Model of extreme hypoglycemia in dogs made ketotic with r,s-1, 3
-butanediol acetoacetate esters.
Ciraolo, Susan T., Stephen F. Previs, Charles A. Fernandez, Kamlesh C.
Agarwal, France David, John Koshy, David Lucas, Alessandra Tammaro,
Michelle P. Stevens, Kou-Yi Tserng, Mitchell L. Halperin, and Henri
Brunengraber.
Departments of Nutrition and Biomedical Engineering, Case Western
Reserve University, Cleveland, OH 44106 and Department of Medicine,
University of Toronto, Toronto, ON.
APStracts 2:0027E, 1995.
The rationale behind this study is that controlled starvation of
poorly differentiated (anaplastic) fast-growing tumor cells, but not
host cells, might be possible in vivo. The energy metabolism of
anaplastic tumor cells, but not host cells, is largely dependent of
carbohydrate metabolism at all times. So, depleting plasma of
carbohydrate fuels could place these tumor cells at a significant
metabolic disadvantage. Hence an animal model was developed in which
all cells would be required to oxidize fatty acids, ketoacids and/or
1,3-butanediol to satisfy their energy needs. To achieve this aim,
one would need ketosis, severe hypoglycemia and low lactatemia.
Anesthetized normal dogs were infused with somatostatin and a mixture
of RS-1,3-butanediol monoacetoacetate and RS-1,3-butanediol
diacetoacetate; these latter compounds are non-ionized precursors of
ketoacids. They were infused at 90% of the dog's caloric requirement.
After establishing a moderate ketosis (2 to 3 mM) over <100 min, a
severe degree of hypoglycemia (close to 0.5 mM) without rebound and
without hyperlactatemia was induced by infusing insulin and
dichloroacetate. Tracer kinetic measurements showed (i) a 20%
decrease in the rate of appearance of glucose, (ii) 50 and 62%
increases in glycerol and non-esterified fatty acid rates of
appearance, reflecting stimulation of lipolysis, and (iii) no change
in the rate of glutamine appearance. We suggest that this model may
prove useful for selectively starving those cancer cells that are
unable to utilize fat-derived fuels, while preserving nutrient supply
to vital organs.
Received 8 July 1994; accepted in final form 7 February 1995.
APS Manuscript Number E261-4.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 25 February 1995.