Infusion Of Branched-chain Amino Acids Research Articles

Abomasal infusion of branched-chain amino acids or branched-chain keto-acids alter lactation performance and liver triglycerides in fresh cows

BackgroundDairy cows are at high risk of fatty liver disease in early lactation, but current preventative measures are not always effective. Cows with fatty liver have lower circulating branched-chain amino acid (BCAA) concentrations whereas cows with high circulating BCAA levels have low liver triglyceride (TG). Our objective was to determine the impact of BCAA and their corresponding ketoacids (branched-chain ketoacids, BCKA) on production performance and liver TG accumulation in Holstein cows in the first 3 weeks postpartum.MethodsThirty-six multiparous Holstein cows were used in a randomized block design experiment. Cows were abomasally infused for the first 21 d postpartum with solutions of 1) saline (CON, n = 12); 2) BCA (67 g valine, 50 g leucine, and 34 g isoleucine, n = 12); and 3) BCK (77 g 2-ketovaline calcium salt, 57 g 2-ketoleucine calcium salt, and 39 g 2-ketoisoleucine calcium salt, n = 12). All cows received the same diet. Treatment effects were determined using PROC GLIMMIX in SAS.ResultsNo differences were detected for body weight, body condition score, or dry matter intake averaged over the first 21 d postpartum. Cows receiving BCK had significantly lower liver TG concentrations compared to CON (6.60% vs. 4.77%, standard error of the mean (SEM) 0.49) during the first 3 weeks of lactation. Infusion of BCA increased milk yield (39.5 vs. 35.3 kg/d, SEM 1.8), milk fat yield (2.10 vs. 1.69 kg/d, SEM 0.08), and lactose yield (2.11 vs. 1.67 kg/d, SEM 0.07) compared with CON. Compared to CON, cows receiving BCA had lower plasma glucose (55.0 vs. 59.2 mg/dL, SEM 0.86) but higher β-hydroxybutyrate (9.17 vs. 6.00 mg/dL, SEM 0.80).ConclusionsOverall, BCAA supplementation in this study improved milk production, whereas BCKA supplementation reduced TG accumulation in the liver of fresh cows.Graphical

The Case | Hyperammonemia in a non-cirrhotic hemodialysis patient

A 78-year-old woman presented with recurrent encephalopathy after hemodialysis initiation. Her medical history included end-stage renal disease, congestive heart failure, and cerebral infarction. Her medication included aspirin, losartan, carvedilol, pravastatin, and lansoprazole. Maintenance hemodialysis was initiated because of refractory volume overload. Two days after dialysis initiation, she was noted to be comatose with hyperammonemia (205 μg/dl). Branched-chain amino acid infusion was administered, resulting in improvement of her mental status.

Acute Exposure to Branched-Chain Amino Acids (BCAAs) Impairs Glucose Homeostasis by Promoting Insulin Resistance in Mice

