• Miles, John M (PI)

Project: Research project

Project Details


The proposed research will continue our work in the area of substrate and
hormonal regulation of ketogenesis in vivo. Previous isotope dilution
studies of ketone body metabolism have used a 14C ketone body tracer, and
have utilized so-called "total ketone body specific activity" because of in
vitro isotopic non-equilibration between the major ketone body pools
(acetoacetate and Beta-hydroxybutyrate); however, the validity of this
approach has recently been questioned. A number of in vitro studies have
suggested that a variety of intermediary metabolites may be involved in
non-hormonal regulation of ketogenesis; this concept, however, has not been
systematically examined in vivo. We have recently developed a method for
the determination of stable isotopic enrichment in ketone bodies using gas
chromatography/mass spectroscopy. In the proposed studies, [3-14C]
Beta-hydroxybutyrate and [3,4-13C2] acetoacetate are used in a dual isotope
modeling technique to determine whole body rates of appearance,
disappearance, and interconversion of ketone bodies. The proposal will
focus initially on validation of the dual isotope model and subsequently on
potential substrate factors involved in the regulation of ketogenesis.
Specifically, these studies will: 1) determine which isotope model (the
dual isotope technique versus "total ketone body specific activity" best
predicts inflow of ketone bodies from an exogenous infusion, and
subsequently compare these isotope dilution methods with endogenous ketone,
and subsequently compare these isotope dilution methods with endogenous
ketone body production determined directly by portal and hepatic venous
catheterization in fed, fasted, and diabetic dogs; 2) determine whether
physiologic increases in Cori and tricarboxylic acid cycle intermediates
can suppress ketogenesis in vivo, independent of hormonal influences and
free fatty acid availability; 3) determine whether an increase in plasma
acetate results in acceleration of ketogenesis in the immediate
postabsorptive state; and 4) determine whether infusion of oxalate, an in
vitro inhibitor of pyruvate carboxylase, can stimulate ketogenesis in vivo,
perhaps by suppressing oxaloacetate availability. These studies should
lead to the development of new techniques for investigating ketone body
metabolism in normal and disease states, and will provide new insights
regarding the role of intermediates of the Cori and tricarboxylic acid
cycles in the in vivo regulation of ketogenesis.
Effective start/end date4/1/843/31/86


  • National Institutes of Health


  • Medicine(all)


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