. Initially, normative values of the first three hours post FDG infusion will be determined in age and size matched adult Sprague-Dawley rats consuming a regular diet. The effects of estrous cycle and age on metabolism will also be assessed. After completion of this phase, the effects of diets and PMS/ARS enzyme blockers will be determined. Subsequently, the study will be expanded to diabetic rats and rats chronically fed with a liquid alcohol diet, two main conditions under which various metabolic derangements are well known to occur. For example, accumulation of sorbitol, one of the main metabolites in the ARS, has recently been postulated to be a main mechanism for the major complications frequently encountered in diabetics in spite of apparent good control of the diabetes. Wernicke's encephalopathy, one of the most dramatic complications in chronic alcoholics, is closely related to a decrease in activities of thiamine pyrophosphate dependent enzymes in the PMS. Our method allows for direct observation of glucose metabolism in the PMS and ARS. The data obtained should provide further insight into in vivo glucose metabolism which may lead towards better treatment strategies of these common but devastating disease processes.
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