ObjectivesIncreased plasma BCAAs are associated with T2D. Current evidence suggests that high BCAAs are detrimental to insulin action and glucose metabolism. Chronic supplementation of BCAAs results in development of insulin resistance whereas dietary restriction of BCAAs improves insulin sensitivity and glucose uptake. While these studies indicate a detrimental impact of long-term use of BCAAs, whether BCAAs can acutely contribute to glucose dysregulation and insulin resistance is not understood. Therefore, we tested the role of acutely elevated BCAAs in glycemic control and insulin sensitivity. Methods8-week-old C57Bl/6 mice on BCAA or vehicle-treated groups fed a normal chow diet underwent jugular catheter implantation. To determine the acute effects of BCAAs, after 2-hr fast, mice were infused with 150mM BCAAs or 0.9% saline solution through the catheter followed by a frequent glucose monitoring and blood sampling for 30 min for assessment of plasma BCAA and insulin levels. Furthermore, hyperinsulinemic-euglycemic clamps, a gold-standard method for assessing insulin sensitivity, were conducted along with raised plasma BCAAs by continuous infusion. Blood glucose was monitored at every 10 min for 120 min, and a variable rate of glucose was infused to maintain euglycemia. Blood glucose was checked by a hand-held glucometer, and plasma BCAAs and insulin were measured by enzymatic and ELISA assays, respectively. Whole-body insulin sensitivity during clamps was determined by glucose infusion rate (GIR). ResultsJugular infusion of BCAAs, but not vehicle, acutely elevated plasma BCAAs that was maintained for 30 min. Whereas vehicle-treated controls did not display any changes from baseline, BCAA-infused mice acutely raised blood glucose by 20% in spite of increasing and maintaining plasma insulin, indicative of possible insulin resistance. This was supported by a significantly lower GIR, an accurate readout of whole-body insulin sensitivity, in mice with an acute, sustained elevation of plasma BCAAs compared to vehicle-treated mice during hyperinsulinemic-euglycemic clamps. ConclusionsThese findings suggest that BCAAs can acutely disturb glucose homeostasis and insulin action. Future studies will aim to determine the underlying mechanisms for BCAA-induced metabolic dysregulation. Funding SourcesNIH R21 AG069140-01; Diabetes Action Foundation

Intravenous branched chain amino acid infusion is associated with early but ill-sustained recovery of overt hepatic encephalopathy in acute-on-chronic liver failure: a pilot protocol

Background and Aim: Hepatic encephalopathy (HE) in acute-on-chronic liver failure (ACLF) is associated with significant morbidity and mortality. There is limited evidence regarding HE management in patients with ACLF. We conducted a prospective, randomized controlled clinical trial to study the efficacy of intravenous branched chain amino acids (IV-BCAA) with lactulose versus lactulose alone for improvement in HE at 24h, day 3 & day 7. Duration of ICU stay and survival at days 7 and 28 was compared.

Effect of Branched-Chain Amino Acid Infusion on In-Hospital Mortality of Patients With Hepatic Encephalopathy and End-Stage Kidney Disease: A Retrospective Cohort Study Using a National Inpatient Database

Renal failure and hepatic cirrhosis are mutually aggravating factors. However, no specific therapeutic strategies for hepatic encephalopathy (HE) and end-stage kidney disease have been established. The coexistence, with an extremely poor prognosis, makes randomized controlled trials unfeasible. We evaluated whether an infusion of branched-chain amino acids was associated with mortality in patients hospitalized for HE and end-stage kidney disease. Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified patients with HE and end-stage kidney disease who received hemodialysis within 2days of admission from July 2011 to March 2017. We divided the patients into those who received branched-chain amino acid infusion within 2days of admission and those who did not. We conducted analyses using overlap weights based on propensity scores to compare in-hospital mortality between the groups. Sub-group analysis was conducted by stratifying patients by Child-Pugh class. We identified 553 eligible patients, including 503 patients who received branched-chain amino acid infusion and 50 who did not. The patients who received branched-chain amino acid infusion had lower mortality than those who did not (10.2% vs. 20.1%, relative risk 0.51, 95% confidence interval 0.27-0.95). Sub-group analysis showed that branched-chain amino acid infusion was associated with decreased in-hospital mortality in patients with Child-Pugh class C (16.2% vs. 39.0%, relative risk 0.41, 95% confidence interval 0.23-0.76). Branched-chain amino acid infusion may improve the prognosis of HE in patients with end-stage kidney disease, particularly those with lower liver function. Further research is necessary to provide a suitable treatment for HE in patients with end-stage kidney disease.

Outcomes of lactulose plus branched-chain amino acid infusion and lactulose alone for hepatic encephalopathy: A retrospective cohort study using a national inpatient database.

