-
1.
Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease.
Harrison, SA, Baum, SJ, Gunn, NT, Younes, ZH, Kohli, A, Patil, R, Koziel, MJ, Chera, H, Zhao, J, Chakravarthy, MV
The American journal of gastroenterology. 2021;(12):2399-2409
-
-
Free full text
-
Abstract
INTRODUCTION AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD. METHODS In this multicenter, 16-week, placebo-controlled, single-blind, randomized clinical study in subjects with NAFLD stratified by type 2 diabetes, AXA1125 24 g, AXA1957 13.5 g or 20.3 g, or placebo was administered twice daily. Key metabolism (MRI-proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR]) and fibroinflammation markers (alanine aminotransferase [ALT], corrected T1 [cT1], keratin-18 [K-18] M65, and N-terminal type III collagen propeptide [Pro-C3]) were evaluated. Safety outcomes included adverse events and standard laboratory assessments. RESULTS Baseline characteristics of the 102 enrolled subjects, including 40 with type 2 diabetes, were consistent with presumed nonalcoholic steatohepatitis. AXA1125 showed consistently greater biologic activity than AXA1957 or placebo. Week 16 changes from baseline with AXA1125 vs placebo: MRI-PDFF -22.9% vs -5.7%, HOMA-IR -4.4 vs +0.7, ALT -21.9% vs -7.2%, K-18 M65 -13.6% vs +20.1%, cT1 -69.6 vs +18.3 ms (P < 0.05), and Pro-C3 -13.6% vs -3.6%. Week 16 changes from baseline with AXA1957 20.3 g: MRI-PDFF -8.1%, HOMA-IR +8.4, ALT -20.7%, K-18 M65 6.6%, cT1 -34.7 ms, and Pro-C3 -15.6%. A greater proportion of subjects treated with AXA1125 achieved clinically relevant thresholds: ≥30% MRI-PDFF, ≥17-IU/L ALT, and ≥80-ms cT1 reductions at week 16. Study products were safe and well tolerated with stable lipid and weight profiles. DISCUSSION Both compositions showed multitargeted activity on relevant NAFLD pathways. AXA1125 demonstrated the greatest activity over 16 weeks, warranting continued clinical investigation in nonalcoholic steatohepatitis subjects.
-
2.
Effects of adequate dietary protein with whey protein, leucine, and vitamin D supplementation on sarcopenia in older adults: An open-label, parallel-group study.
Lin, CC, Shih, MH, Chen, CD, Yeh, SL
Clinical nutrition (Edinburgh, Scotland). 2021;(3):1323-1329
Abstract
BACKGROUND & AIMS Sarcopenia is defined as a syndrome characterized by declines in skeletal muscle mass and strength or an alteration in physical function. Although some studies showed nutritional supplementation alone might have health benefits for older sarcopenic patients, their results were inconsistent and remain controversial. The objective of this study was to evaluate if a diet with high protein supplementation (Supp) can lead to better improvement than additional protein intake via dietary counseling (Diet) in maintaining the muscle mass and strength among sarcopenic elders. METHODS This was an open-label, parallel-group (Supp vs. Diet) trial. In total, 56 sarcopenic elders completed this study. All subjects were advised to achieve adequate protein intake (1.2-1.5 g/kg body weight/day). This amount of protein is recommended for the elderly and is thought to prevent or retard muscle loss due to aging. The diet group (n = 28) was recommended to consume an ordinary protein-rich diet via counselling whereas the Supp group (n = 28) received a vitamin D- and leucine-enriched whey protein supplement for 12 weeks. The appendicular muscle mass index (AMMI), handgrip strength, gait speed, and calorie and macronutrients intake were evaluated after 4 and 12 weeks of the diet intervention. RESULTS Total energy and protein intake increased in both groups. The Supp group had higher intake than the Diet group. The AMMI increased in both groups, and handgrip strength improved in the Diet group. However, no significant differences in AMMI or handgrip strength were found between the two groups. Compared to the Diet group, the Supp group had better improvement in gait speed after 12 weeks of the supplement intervention especially in subjects younger than 75 years. CONCLUSIONS The AMMI can be improved as long as sufficient protein is consumed (1.2-1.5 g/kg body weight/day) in sarcopenic elders. Nutritional supplement allows the sarcopenic elderly to more conveniently meet their protein requirements. Supplementation with whey protein and vitamin D can further improve gait speed in elderly sarcopenic subjects, especially in the "younger" age group. TRIAL REGISTRATION ClinicalTrials.gov NCT03860194.
-
3.
Effects of resistance training using elastic bands on muscle strength with or without a leucine supplement for 48 weeks in elderly patients with type 2 diabetes.
