Nitrogen sparing induced by leucine compared with that induced by its keto analogue, alpha-ketoisocaproate, in fasting obese man. W E Mitch, … , M Walser, D G Sapir J Clin Invest. 1981;67(2):553-562. https://doi.org/10.1172/JCI110066. Research Article We measured the effects of seven consecutive daily infusions of alpha-ketoisocaproate (the alpha-keto analogue of leucine) or leucine itself on urinary urea and total nitrogen excretion during fasting. Two study protocols were undertaken. In protocol I, subjects underwent three separate 14-d fasts: one during which 34 mmol/d of leucine were infused on days 1--7; a second during which 34 mmol/d of alpha-ketoisocaproate were infused on days 1--7; and a third control fast during which no infusions were given. Infusions of alpha-ketoisocaproate significantly reduced daily urine urea nitrogen excretion compared with both the control fasts and the fasts in which leucine was infused (P less than 0.001). This nitrogen-sparing effect of alpha-ketoisocaproate persisted during days 8--14 even though no further infusions were given. Daily urinary urea nitrogen excretion during fasts when leucine was administered did not differ from values observed during control fasts. In protocol II, subjects were starved on two occasions for 14 d. During one fast, infusions of 11 mmol/d of alpha- ketoisocaproate were given on days 1--7; during the control fast, no infusions were given. Daily urine urea nitrogen excretion was lower (P less than 0.001) on days 1--7 and also on days 8--14 of the fast during which alpha- ketoisocaproate was given. The nitrogen-sparing effect of alpha-ketoisocaproate could not be related to changes in circulating levels of amino acids, […] Find the latest version: https://jci.me/110066/pdf Nitrogen Sparing Induced by Leucine Compared with That Induced by its Keto Analogue, a-Ketoisocaproate, in Fasting Obese Man WILLIAM E. MITCH, MACKENZIE WALSER, and DANIEL G. SAPIR, Department of Pharmacology and Experimenital Therapeutics and Department of Medicine, Johns Hopkins University School of Medicine, Baltimitore, Marylanid 21205 A B S T R A C T We measured the effects of seven We conclude that a-ketoisocaproate infusions de- consecutive daily infusions of a-ketoisocaproate (the crease the nitrogen wasting of starvation, whereas leu- a-keto analogue of leucine) or leucine itself on urinary cine, studied under identical conditions, does not. urea and total nitrogen excretion during fasting. Two study protocols were undertaken. In protocol I, subjects INTRODUCTION which underwent three separate 14-d fasts: one during In in vitro experiments, branched-chain amiino acids, 34 mmol/d of leucine were infused on days 1-7; a sec- particularly leucine, have been shown to stimulate pro- ond during which 34 mmol/d of a-ketoisocaproate were in In addition, infused on days 1-7; and a third control fast during tein synthesis skeletal muscle (1, 2). Infusions of a-ketoiso- leucine has been reported to diminish the rate of mus- which no infusions were given. cle protein degradation of the isolated rat hemidia- caproate significantly reduced daily urine urea nitrogen phragm (1), an effect which is apparently attributable to excretion compared with both the control fasts and the acid. In man, in- was infused < This ni- its a-keto analogue, a-ketoisocaproic fasts in which leucine (P 0.001). fusion of valine, isoleucine, and leucine has been trogen-sparing effect of a-ketoisocaproate persisted shown to reduce nitrogen wasting during the im- during days 8-14 even though no further infrisions Finally, it has been were given. Daily urinary urea nitrogen excretion dur- mediate postoperative period (3). did not dif- reported recently that infusion of leucine improved ni- ing fasts when leucine was administered in to de- fer from values observed during control fasts. In proto- trogen balance of fasting individuals addition starved on two occasions for 14 d. creasing glucose turnover and the concentrations of cir- col II, subjects were culating plasma amino acids (4). Thus, leucine and/or During one fast, infusions of 11 mmol/d of a-ketoisocap- its metabolic products appear to have an important roate were given on days 1-7; during the control fast, in of man, as well no infusions were given. Daily urine urea nitrogen regulatory role protein metabolism < on 1-7 and also as the experimental animal. excretion was lower (P 0.001) days In fasting human subjects, infusion of a combination on days 8-14 of the fast during which a-ketoisocaproate was given. of the a-keto analogues of valine, leucine, and isoleu- effect of cine decreases urea nitrogen excretion and improves The nitrogen-sparing a-ketoisocaproate nitrogen balance (5). Comparable experiments with could not be related to