MODEL OF EXTREME HYPOGLYCEMIA IN DOGS MADE KETOTIC WITH (R,S)-1,3-BUTANEDIOL ACETOACETATE ESTERS

The rationale behind this study is that controlled starvation of poorl y differentiated (anaplastic) fast-growing tumor cells, but not host c ells, might be possible in vivo. The energy metabolism of anaplastic t umor cells, but not host cells, is largely dependent on carbohydrate m etabolism at all times. Therefore depleting plasma of carbohydrate fue ls could place these tumor cells at a significant metabolic disadvanta ge. Hence an animal model was developed in which all cells would be re quired to oxidize fatty acids, ketoacids, and/or 1,3-butanediol to sat isfy 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 monoa cetoacetate and (R,S)-1,3-butanediol diacetoacetate; these latter comp ounds are nonionized precursors of ketoacids. They were infused at 90% of the dog's caloric requirement. After establishment of a moderate k etosis (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 show ed 1) a 20% decrease in the rate of appearance of glucose, 2) 50 and 6 2% increases in glycerol and nonesterified fatty acid rates of appeara nce, 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.