Yamamoto, Y, Nagai, Y, Kawanabe, S, Hishida, Y, Hiraki, K, Sone, M, Tanaka, Y
Endocrine journal. 2021;(3):291-298
-
-
Free full text
-
Abstract
Type 2 diabetes is associated with sarcopenia. Resistance training and appropriate nutritional therapy are reported to be effective for muscle strength and mass. This study aimed to evaluate the effect of resistance training using elastic bands at home combined with a leucine-rich amino acid supplement on muscle strength, physical function, and muscle mass in elderly type 2 diabetes. We conducted a 48-week prospective single-center randomized controlled trial in 60 patients who were randomly allocated to one of three groups: control (C), resistance exercise (R), and resistance exercise plus supplement (RL). R and RL groups performed daily bodyweight resistance training with elastic bands exercises at home, and the RL group also took 6 g of a leucine-rich amino acid supplement daily. Knee extension strength (muscle strength), grip strength, usual gait speed (physical function), muscle mass, and cognitive function were assessed at 0 and 48 weeks. Although the change in knee extension strength from baseline was significantly increased by 6.4 Nm (95% CI 1.0, 11.7) in the RL group (p = 0.036), no significant difference was observed among the three groups (p = 0.090). Physical function, muscle mass, and cognitive function also had no changes during the study period among the three groups. No additive effect of a leucine-rich amino acid supplement on muscle strength or mass was observed. Although a post hoc analysis comparing with or without resistance training (C group vs. R + RL group) found that knee extension strength was significantly increased (p = 0.028), and cognitive decline was less (p = 0.046) than in the C group.
-
4.
Comparative Effects of the Branched-Chain Amino Acids, Leucine, Isoleucine and Valine, on Gastric Emptying, Plasma Glucose, C-Peptide and Glucagon in Healthy Men.
Elovaris, RA, Bitarafan, V, Agah, S, Ullrich, SS, Lange, K, Horowitz, M, Feinle-Bisset, C
Nutrients. 2021;(5)
Abstract
(1) Background: Whey protein lowers postprandial blood glucose in health and type 2 diabetes, by stimulating insulin and incretin hormone secretion and slowing gastric emptying. The branched-chain amino acids, leucine, isoleucine and valine, abundant in whey, may mediate the glucoregulatory effects of whey. We investigated the comparative effects of intragastric administration of leucine, isoleucine and valine on the plasma glucose, C-peptide and glucagon responses to and gastric emptying of a mixed-nutrient drink in healthy men. (2) Methods: 15 healthy men (27 ± 3 y) received, on four separate occasions, in double-blind, randomised fashion, either 10 g of leucine, 10 g of isoleucine, 10 g of valine or control, intragastrically, 30 min before a mixed-nutrient drink. Plasma glucose, C-peptide and glucagon concentrations were measured before, and for 2 h following, the drink. Gastric emptying of the drink was quantified using 13C-acetate breath-testing. (3) Results: Amino acids alone did not affect plasma glucose or C-peptide, while isoleucine and valine, but not leucine, stimulated glucagon (p < 0.05), compared with control. After the drink, isoleucine and leucine reduced peak plasma glucose compared with both control and valine (all p < 0.05). Neither amino acid affected early (t = 0-30 min) postprandial C-peptide or glucagon. While there was no effect on overall gastric emptying, plasma glucose at t = 30 min correlated with early gastric emptying (p < 0.05). (4) Conclusion: In healthy individuals, leucine and isoleucine lower postprandial blood glucose, at least in part by slowing gastric emptying, while valine does not appear to have an effect, possibly due to glucagon stimulation.
-
5.
Prognostic value of leucine/phenylalanine ratio as an amino acid profile of heart failure.