Previous randomized controlled trials of branched-chain amino acid infusion for hepatic encephalopathy involved a small number of patients, and the effectiveness of branched-chain amino acid infusion has not been clarified. We evaluated whether branched-chain amino acid infusion in addition to lactulose treatment was associated with short-term outcomes in a large population of patients. Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified inpatients with hepatic encephalopathy who received lactulose within 2days of admission from July 2011 to March 2017. We divided the patients into those who received branched-chain amino acid infusion within 2days of admission in addition to lactulose treatment and those who did not. We conducted propensity-score inverse probability of treatment weighting analyses to compare in-hospital mortality, consciousness at discharge, in-hospital complications, length of stay, and total hospitalization costs between the groups. We identified 8051 patients with hepatic encephalopathy treated with lactulose, including 7560 patients who received lactulose plus branched-chain amino acid infusion and 491 who received lactulose alone. The lactulose plus branched-chain amino acid infusion group had a significantly lower mortality than the lactulose alone group (9.6% vs. 15.0%, odds ratio 0.60, 95% confidence interval 0.44-0.82). The lactulose plus branched-chain amino acid infusion group also had a lower proportion of patients with impaired mental status at discharge, and lower total hospitalization costs than the lactulose alone group. Branched-chain amino acid infusion together with lactulose may improve the prognosis of hepatic encephalopathy.

Valine Metabolism Is Altered in Obese Adolescents with Polycystic Ovary Syndrome and Relates to Insulin Sensitivity

Polycystic Ovarian Syndrome (PCOS) is common and associated with insulin resistance (IR). The mechanism of IR in PCOS is unclear, likely multifactorial, and may relate to branched-chain amino acids (BCAA) and mitochondrial metabolism. We quantitated differences in BCAA and BCAA breakdown product short chain (C3-C5) acylcarnitines in response to hyperinsulinemia in obese girls with and without PCOS, and assessed the relationship to IR and hyperandrogenism. Obese girls with PCOS [n=15, 14.5 ± 1.6 years, BMI %ile 98.5 ± 1.0] and without PCOS [n=6; 13.2 ± 1.2 years, BMI %ile 98.0 ± 1.1] were studied. Insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp and a testosterone panel obtained. Nontargeted metabolomics were performed in plasma samples obtained before and after the clamp. T-tests were used for group comparisons, with the Benjamini-Hochberg procedure (false discovery rate (FDR) set to 0.05) to control for multiple testing. Spearman’s correlation coefficient was calculated for BCAA vs. glucose infusion rate (GIR) and free androgen index (FAI). The groups had similar demographic, physical activity, diet attributes, HbA1c and lipids. Girls with PCOS had higher FAI and worse IR than controls. FAI related negatively to short chain acylcarnitines C4 (r = -0.74, p=0.0002) and C3 (r=-0.60, p =0.007). During hyperinsulinemia, girls with PCOS had higher valine (FDR-adjusted p=0.04) and lower valine breakdown product C4 butyrylcarnitine (FDR-adjusted p=0.01). End-clamp valine correlated with GIR (r= -0.59, p= 0.006) as did C4 butyrylcarnitine (r=0.44, p=0.04). Under hyperinsulinemia, a metabolomic signature was revealed in obese girls with PCOS, distinct from that in uncomplicated obesity. Valine was higher in girls with PCOS, while C4 acylcarnitine, its direct mitochondrial metabolite, was lower. Further work is needed to determine if BCAA metabolism is a modifiable target to improve insulin sensitivity or simply a useful biomarker. Disclosure A. Carreau: None. H. Rahat: None. Y. Garcia Reyes: None. L. Pyle: None. K.J. Nadeau: None. M. Cree-Green: None.

Acute hyperammonemic encephalopathy after fluoropyrimidine-based chemotherapy: A case series and review of the literature.

