(Scanned from the applicant's description) Gluconeogenesis plays a major role in the metabolic alterations, which threaten the health and the life of diabetic patients. We seek to expand our understanding of the dysregulation of gluconeogenesis in type I diabetics by a combination of clinical investigations, development of new techniques for measuring gluconeogenesis, and basic science studies in animals. Over the next three years, we plan to achieve the following specific aims: 1. To test the usefulness of measuring the hepatic flux ratio (pyruvate carboxylase)/(pyruvate dehydrogenase) as an index of liver insulinization in clinical investigations of type I diabetes. This ratio will be determined noninvasively via the 13C-labeling pattern of urinary phenylacetylglutamine. We plan to compare the gluconeogenic status of normal subjects and type I diabetics (kept in good control by an infusion of insulin, acutely deprived of infused insulin, and poorly controlled). The study will involve administering [3-13C]pyruvate, 2H2O [6,6-2H2]glucose, and phenylbutyrate, and assaying (i) the '3C-labeling pattern of urinary phenylacetylglutamine, (ii) fractional gluconeogenesis via the 2H enrichment ratio C5/C2 of plasma glucose, and (iii) the turnover of glucose. 2. To work out new procedures to determine fractional gluconeogenesis from the 2H enrichment ratio C5/C2 of plasma glucose in subjects ingesting 2H2O. The procedure will be applicable to small samples from children, and to glucose samples labeled with '3C in addition to 2H. 3. To characterize, in perfused livers from normal rats and diabetic BB rats, the involvement of ATP-citrate lyase in the gluconeogenic pathway, specifically in the transfer, from mitochondria to the cytosol, of oxaloacetate derived from lactate (which itself was formed during Con cycling and muscular exercise). We hypothesize that an active citrate cleavage pathway persists in the liver under non-lipogenic conditions such as starvation. This process contributes to the recycling of lactate to glucose and to the detoxification of xenobiotics via acetylation. We hope that the data of our investigations will help to devise new strategies for improving the treatment of type I diabetic patients.
| Kasumov, Takhar; Brunengraber, Laura L; Comte, Blandine et al. (2004) New secondary metabolites of phenylbutyrate in humans and rats. Drug Metab Dispos 32:10-9 |
| Previs, Stephen F; Fatica, Richard; Chandramouli, Visvanathan et al. (2004) Quantifying rates of protein synthesis in humans by use of 2H2O: application to patients with end-stage renal disease. Am J Physiol Endocrinol Metab 286:E665-72 |