Hiraiwa, H, Okumura, T, Kondo, T, Kato, T, Kazama, S, Kimura, Y, Ishihara, T, Iwata, E, Shimojo, M, Kondo, S, et al
Heart and vessels. 2021;(7):965-977
Abstract
Heart failure (HF) causes a hypercatabolic state that enhances the catabolic activity of branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in the heart and skeletal muscles and reduces protein synthesis in the liver. Consequently, free plasma aromatic amino acids (AAA, tyrosine and phenylalanine) are increased. To date, we have reported the prognostic value of the BCAA/AAA ratio (Fischer's ratio) in patients with HF. However, the leucine/phenylalanine ratio, which is a simpler index than the Fischer's ratio, has not been examined. Therefore, the prognostic value of the leucine/phenylalanine ratio in patients with HF was investigated. Overall 157 consecutive patients hospitalized for worsening HF (81 men, median age 78 years) were enrolled in the study. Plasma amino acid levels were measured when the patients were stabilized at discharge. Cardiac events were defined as a composite of cardiac death and hospitalization for worsening HF. A total of 46 cardiac events occurred during the median follow-up period of 238 (interquartile range 93-365) days. The median leucine/phenylalanine ratio was significantly lower in patients with cardiac events than in those without cardiac events (1.4 vs. 1.8, P < 0.001). The best cutoff value of the leucine/phenylalanine ratio was determined as 1.7 in the receiver operating characteristic (ROC) curve for cardiac events. Following a Kaplan-Meier survival analysis, the low group (leucine/phenylalanine ratio < 1.7, n = 72) had more cardiac events than the high group (leucine/phenylalanine ratio ≥ 1.7, n = 85) (log-rank, P < 0.001). Multivariate Cox proportional hazards regression analysis showed that the leucine/phenylalanine ratio was an independent predictor of cardiac events. Furthermore, on comparing the prognostic values for cardiac events based on ROC curves of leucine levels, BCAA levels, Fischer's ratio, and leucine/phenylalanine ratio, the leucine/phenylalanine ratio was the most accurate in predicting future cardiac events (area under the curve 0.763,; sensitivity 0.783,; specificity 0.676,; P < 0.001). The leucine/phenylalanine ratio could be a useful predictor of future cardiac events in patients with HF, reflecting an imbalance in amino acid metabolism.
-
6.
Leucine Supplementation Increases Muscle Strength and Volume, Reduces Inflammation, and Affects Wellbeing in Adults and Adolescents with Cerebral Palsy.
Theis, N, Brown, MA, Wood, P, Waldron, M
The Journal of nutrition. 2021;(1):59-64
-
-
Free full text
-
Abstract
BACKGROUND Spastic cerebral palsy (CP) is characterized by muscle weakness owing, in part, to a blunted muscle protein synthetic response. This might be normalized by long-term leucine supplementation. OBJECTIVES The study assessed the effects of 10 wk leucine supplementation in adolescents and adults with CP. METHODS The study was a single-center randomized controlled trial. Twenty-four participants were randomly assigned to a control group (n = 12) or a leucine group (n = 12). l-Leucine (192 mg/kg body mass) was dissolved in water and administered daily for 10 wk. The primary outcome measures of elbow flexor muscle strength and muscle volume (measured by 3D ultrasound technique) and inflammation [C-reactive protein (CRP) concentration] were assessed before and after the 10 wk, alongside the secondary outcomes of body composition (measured by CP-specific skinfold assessment), metabolic rate (measured by indirect calorimetry), and wellbeing (measured by a self-reported daily questionnaire). Data were compared via a series of 2-factor mixed ANOVAs. RESULTS Twenty-one participants completed the intervention (control group: n = 11, mean ± SD age: 18.3 ± 2.8 y, body mass: 48.8 ± 11.9 kg, 45% male; leucine group: n = 10, age: 18.6 ± 1.7 y, body mass: 58.3 ± 20.2 kg, 70% male). After 10 wk, there was a 25.4% increase in strength (P = 0.019) and a 3.6% increase in muscle volume (P = 0.001) in the leucine group, with no changes in the control group. This was accompanied by a 59.1% reduction in CRP (P = 0.045) and improved perceptions of wellbeing (P = 0.006) in the leucine group. No changes in metabolism or body composition were observed in either group (P > 0.05). CONCLUSIONS Improvements in muscle strength and volume with leucine supplementation might provide important functional changes for adults and adolescents with CP and could be partly explained by reduced inflammation. The improved wellbeing highlights its capacity to improve the quality of daily living. This trial was registered at clinicaltrials.gov as NCT03668548.
-
7.
Leucine-Enriched Protein Supplementation Increases Lean Body Mass in Healthy Korean Adults Aged 50 Years and Older: A Randomized, Double-Blind, Placebo-Controlled Trial.
Kang, Y, Kim, N, Choi, YJ, Lee, Y, Yun, J, Park, SJ, Park, HS, Chung, YS, Park, YK
Nutrients. 2020;(6)
Abstract
Early prevention of sarcopenia could be an important strategy for muscle retention, but most studies have focused on subjects aged 65 or older. Therefore, in this study we investigated the effects of leucine-enriched protein supplementation on muscle condition in a sample including late middle-aged adults. A 12-week intervention was performed for 120 healthy community-dwelling adults by providing either leucine-enriched protein supplement [leucine 3 g, protein mixture (casein 50% + whey 40% + soy 10%) 17 g, vitamin D 800IU (20 µg), calcium 300 mg, fat 1.1 g, carbohydrate 2.5 g] or isocaloric carbohydrate supplement twice per day. Appendicular skeletal muscle mass index (ASMI) and lean body mass (LBM) were measured by dual-energy X-ray absorptiometry. A total of 111 participants completed the study, with a dropout rate of 9.2%. LBM normalized by height and body weight (LBM/Wt) was significantly increased (p < 0.001) in the intervention group (0 wk: 633.9 ± 8.5 vs. 12 wk 636.9 ± 8.4 in the intervention group; 0 wk: 638.6 ± 8.3 vs. 12 wk: 632.9 ± 8.1 in the control group). In subgroup analyses, significant differences remained only in subjects between 50 and 64 years of age. We concluded that leucine-enriched protein supplementation can have beneficial effects by preventing muscle loss, mainly for late middle-aged adults.