Acute hyperammonemic encephalopathy induced by fluoropyrimidines (FPs) is a rare complication. Its pathophysiology remains unclear, especially given the currently used regimens, including intermediate-doses of 5-fluorouracil (5-FU) or oral FP agents. We aimed to characterize the clinical manifestations in cancer patients who developed hyperammonemic encephalopathy after receiving FP-based chemotherapy.We retrospectively reviewed 1786 patients with gastrointestinal or primary-unknown cancer who received FP-based regimens between 2007 and 2012. Eleven patients (0.6%) developed acute hyperammonemic encephalopathy. The incidence according to the administered anticancer drugs were as follows: 5-FU (8 of 1176, 0.7%), S-1 (1 of 679, 0.1%), capecitabine (2 of 225, 0.9%), and tegafur-uracil (UFT) (0 of 39, 0%). Ten patients (90.9%) had at least 1 aggravating factor, including infection, dehydration, constipation, renal dysfunction, and muscle loss. All the 10 patients met the definition of sarcopenia. Median time to the onset of hyperammonemic encephalopathy in the cycle was 3 days (range: 2–21). Three patients (27.3%) developed encephalopathy during the first cycle of the regimen and the remaining 8 patients during the second or more cycles. Seven patients (63.6%) had received at least 1 other FP-containing regimen before without episodes of encephalopathy.All patients recovered soon after immediate discontinuation of chemotherapy and supportive therapies, such as hydration, infusion of branched-chain amino acids, and oral lactulose intake, with a median time to recovery of 2 days (range: <1–7). Four patients (36.4%) received FP-based regimens after improvement of symptoms; 3 patients were successfully managed with dose reduction, and 1 patient, who had developed encephalopathy due to S-1 monotherapy, received modified FOLFOX-6 therapy without encephalopathy later.FP-associated acute hyperammonemic encephalopathy is extremely rare, but a possible event at any time and even during the administration of oral FP agents. Particular attention is warranted when giving FP-based therapy for patients with aggravating factors, such as sarcopenia. This complication can be properly managed with early detection.

Intraoperative infusion of branched-chain amino acids in patients undergoing gastrointestinal tumor surgery.

BackgroundThe purpose of this study is to investigate the effects of intraoperative infusion of branched-chain amino acids (BCAA) in patients undergoing gastrointestinal tumor surgery.MethodsSixty-one patients with gastrointestinal tumors undergoing gastrointestinal surgery were enrolled and randomly assigned to receive an intraoperative infusion of 3-compound BCAA solution (N = 20), amino acids (AA) solution (N = 21), or normal saline (NS) (N = 20). Nasopharyngeal temperature, blood glucose (BG), plasma insulin, and blood free fatty acids (FFA) concentrations were measured at 30 min before and 10 min after induction (T0,T1), 30 min and 2 h after skin incision (T2,T3), and 1 h after tracheal extubation (T4). Intensity of shivering and pain was accessed at 1 h after extubation.ResultsThe temperature in the BCAA and AA group was significantly higher than that in the NS group at T4 (P = 0.014 and 0.033). The incidence of shivering in the BCAA and AA group was significantly lower than in the NS group (P = 0.027 and 0.012). BG increased in AA group at T3 and T4 (P = 0.001 and 0.045). The plasma insulin concentration increased in the BCAA and AA group from T1 to T3. The plasma FFA concentrations in the BCAA group were lower than in the AA and NS group from T2 to T4.ConclusionsIntraoperative BCAA and AA infusion alleviated postoperative hypothermia and shivering. BCAA infusion also inhibited fat mobilization, without adversely affecting blood glucose.Trial registrationChiCTR-TRC-14004668Electronic supplementary materialThe online version of this article (doi:10.1186/s12957-015-0751-y) contains supplementary material, which is available to authorized users.

Rapid determination of branched chain amino acids in human blood plasma by pressure-assisted capillary electrophoresis with contactless conductivity detection.

