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Plasma glucose, free fatty acid, ketone, and triglyceride concentrations were measured at frequent intervals after the administration of alloxan to rats. Hepatic triglyceride levels were determined in the same animals. During the second 24-hr period after alloxan administration, severe ketoacidosis developed and triglyceride concentrations in the liver became markedly elevated. This finding was incompatible with the thesis that enhanced ketogenesis under circumstances of increased free fatty acid delivery to the liver requires diminished triglyceride synthesis. Plasma insulin and glucagon concentrations were determined at each time point. Initial changes in plasma glucose, ketones, free fatty acids, and triglycerides were accompanied by a fall in insulin concentrations, but no change occurred in glucagon levels. However, concentrations of the latter hormone increased dramatically in the second 24 hr after alloxan treatment and probably contributed to the development of the extreme hyperglycemia observed during this time period.

The effect of (+)-decanoylcarnitine, a potent inhibitor of long-chain acylcarnitine transferase, was tested for its ability to inhibit hepatic ketogenesis both in the isolated perfused liver and in vivo in severely ketotic alloxan diabetic rats. In vitro the inhibitor caused an almost complete block in ketone body production. In vivo (+)-decanoylcarnitine caused a rapid reversal of ketosis under conditions where large doses of insulin had little effect. A combination of the two agents produced an even more striking fall in plasma ketone levels.While (+)-decanoylcarnitine alone had no effect on plasma glucose levels it enhanced the hypoglycemic effect of insulin in anesthetized animals. Loss of this effect was noted in nonanesthetized animals, possibly as a result of increased muscle activity. Studies in the isolated perfused liver indicated that the blockade of fatty acid oxidation and ketogenesis produced by (+)-decanoylcarnitine was rapidly reversible upon removal of the inhibitor.

A series of experiments was performed during the induction of starvation ketosis and in the acute reversal of the ketotic state. In contrast to the predictions of two widely held theories of ketogenesis, control of acetoacetate production by the liver appeared to be unrelated to changes in fatty acid mobilization from the periphery, fatty acid oxidation, fatty acid synthesis, or the acetyl coenzyme A concentration in the liver.Ketosis of fasting was shown to be reversible within 5 minutes by the injection of glucose or insulin. This effect was due to a prompt cessation of acetoacetate production by the liver. The possibility is raised that the ketosis of fasting is due to a direct activation of acetoacetate-synthesizing enzymes secondary to a starvation-induced depression of insulin secretion by the pancreas.