Changes in the concentrations of glucose, free fatty acids, insulin and ketone bodies in the blood during sodium \-hydroxybutyrate infusions in man

A B S T R A C T The metabolic and kinetic responses to rapidly intravenously administered sodium acetoacetate (1.0 mmol/kg body wt) was studied after an overnight fast in 12 male and female adults weighing between 88 and 215% of average body weight. Blood was obtained before, during, and after the infusion for determination of circulating concentrations of immunoreactive insulin, glucose, acetoacetate, 9-hydroxybutyrate and free fatty acids. In three obese subjects the studies were repeated after 3 and 24 days of total starvation.After the overnight fast acetoacetate rose rapidly reaching a peak concentration at the end of the infusion; 9-hydroxybutyrate concentrations also increased rapidly and exceeded those of acetoacetate 10 min postinfusion. Total ketone body concentration at the end of the infusion period was comparable to that found after prolonged starvation. After the initial mixing period, acetoacetate, P-hydroxybutyrate and total ketone bodies rapidly declined in a parallel manner. There were no obvious differences between the subjects with regard to their blood concentrations of ketone bodies. The mean plasma free fatty acid concentration decreased significantly during the 20th to 90th min postinfusion period; for example the control concentration of 0.61 mmol/liter fell to 0.43 mmolAiter at 60 min. In the three obese subjects studied repeatedly, fasting plasma free fatty acids decreased with acetoacetate infusion from 0.92 to 0.46 mmol/liter after the 3 day fast and from 1.49 to 0.71 mmol/liter after the 24 day fast. Acetoacetate infusion caused no changes in blood glucose concentration after an overnight fast. However, in the three obese subjects restudied after 3-and 24-day fasts blood glucose decreased, respectively, from 3.49 to 3.22 mmol/ liter and from 4.07 to 3.49 mmol/liter. The mean serum insulin concentration in all subjects significantly increased from 21 to 46 /U/ml at the completion of the Received for publication 13 March 1973 (aid in revised form 11 June 1973. infusion and rapidly declined. In the three obese subjects restudied after 3-and 24-day fasts an approximate twofold increase of serum insulin was observed after each acetoacetate infusion.The mean fractional utilization rate of exogenously derived ketone bodies for all 12 subjects after an overnight fast was 2.9% min'. In the three obese subjects studied after an overnight, 3 and 24 day fast the mean fractional utilization rates were 2.1%, 1.5%, and 0.6% min', respectively. Ketone body volumes of distribution in the overnight fasted subjected varied from about 18% to 31% of body wt, suggesting that ketone nodies are not homogenously distributed in the body water. In the three obese subjects restudied after 3-and 24-day fasts volumes of distribution remained approximately constant. When total ketone body concentrations in the blood were below 2.0 mmol/liter, there was a linear relationship between ketone body utilization rates and ketone body concentrations; no correlation was found when blood concentrations were higher.

Section: Discussionsupporting

confidence: 59%

mentioning

confidence: 99%

Rapid Intravenous Sodium Acetoacetate Infusion in Man METABOLIC AND KINETIC RESPONSES

Owen¹,

Reichard²,

Markus³

et al. 1973

“…Transient increments in plasma insulin have been observed with acute bolus infusions of AcAc in man (27). However, previous investigators have also noted that continuous infusions of ketone acids fail to increase plasma insulin in peripheral blood (18,28,29). Although growth hormone was not measured in the present study, other reports have shown that increased levels of growth hormone are without effect on total urinary nitrogen excretion in prolonged starvation (30).…”

Section: Discussioncontrasting

confidence: 50%

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

Sherwin¹,

Hendler²,

Felig³

1975

326

119

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).

“…It is well known that infusions of Na AcAc (27) or Na fOHB (28,29) in man and other species induce a decrease in plasma concentration of glucose, FFA, and glycerol. Our results are consistent with these data and show that the same effect is observed with infusions of AcAc acid.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Sodium Acetoacetate and Acetoacetic Acid Infusions on Alanine and Glutamine Metabolism in Man

Féry¹,

Balasse²

1980

A B S T R A C T It has been suggested that ketone bodies might participate in the nitrogen-sparing process occurring during prolonged starvation by inhibiting the muscular production of alanine and glutamine, which are the main gluconeogenic amino acids. The results of the ketone infusion studies on which this theory is based have been reevaluated in this study by following the plasma levels of ketone bodies, alanine, glutamine, and other substrates during 11.5 h in five groups of normal overnight-fasted subjects. Subjects of groups I, II, and III were infused for 3 h, respectively, with Na acetoacetate, Na bicarbonate, or free acetoacetic acid administered in comparable amounts (about 20 ,tmol/kg per min), whereas group IV was infused with hydrochloric acid (7.0 ,umol/kg per min). A control group (V) received no infusion. Na acetoacetate induced a rise in blood pH (+0.1±0.003) and a fall in the plasma levels of alanine (-41.8±4.6%) and glutamine (-10.6± 1.4%), whereas free acetoacetic acid had a barely detectable lowering effect on blood pH and induced a rise in alanine (+22.5±8.0%) and glutamine (+14.6+3.2%) levels. Both infusions were associated with a lowering of plasma glucose, which therefore seems independent of the changes in alanine and glutamine concentrations. Sodium bicarbonate reproduced the alkalinizing effect and the hypoalaninemic action of Na acetoacetate, which seems thus unrelated to hyperketonemia. On the other hand, acidification of blood with hydrochloric acid did not mimic the effects of acetoacetic acid.If the hyperalaninemic and hyperglutaminemic effects of ketone bodies infused in their physiological form (free acids) reflect a stimulation of the muscular This wvork was presented in part at