A CE method with contactless conductivity detection has been developed for the clinical determination of the branched chain amino acids (BCAAs) valine, isoleucine and leucine in human blood plasma. The CE separation was performed in an optimised BGE with composition of 3.2 M acetic acid in 20% v/v methanol, pH 2.0. The achieved separation time was 125 s when using a capillary with an effective length of 14.7 cm, electric field intensity of 0.96 kV/cm and simultaneous application of a hydrodynamic pressure of 50 mbar. The separation efficiency in blood plasma equalled 461 000 theoretical plates/m for valine and isoleucine, and 455 000 theoretical plates/m for leucine; the detection limits are equal to 0.4 μM for all three amino acids. The RSD values for repeatability of the migration time equalled 0.1% for measurements during a single day and 0.3% for measurements on different days; the RSD values for repeatability of the peak areas equalled 2.3-2.6% for measurements during a single day and 2.7-4.6% for measurements on different days. It followed from the performed tests that the plasmatic levels of BCAAs attain a maximum 60 min after intravenous application of an infusion of BCAAs.

Effects of Branched-Chain Amino Acid Infusions on Liver Regeneration and Plasma Amino Acid Patterns in Partially Hepatectomized Rats

Even though solutions of high branched-chain amino acids (BCAAs) are known to be beneficial to patients with hepatic encephalopathy, data on the effects of BCAA on liver regeneration are limited. Two groups of young adult rats were utilized in this study: standard total parenteral nutrition solutions were administered to group SS (22.59% of BCAAs in total amino acids) and solutions high in BCAAs were given to group HS (34.44% of BCAAs). After 2 days of infusion, 70% partial hepatectomy was performed and the TPN infusions were continued for another 3 days. Liver regeneration was estimated and changes in serum amino acid patterns were determined 3 days after hepatectomy. Thymidine incorporation into liver DNA, in group HS was significantly higher than that in group SS (378±56 vs. 324±38, p=0.032). In group SS, the total concentration of BCAAs decreased (165.11±39.90mg/dL and 145.56±29.53mg/dL, p=0.014) over the experimental period, whereas that of aromatic amino acids (AAAs) increased (226.56±36.5mg/dL and 247.00±48.36mg/dL, p=0.104). However, group HS showed no changes in BCAA or AAA sums over the experimental period. After major hepatectomy, supplementation with high BCAAs helps not only to maintain a stable plasma BCAA/AAA ratio, but also promotes liver regeneration.

Effects of branched chain amino acids infusion on whole‐body plasma glucose disposal: a pilot study

The physiological importance of the inhibition of muscle glucose uptake simultaneously with the stimulation of muscle protein synthesis, when the plasma concentrations of both glucose and amino acids are elevated, as in the fed state, is not clear. We tested the hypothesis that a branched chain amino acids (BCAA) infusion, known to increase protein accumulation, impairs insulin‐stimulated whole‐body glucose disposal. Two groups of young, healthy males and females (n = 5/group) were studied in the postabsorptive state (3 hours) and during a 3 hour euglycemic, hyperinsulinemic (40 mIU/m‐2/min) clamp. The control group (BAS) was infused with BCAA sufficient to maintain plasma BCAA at the basal concentrations during the clamp, while the other group (HI) received a six hour BCAA infusion (1.66 umol/kg/min) to increase BCAA 4‐fold. Subjects in both groups were insulin sensitive as determined by the HOMA index. Glucose disposal rate during the clamp, as determined by 6,6‐d2 glucose infusion and adjusted to the prevailing plasma insulin concentrations, was lower in the HI group (0.53 umol/kg/min +/− 0.05 vs. 0.93 umol/kg/min +/− 0.11; HI vs. BAS; p=0.005). We conclude that increased concentrations of plasma BCAA decrease whole‐body glucose disposal in healthy humans. This protocol will allow us to study the role of plasma amino acids in modulating glucose uptake in skeletal muscle in humans.

