Effect of ketone infusions on amino acid and nitrogen metabolism in man.

Abstract

A B S T R A C T To evaluate the role of hyperketonemia in the hypoalaninemia and decreased protein catabolism of prolonged starvation, Na DL-P-hydroxybutyrate was administered as a primed continuous 3-6-h infusion in nonobese subjects and in obese subjects in the postabsorptive state and after 3 days and 3-51 wk of starvation. An additional obese group received 12-h ketone infusions on 2 consecutive days after 5-10 wk of fasting.The ketone infusion in nonobese and obese subjects studied in the postabsorptive state resulted in total blood ketone acid levels of 1.1-1.2 mM, a 5-15 mg/100 ml decrease in plasma glucose, and unchanged levels of insulin, glucagon, lactate, and pyruvate. Plasma alanine fell by 21% (P <0.001) in 3 h. In contrast, other amino acids were stable or varied by less than 10%. Infusions lasting 6 h reduced plasma alanine by 37%, reaching levels comparable to those observed in prolonged starvation. Equimolar infusions of NaCl and/or administration of NaHCOs failed to alter plasma alanine levels.During prolonged fasting, plasma alanine, which had fallen by 40% below prefast levels, fell an additional 30% in response to the ketone infusion. In association with repeated prolonged (12 h) infusions in subjects fasted 5-10 wk, urinary nitrogen excretion fell by 30%, returning to base line after cessation of the infusions and paralleling the changes in plasma alanine. Ketone infusions resulted in two-to fourfold greater increments in blood ketone acids in fasted as compared to postabsorptive subjects.It is concluded that increased blood ketone acid levels induced by infusions of Na DL-P-hydroxybutyrate result in hypoalaninemia and in nitrogen conservation in starvation. These data suggest that hyperketonemia may be a contributory factor in the decreased availability of circulating alanine and reduction in protein catabolism characteristic of prolonged fasting. INTRODUCTIONIn fasting man survival is dependent upon the conservation of body protein stores as well as the continuous supply of energy-yielding fuels for brain metabolism (1). The need for gluconeogenesis and concomitantly the rate of protein breakdown progressively decline in prolonged starvation as ketone acids replace glucose as the major fuel consumed by the brain (2). The diminution in hepatic gluconeogenesis in prolonged fasting is mediated by a reduction in circulating glucogenic amino acids, particularly alanine, and a decrease in the outflow of these amino acids from muscle (3, 4). After a prolonged fast, plasma alanine decreases to a greater extent than that of all other amino acids, while splanchnic uptake and peripheral release of alanine are reduced to less than 50% of postabsorptive levels (3, 4).

Loss of acetoacetate coenzyme A transferase activity in tumours of peripheral tissues

“…This leads to a decrease in gluconeogenesis from alanine and lactate in the liver, which is probably due to a decreased protein degradation in skeletal muscle. Infusion of ketone-bodies into humans results in a specific decline in plasma alanine comparable with that observed during starvation (Sherwin et al, 1975). This suggests that ketone-bodies play a direct role in preventing protein catabolism during starvation, possibly due to their inhibitory action on branched-chain amino acid oxidation (Buse et al, 1972).…”

Hepatic glycogen synthase deficiency: An infrequently recognized cause of ketotic hypoglycemia

“…With more prolonged fasting, however, severe hyperketonemia and free fatty acid elevation inhibit release of alanine from skeletal muscle leading to decreased gluconeogenic precursors and worsening hypoglycemia. [15,16] …”

Reduction of weight loss and tumour size in a cachexia model by a high fat diet

“…Normal tissues would be significantly reduced (Table IV). Non tumour-bearing mice able to utilize both FFA and ketone bodies as an energy fed a diet with increasing proportions of energy derived from source and the hyperketonemia would promote nitrogen MCT do not have a significantly different blood glucose or conservation (Sherwin et al, 1975), which in turn would plasma insulin level from those fed a normal diet, and, reduce gluconeogenic precursors to the liver. Loss of body tumour-bearing mice fed the high fat diets do not have a fat in non tumour-bearing mice fed high MCT diets is not significantly different blood glucose level from the due to a reduced dietary intake, but may be associated with corresponding non-tumour bearing groups.…”