changes in circulating levels or insulin in either the three branched-chain amino acids themselves have of amino acids, ketone bodies, not been carried out. To determine whether leucine, protocol. adminiistered as such or as its a-keto analogue is more effective in promoting nitrogen sparing during starva- An Abstract pertaining to this work was published in 1978. Clin. Res. 27: 373A. tion, we have compared the effects of equimolar in- Dr. Mitch's present address is Department of Medicine, frision of leucine and a-ketoisocaproate on urea nitro- Peter Bent Brigham Hospital, Boston, \Massachusetts 02115. gen and total nitrogen excretion of fasting subjects. To Dr. Mitch is the recipient of Research Career Development determine whether the nitrogen-sparing effect of Award AM 00750. Dr. Sapir is the Irving Blum Scholar in infusing the a-keto analogues of leucine, valine, and Renal Disease. Address reprint requests to Dr. Daniel G. Sapir. isoleucine in the previous study (5) was attributable en- Receivedlfor publicatiotn 21 April 1980 and ini revised form tirely to the leucine analogue, we also examined the 8 October 1980. effects on nitrogen excretion of infusing 11 mmol/d of J. Clin. Invest. ©) The American Society for Clinical Investigation, Inc. 0021-9738/81/02/0553110 $1.00 553 Volume 67 February 1981 553-562 a-ketoisocaproate, the quantity administered during RESULTS the previous study. Nitrogen excretion. Before beginning the fasts, the METHODS average daily urea nitrogen excretion of subjects, who Two male and nine female volunteers participated in one or subsequently received 11 or 34 mmol of a-ketoiso- both of two study protocols. Informed consent was obtained for starvation protocols and for infusions of leucine or a-keto- caproate, 34 mmol of leucine, or underwent a control isocaproate. The average age of the subjects was 37 yr (range fast without infusions was not significantly different. 20-61). Their average weight upon entering the first study In Table I are shown mean values of the daily urea was 135 kg (range 74.5-200 kg) and their average height was nitrogen excretion for days 1-7 and 8-14 of the three 163.8 cm. They averaged 222% of ideal body weight (based on 1959 Metropolitan Life Insurance Company Tables; Metro- fasts of protocol I. Tables II-V give the individual data: politan Life Insurance Company, New York). No patient had a the control fast without infusions and the two fasts fasting blood glucose greater than 120 mg/dl or evidence of when either 34 mmol/d of a-ketoisocaproate or 34 abnormal cardiac, thyroid, hepatic, or renal function. During mmol/d of leucine were infused on days 1-7. When the 4 d before beginning a study, the subjects ate diets con- sisting of at least 2,500 kcal/d containing a minimum of 300 these results were analyzed by the technique of analy- g/d of carbohydrate and 75 g/d of protein. They were taking sis of variance, infusions of a-ketoisocaproate were no drugs with the exception of one female subject who took associated with significantly lower urea nitrogen excre- 40 mg/d of megesterol acetate throughout her studies. tion compared with the control fast, both for the initial In protocol I, five females and one male each underwent 7-d period ofa-ketoisocaproate infusion and for the next three separate fasts, each fast lasting 14 d. During the first 7 d'of one fast, they received a daily intravenous infusion of 34 7 d in which no infusions were given. Compared with mmol of sodium a-ketoisocaproate in 250 ml water over a 2-3 the fast during which leucine was infused, a-ketoiso- h period. During the first 7 d of a second fast, they were in- caproate also resulted in a significantly lower rate of fused with 34 mmol of leucine contained in 500 ml of 0.45% urea nitrogen excretion on days 1-7 and 8-14. The dif- NaCl over a 3-h period. During the third fast, which served as a control, they received no infusions. ference is also present if the amount of nitrogen con- In protocol II, four females and two males each fasted for tained in the leucine infusions is subtracted from the two 14-d periods. During the first 7 d of one fast, they received amount of urea nitrogen excretion. In contrast with the a daily intravenous infusion of 11 mmol of sodium a-ketoiso- nitrogen-sparing effect of a-ketoisocaproate, urinary caproate in 150 ml of water administered over a 2-h period. urea nitrogen excretion rates on days 1-7 and 8-14 dur- During the other fast, no infusions were given (control study). In each of the two protocols, 4 wk or more separated each ing the leucine infusion fast were not significantly dif- fast, and the sequence of the study, with respect to the infu- ferent from those of the control fast, even if the quan- sions and the control fast, was varied.