The Effect of Branched Chain Amino Acids on Skeletal Muscle Mitochondrial Function in Young and Elderly Adults

A reduction in maximal mitochondrial ATP production rate (MAPR) and mitochondrial DNA (mtDNA) abundance occurs with age in association with muscle weakness and reduced endurance in elderly people. Branched chain amino acids (BCAA) have been extensively used to improve physical performance. The objective was to determine whether an 8-h infusion of BCAA enhances MAPR equally in healthy young and elderly adults. Using a crossover study design, we compared the effect BCAA vs. saline infusion in 12 young (23.0 +/- 0.8 yr) and 12 elderly (70.7 +/- 1.1 yr) participants matched for sex and body mass index. Skeletal muscle MAPR and mtDNA abundance were measured in muscle biopsy samples obtained before and at the end of the 8-h infusion. In young participants, MAPR with the substrates glutamate plus malate (supplying electrons to complex I) and succinate plus rotenone (complex II) increased in response to BCAA infusion, relative to a decline in MAPR in response to the saline infusion. In contrast, MAPR was unaffected by BCAA infusion in the elderly participants. Moreover, mtDNA abundance was lower in the elderly compared with the young participants but was unaffected by the BCAA infusion. Insulin and C-peptide concentrations declined over time during the saline infusion, but these declines were prevented by the BCAA infusion. BCAA increased skeletal muscle MAPR in the young participants in comparison with saline, but this effect was not seen in the elderly participants indicating, that unlike in the young, BCAA does not increase muscle mitochondrial function in the elderly.

“Acquired” hepatocerebral degeneration in a patient heterozygote carrier for a novel mutation in ATP7B gene

Acquired hepatocerebral degeneration (AHD) is a rare type of hepatic encephalopathy characterized by neuropsychiatric symptomatology, and peculiar neuroradiologic findings, without the clinical evidence of Wilson’s disease (WD). We studied a patient with AHD responsive to penicillamine who was heterozygote carrier for a novel mutation in the ATP7B gene, and discussed the possible role of the mutation in facilitating the appearance of the syndrome. A 37-year-old man with liver cirrhosis related to chronic hepatitis C was admitted because of progressive consciousness impairment. Family history was negative for WD. Ammoniemia was 176 lmol/L (NR, 9–33 lmol/L); total bilirubin 1.71 mg/dL (NR, 0.2–1.3 mg/dL); serum albumin 2.6 g/dL (NR, 3.3–5 g/dL); AST 62 U/L (NR, 10–45 U/L). Electroencephalogram disclosed diffuse slow wave activity. After rifaximin, lactulose, and branched chain amino acid infusion, his arousal state went back normal in about 12 hours, and ammonia levels decreased to 94 lmol/L.

Simultaneous Infusion of Glutamine and Branched‐Chain Amino Acids (BCAA) to Septic Rats Does Not Have More Favorable Effect on Protein Synthesis in Muscle, Liver, and Small Intestine Than Separate Infusions

Glutamine and branched-chain amino acids (BCAA; valine, leucine, and isoleucine) are used as nutrition supplements in the treatment of proteocatabolic illness. We hypothesized that simultaneous administration of BCAA and glutamine affects protein metabolism more significantly than separate administration. In the present study, we evaluated their effect on protein synthesis in skeletal muscle, liver, and jejunum of septic rats. Twenty-four hours after induction of sepsis by subcutaneous injection of turpentine, the rats were infused for 6 hours with 5 mL of 1.75% glutamine, 1.75% BCAA, 1.75% glutamine+BCAA, or saline solution. The control group consisted of intact rats infused with saline. Protein synthesis was measured at the end of infusion by a "flooding method" with [3,4,5-(3)H]phenylalanine. In turpentine-treated animals, we observed a decrease in glutamine concentration in blood plasma and skeletal muscle, a decrease in BCAA concentration in liver and jejunum, and a decrease in protein synthesis in all tissues. Glutamine or glutamine+BCAA infusion increased glutamine concentration in plasma and muscle and stimulated protein synthesis in the liver. The BCAA infusion enhanced concentrations of BCAA in plasma and tissues, but the effect of BCAA on protein synthesis was insignificant. Synergistic effect of simultaneous infusion of glutamine and BCAA on protein synthesis was not observed. We conclude that glutamine infusion to rats with septic injury may significantly improve impaired protein synthesis in the liver and that there is no synergistic effect of glutamine and BCAA infusion on protein synthesis in skeletal muscle, liver, and jejunum.

