The long-term goal of our investigations is to devise new strategies for the treatment of nutritional diseases such as diabetes and some inborn errors of nutrient metabolism. During the current grant period, we developed artificial nutrients for parenteral and enteral nutrition ,ie 13-diol ketone body esters. These could partly replace lipid emulsions. We also defined conditions of applicability of the non-invasive chemical biopsy of the liver, using stable isotopes and isotopomer analysis. During the next five years, we seek to further develop these two research tracks by achieving the following specific aims: 1. To characterize in animal models the metabolism and safety of 1,3- diol ketone body esters which are potential sources of calories for oral and parenteral nutrition. 2. To determine the pharmacokinetics and the metabolism of 1,3- butanediol from diacetoacetate in normal humans and test its usefulness in patients suffering pathologies which could be alleviated by therapeutic ketosis (intractable epilepsy, defects in the pyruvate dehydrogenase complex.) 3. To devise a non-invasive clinical test to assess the activity ratio (pyruvate carboxylase)/(pyruvate dehydrogenase) in the liver of normal subjects, of children with inborn errors of pyruvate metabolism, and of children and young adults with juvenile diabetes.The involves the oral administration of [3-13C] pyruvate, and the assay of the 13C-labeling pattern of endogenous phenylacetylglutamine isolated from urine. This activity ratio will be correlated wit h measurements of gluconeogenesis based on the incorporation of deuterium from heavy water into glucose. We hope this technique will allow one to identify those diabetic patients who could benefit from the intraperitoneal administration of insulin. 4. To resolve, in animal models, the major discrepancies existing between the techniques presently used to measure rates of fatty acid and cholesterol synthesis in humans, and to identify a reliable technique applicable to humans.
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