Rapid Intravenous Sodium Acetoacetate Infusion in Man METABOLIC AND KINETIC RESPONSES

Abstract

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.

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

“…The data thus suggest a progressive diminution or saturation in the rate of total ketone degradation during starvation. These findings are in agreement with previous conclusions based on observations of forearm uptake and splanchnic production of ketone bodies (33,34) and the disappearance rate of bolus injections of AcAc (27).…”

“…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).…”

Hepatic Ketogenesis and Gluconeogenesis in Humans

“…Support for this proposal can be obtained from the observations that the maximum rates of total ketone-body utilization (oxidation) and production were achieved at blood concentration of about 2-3 mmol/liter (32,33), a value found in both lean and obese subjects after about 3 days of starvation (1,2,5).…”

Acid-Base Aspects of Ketoacidosis

“…Arterial blood pH levels generally are in the range of 7.30-7.35 [12,48,59] and plasma HCO3 concentrations approximately 17-22 mmol/1 [48,49,59]. The increase in serum ketoanions (P-OHB plus AcAc) approximates the decrement in se rum [HCO3], i.e., about 6-9 mmol/1 [9,12,14,48,56,60,61]. The P-OHB/AcAc concentration ratio [12,34,48,60] is similar to that noted in DKA, and plasma ace tone as in DKA [15,16] may be equal to or greater than that of AcAc [60].…”