Interrelationship between Physical Activity and Branched-Chain Amino Acids

Some athletes can have quite high intakes of branched-chain amino acids (BCAAs) because of their high energy and protein intakes and also because they consume protein supplements, solutions of protein hydrolysates, and free amino acids. The requirement for protein may actually be higher in endurance athletes than in sedentary individuals because some amino acids, including the BCAAs, are oxidized in increased amounts during exercise compared with rest, and they must therefore be replenished by the diet. In the late 1970s, BCAAs were suggested to be the third fuel for skeletal muscle after carbohydrate and fat. However, the majority of later studies, using various exercise and treatment designs and several forms of administration of BCAAs (infusion, oral, and with and without carbohydrates), have failed to find a performance-enhancing effect. No valid scientific evidence supports the commercial claims that orally ingested BCAAs have an anticatabolic effect during and after exercise in humans or that BCAA supplements may accelerate the repair of muscle damage after exercise. The recommended protein intakes for athletes (1.2 to 1.8 g . kg body mass(-1) . d(-1)) do not seem to be harmful. Acute intakes of BCAA supplements of about 10-30 g/d seem to be without ill effect. However, the suggested reasons for taking such supplements have not received much support from well-controlled scientific studies.

Effect of plasma insulin and branched-chain amino acids on skeletal muscle protein synthesis in fasted lambs.

The increase in fractional rate of protein synthesis (Ks) in the skeletal muscle of growing rats during the transition from fasted to fed state has been explained by the synergistic action of a rise in plasma insulin and branched-chain amino acids (BCAA). Since growing lambs also exhibit an increase in Ks with level of feed intake, the objective of the present study was to determine if this synergistic relationship between insulin and BCAA also occurs in ruminant animals. Six 30 kg fasted (72 h) lambs (8 months of age) received each of four treatments, which were based on continuous infusion into the jugular vein for 6 h of: (1) saline (155 mmol NaCl/l); (2) a mixture of BCAA (0.778 micromol leucine, 0.640 micromol isoleucine and 0.693 micromol valine/min.kg); (3) 18.7 micromol glucose/min.kg (to induce endogenous insulin secretion); (4) co-infusion of BCAA and glucose. Within each period all animals received the same isotope of phenylalanine (Phe) as follows: (1) L-[1-13C]Phe; (2) L-phenyl-[ring 2H5]-alanine; (3) L-[15N]Phe; (4) L-[ring 2,6-3H]Phe. Blood was sampled serially during infusions to measure plasma concentrations of insulin, glucose and amino acids, and plasma free Phe isotopic activity; biopsies were taken 6 h after the beginning of infusions to determine Ks in m. longissimus dorsi and vastus muscle. Compared with control (saline-infused) lambs, Ks was increased by an average of 40% at the end of glucose infusion, but this effect was not statistically significant in either of the muscles sampled. BCAA infusion, alone or in combination with glucose, also had no significant effect on Ks compared with control sheep. Ks was approximately 60% greater for vastus muscle than for m. longissimus dorsi (P<0.01), regardless of treatment. It is concluded that there are signals other than insulin and BCAA that are responsible for the feed-induced increase in Ks in muscle of growing ruminant animals.

Improvement of regional cerebral blood flow after treatment with branched-chain amino acid solutions in patients with cirrhosis

