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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK035543-10
Application #
2139595
Study Section
Metabolism Study Section (MET)
Project Start
1985-04-01
Project End
1999-06-30
Budget Start
1995-07-14
Budget End
1996-06-30
Support Year
10
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Nutrition
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Roe, Charles R; Brunengraber, Henri (2015) Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: Review of 15 years Experience. Mol Genet Metab 116:260-8
Kinman, Renee P; Kasumov, Takhar; Jobbins, Kathryn A et al. (2006) Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. Am J Physiol Endocrinol Metab 291:E860-6
Okere, Isidore C; McElfresh, Tracy A; Brunengraber, Daniel Z et al. (2006) Differential effects of heptanoate and hexanoate on myocardial citric acid cycle intermediates following ischemia-reperfusion. J Appl Physiol 100:76-82
Bian, Fang; Kasumov, Takhar; Thomas, Katherine R et al. (2005) Peroxisomal and mitochondrial oxidation of fatty acids in the heart, assessed from the 13C labeling of malonyl-CoA and the acetyl moiety of citrate. J Biol Chem 280:9265-71
Kasumov, Takhar; Adams, Jillian E; Bian, Fang et al. (2005) Probing peroxisomal beta-oxidation and the labelling of acetyl-CoA proxies with [1-(13C)]octanoate and [3-(13C)]octanoate in the perfused rat liver. Biochem J 389:397-401
Yu, Lynn; Sinha, Amit K; Previs, Stephen F (2005) Effect of sampling interval on the use of ""doubly labeled"" water for measuring CO2 production. Anal Biochem 337:343-6
Reszko, Aneta E; Kasumov, Takhar; David, France et al. (2004) Peroxisomal fatty acid oxidation is a substantial source of the acetyl moiety of malonyl-CoA in rat heart. J Biol Chem 279:19574-9
Bederman, Ilya R; Kasumov, Takhar; Reszko, Aneta E et al. (2004) In vitro modeling of fatty acid synthesis under conditions simulating the zonation of lipogenic [13C]acetyl-CoA enrichment in the liver. J Biol Chem 279:43217-26
Reszko, Aneta E; Kasumov, Takhar; David, France et al. (2004) Regulation of malonyl-CoA concentration and turnover in the normal heart. J Biol Chem 279:34298-301
Bederman, Ilya R; Reszko, Aneta E; Kasumov, Takhar et al. (2004) Zonation of labeling of lipogenic acetyl-CoA across the liver: implications for studies of lipogenesis by mass isotopomer analysis. J Biol Chem 279:43207-16

Showing the most recent 10 out of 62 publications