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

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Differential Effects of Sodium Acetoacetate and Acetoacetic Acid Infusions on Alanine and Glutamine Metabolism in Man Differential Effects of Sodium Acetoacetate and Acetoacetic Acid Infusions on Alanine and Glutamine Metabolism in Man Françoise Féry, Edmond O. Balasse J Clin Invest. 1980;66(2):323-331. https://doi.org/10.1172/JCI109860. Research Article 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 μmol/kg per min), whereas group IV was infused with hydrochloric acid (7.0 μmol/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 […] Find the latest version: https://jci.me/109860/pdf Differential Effects of Sodium Acetoacetate and Acetoacetic Acid Infusions on Alanine and Glutamine Metabolism in Man FRAN§OISE FERY and EDMOND 0. BALASSE, Metabolic Unit, Hopital St. Pierre and Laboratory of Experimenital Medicine, University of Brussels, 1000 Brussels, Belgium A B S T R A C T It has been suggested that ketone output of these amino acids, the participation of ketone bodies might participate in the nitrogen-sparing proc- bodies in the nitrogen-sparing process of prolonged ess occurring during prolonged starvation by inhibiting fasting seems very unlikely. On the other hand, during the muscular production of alanine and glutamine, brief starvation, when both ketogenesis and gluconeo- which are the main gluconeogenic amino acids. The genesis are markedly stimulated, ketone bodies might results of the ketone infusion studies on which this indirectly contribute in supplying the liver and the theory is based have been reevaluated in this study kidney with gluconeogenic substrates. by following the plasma levels of ketone bodies, alanine, glutamine, and other substrates during 11.5 h INTRODUCTION in five groups of normal overnight-fasted subjects. Subjects of groups I, II, and III were infused for 3 h, A few years ago, Sherwin et al. (1) suggested that the respectively, with Na acetoacetate, Na bicarbonate, or reduction in alanine (ALA)' levels and the remarkable free acetoacetic acid administered in comparable protein conservation observed during prolonged fast- amounts (about 20 ,tmol/kg per min), whereas group ing could be related to hyperketonemia. They showed, IV was infused with hydrochloric acid (7.0 ,umol/kg indeed, that the infusion of sodium f3-hydroxybutyrate per min). A control group (V) received no infusion. Na (,3OHB) in postabsorptive or fasted subjects reduces acetoacetate induced a rise in blood pH (+0.1±0.003) the plasma concentration of ALA, the most important and a fall in the plasma levels of alanine (-41.8±4.6%) glucogenic amino acid (2). Furthermore, they demon- and glutamine (-10.6± 1.4%), whereas free acetoacetic strated in obese subjects fasted for several weeks, that acid had a barely detectable lowering effect on blood the hypoalaninemic effect of prolonged Na ,BOHB pH and induced a rise in alanine (+22.5±8.0%) and infusion was associated with a decrease in the excretion glutamine (+14.6+3.2%) levels. Both infusions were of urea, ammonia, and total nitrogen in urine. Plasma associated with a lowering of plasma glucose, which glutamine (GLN) concentration was not measured in therefore seems independent of the changes in alanine these studies, but since it represents the main pre- and glutamine concentrations. Sodium bicarbonate cursor for renal ammonia produiction (3), these authors reproduced the alkalinizing effect and the hypo- hypothesized that ketone bodies might also reduce the alaninemic action of Na acetoacetate, which seems concentration of this amino acid, which plays a key thus unrelated to hyperketonemia. On the other hand, role in renal gluconeogenesis (4). These experiments acidification of blood with hydrochloric acid did not led to the suggestion that during prolonged starvation, mimic the effects of acetoacetic acid. ketone bodies serve not only as a substrate replacing If the hyperalaninemic and hyperglutaminemic glucose for the brain, but also as a signal to muscle, effects of ketone bodies infused in their physiological resulting in a diminution of ALA and GLN production form (free acids) reflect a stimulation of the muscular and consequently a reduction in gluconeogenesis from proteins, this process favoring nitrogen sparing. How- This wvork was presented in part at the 10th Congress of the ever, soime metabolic aspects of fasting cannot easily