Objective The administration of solutions rich in branched-chain amino acids leads to mental recovery from acute hepatic encephalopathy in patients with liver cirrhosis. However, the mechanism of action of branchedchain amino acids remains unclear. The purpose of this study was to evaluate the effect of intravenous infusion of branched-chain amino acids on brain perfusion in patients with liver cirrhosis. Methods Single photon emission computed tomography scans were performed in 14 patients with liver cirrhosis before and after the administration of branched-chain amino acids in a single-day split-dose protocol. The per cent change in regional brain perfusion was calculated in high frontal, parietal, temporal, occipital lobes and cerebellum. Thereafter, statistical parametric mapping was performed to identify brain regions with abnormal cerebral perfusion. Results Intravenous infusion of solutions enriched with branched-chain amino acids induced a 13-20% increase in regional cerebral blood flow. Cirrhotic patients had regions of significant hypoperfusion, as determined by statistical parametric mapping, in the left superior parietal and posterior cingulate as compared to the control group. This hypoperfusion of parietal and cingulate regions was not detected after treatment with solutions of branchedchain amino acids. Conclusions The results of the present study suggest that administration of solutions enriched with branched-chain amino acids improves cerebral perfusion in patients with cirrhosis.

Effects of branched-chain amino acids on placental amino acid transfer and insulin and glucagon release in the ovine fetus

Objective: Competition for placental amino acid transporters can affect the fetal supply of amino acids. Specifically, the branched-chain amino acids—isoleucine, leucine, and valine—may inhibit the transfer of other amino acids. This study was undertaken to determine the effect of branched-chain amino acids on the umbilical uptake of amino acids. Study Design: Six late-gestation ewes were infused sequentially for 2 hours with 3 different mixtures of amino acids: (1) one that was comparable to commercial parenteral nutrition preparations, (2) the same solution without branched-chain amino acids, and (3) branched-chain amino acids alone. Maternal and fetal blood samples were collected simultaneously for the determination of uterine and umbilical uptake values of amino acids, and for concentrations of arterial insulin, glucagon, glucose, and lactate before (control) and during (experimental) infusion. Results: Umbilical uptake of branched-chain amino acids increased significantly when they were present in the infusates. The fetal uptake of several other amino acids could be increased by increasing their maternal concentrations. Inhibition of umbilical uptake by branched-chain amino acids could be shown for threonine and methionine. The infusion of branched-chain amino acids alone did not affect maternal and fetal insulin or glucagon concentrations. Conclusions: In late-gestation sheep, an increase in maternal plasma concentration of branched-chain amino acids led to increased branched-chain amino acid umbilical uptake, but branched-chain amino acids can also inhibit the transport of some amino acids to the fetus. Changes in fetal plasma concentration and uptake of branched-chain amino acid appear to have no significant effect on fetal insulin or glucagon. (Am J Obstet Gynecol 2001;185:487-95.)

Branched chain amino acids activate messenger ribonucleic acid translation regulatory proteins in human skeletal muscle, and glucocorticoids blunt this action.

Branched chain amino acids (BCAA) are particularly effective anabolic agents. Recent in vitro studies suggest that amino acids, particularly leucine, activate a signaling pathway that enhances messenger ribonucleic acid translation and protein synthesis. The physiological relevance of these findings to normal human physiology is uncertain. We examined the effects of BCAA on the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (eIF4E-BP1) and ribosomal protein S6 kinase (p70(S6K)) in skeletal muscle of seven healthy volunteers. We simultaneously examined whether BCAA affect urinary nitrogen excretion and forearm skeletal muscle protein turnover and whether the catabolic action of glucocorticoids could be mediated in part by inhibition of the action of BCAA on the protein synthetic apparatus. BCAA infusion decreased urinary nitrogen excretion (P < 0.02), whole body phenylalanine flux (P < 0.02), plasma phenylalanine concentration (P < 0.001), and improved forearm phenylalanine balance (P = 0.03). BCAA also increased the phosphorylation of both eIF4E-BP1 (P < 0.02) and p70(S6K) (P < 0.03), consistent with an action to activate the protein synthetic apparatus. Dexamethasone increased plasma phenylalanine concentration (P < 0.001), prevented the BCAA-induced anabolic shift in forearm protein balance, and inhibited their action on the phosphorylation of p70(S6K). We conclude that in human skeletal muscle BCAA act directly as nutrient signals to activate messenger ribonucleic acid translation and potentiate protein synthesis. Glucocorticoids interfere with this action, and that may be part of the mechanism by which they promote net protein catabolism in muscle.