AJP - Endocrinology and Metabolism, Vol 269, Issue 1 E67-E75, Copyright © 1995 by American Physiological Society
Model of extreme hypoglycemia in dogs made ketotic with (R,S)-1,3-butanediol acetoacetate esters
S. T. Ciraolo, S. F. Previs, C. A. Fernandez, K. C. Agarwal, F. David, J. Koshy, D. Lucas, A. Tammaro, M. P. Stevens, K. Y. Tserng and al. et
Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA.
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 on carbohydrate metabolism at all
times. Therefore 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
(R,S)-1,3-butanediol monoacetoacetate and (R,S)-1,3-butanediol
diacetoacetate; these latter compounds are nonionized precursors of
ketoacids. They were infused at 90% of the dog's caloric requirement. After
establishment of a moderate ketosis (2-3 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 1) a 20% decrease in the rate of appearance of
glucose, 2) 50 and 62% increases in glycerol and nonesterified fatty acid
rates of appearance, reflecting stimulation of lipolysis, and 3) 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.