International Diabetes Federation, Vienna, Austria, Sep- tern)er 1979. IAbbreviations used in this paper: ALA, alanine; AcAc, Received for publication 19 October 1979 and in revised acetoacetate; /3OHB, ,8-hydroxybutyrate; FFA, free fatty acid; form 8 April 1980. GLN, glutamine. J. Clin. Invest. (D The American Society for Clinical Investigation, Inc. * 0021-9738/80/08/0323/09 $1.00 323 Volume 66 August 1980 323-331 be accounted for by this theory. For instance, during only, the study was terminated at the end of the 3 h infusion brief starvation (a few days), muscular ALA release is period. No untoward effect was observed during or after increased (5) despite an already marked hyperketo- these experiments. Analysis. Standard enzymatic methods were used to nemia. On the other hand, it is difficult to conceive determine plasma concentrations of AcAc (9), /3OHB (9), that the inhibitory effect of ketones on muscular ALA glucose (10), lactate (11), GLN (12), and ALA (13). All deter- release and nitrogen excretion would be most promi- minations were performed after prior deproteination of plasma nent after prolonged fasting, since at that time uptake with perchloric acid as described (14), except for ALA, which is currently determined in our laboratory without prior of ketones by muscle is markedly reduced (6, 7) as deproteination.2 Free fatty acids (FFA) were determined compared with early starvation. Recent studies by according to Trout et al. (15). Plasma immunoreactive insulin Yang et al. (8) on obese patients submitted to an was assayed using a Sephadex anti-insulin complex (Phadebas hypocaloric diet also tend to refute the hypothesis of a insulin test, Uppsala, Sweden). protein-sparing effect of Blood gas analysis (pH, Pco2, and total bicarbonate) were ketone bodies: these authors obtained at the beginning and end of the infusions in groups noticed that the negative nitrogen balance was not I and II. More frequent determinations were performed improved when a ketogenic rather than a nonketogenic during the infusion and early postinfusion period in two diet was provided to the patients receiving an identical patients of group I and in all patients of groups III-V. All protein and caloric supply. assays were made in duplicate. Statistical methods. Results obtained at the various time Because ofthese considerations, we reassessed in the points of the studies were expressed as changes from the present work the influence of infusions of ketone corresponding last basal value (+SEM) (Figs. 1-3). The bodies on ALA levels and extended our analysis to statistical significance of these changes was evaluated within changes in GLN concentration. Our data confirm the each group by a paired t test. Results of all groups were submitted to a one-way analysis of variance at each time hypoalaninemic effect of ketone bodies infused as point and whenever a difference was detected at a statistically their sodium salt. They demonstrate that this effect significant level (P < 0.05), simultaneous pair-wise com- can be entirely reproduced when sodium acetoacetate parison between groups was made by a t test using the (AcAc) is replaced by equimolar amounts of sodium SE derived from the analysis of variance (16). bicarbonate inducing the same degree of Preparation of material for infusion. Sodium AcAc was blood prepared from ethyl-AcAc (Merck-Schuchardt, Muinchen, alkalinization. When acetoacetate was delivered as Germany) as described (14). AcAc acid was obtained by free acid, a rise rather than a fall in ALA and GLN mixing 1.6 M Na AcAc with increasing amounts of strongly concentrations was observed. This effect was inde- acidic cation exchange resin (Amberlite IR-120, Mallinckrodt pendent of the acidification process, in that it could Inc., St. Louis, Mo.) under pH monitoring until the solution not reached a pH of 2.6. Since the pK of AcAc acid is 3.6, 90% of be reproduced with infusions of hydrochloric acid. the AcAc acid should be in its free form. After this ion- exchange procedure, the recovery of AcAc acid (as determined METHODS enzymatically) was only 49±2% of the expected amount, probably because of decarboxylation of part of the AcAc Subjects and procedures. The studies were performed acid to acetone. The latter was removed by exposing the on postabsorptive healthy subjects of both sexes, aged 18-47 AcAc acid solution to a stream of nitrogen in an ice bath for yr (Table I).
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