-
8.
Effect of a leucine-rich supplement in combination with nutrition and physical exercise in advanced cancer patients: A randomized controlled intervention trial.
Storck, LJ, Ruehlin, M, Gaeumann, S, Gisi, D, Schmocker, M, Meffert, PJ, Imoberdorf, R, Pless, M, Ballmer, PE
Clinical nutrition (Edinburgh, Scotland). 2020;(12):3637-3644
Abstract
BACKGROUND & AIMS Branched-chain amino acids and specifically leucine stimulate protein synthesis and may overcome an anabolic resistance in malnourished and cachectic cancer patients. Therefore, we hypothesized that the addition of a leucine-rich supplement to a multimodal therapy improves physical function in advanced cancer patients. METHODS This single center, randomized trial examined a multimodal therapy over 12 weeks in patients with advanced cancer. The intervention group received a leucine-rich supplement in combination with a nutrition and physical exercise program. Patients in the control group received standard care. Primary endpoint was physical function measured with the short physical performance battery (SPPB). Secondary endpoints were further physical performance tests, nutritional status, dietary intake, fatigue, quality of life (QoL) and clinical course. All parameters were evaluated at baseline, after three and at six months. RESULTS 23 women and 29 men with an average age of 63.1 ± 10.3 (range 30-81) years and BMI of 25.4 ± 4.7 kg/m2 were randomized either to the intervention (n = 27) or control (n = 25) group. Patients in the intervention group joined a mean of 28.4 ± 7.4 training sessions (78.8%), 3.2 ± 0.6 nutritional counselling sessions (106.7%) and consumed on average 85.4 ± 33.2 supplements (71.2%). Inter-group comparison showed no significant difference in the primary endpoint SPPB after three (p = 0.184, 95% CI: -1.43, 0.29) and six months (p = 0.986, 95% CI: -0.87, 0.89). However, the secondary endpoint handgrip strength improved significantly from 35.8 ± 9.8 kg at baseline to 37.6 ± 10.0 kg at three months in the intervention group compared to 35.7 ± 8.8 kg at baseline to 34.0 ± 10.1 kg at three months in the control group (p < 0.001, 95% CI: -6.03, -1.97). The inter-group difference for changes in the further secondary endpoints nutritional status, dietary intake, fatigue, QoL and clinical course showed a trend towards an improvement in the intervention group, however, the differences were not significant after three and six months. CONCLUSIONS The present trial demonstrated a good adherence to the multimodal therapy as well as a significant improvement of handgrip strength in patients with advanced cancer. In addition, the clinical course data underlined the safety of the program. However, we failed to show significant improvements in further physical performance tests, especially our primary outcome factor SPPB as well as nutritional status, fatigue or QoL.
-
9.
The Effects of Timing of a Leucine-Enriched Amino Acid Supplement on Body Composition and Physical Function in Stroke Patients: A Randomized Controlled Trial.
Ikeda, T, Morotomi, N, Kamono, A, Ishimoto, S, Miyazawa, R, Kometani, S, Sako, R, Kaneko, N, Iida, M, Kawate, N
Nutrients. 2020;(7)
Abstract
The combination of exercise and nutritional intervention is widely used for stroke patients, as well as frail or sarcopenic older persons. As previously shown, supplemental branched chain amino acids (BCAAs) or protein to gain muscle mass has usually been given just after exercise. This study investigated the effect of the timing of supplemental BCAAs with exercise intervention on physical function in stroke patients. The participants were randomly assigned to two groups based on the timing of supplementation: breakfast (n = 23) and post-exercise (n = 23). The supplement in the breakfast group was provided at 08:00 with breakfast, and in the post-exercise group it was provided just after the exercise session in the afternoon at 14:00-18:00. In both groups, the exercise intervention was performed with two sessions a day for two months. The main effects were observed in body fat mass (p = 0.02, confidence interval (CI): 13.2-17.7), leg press strength (p = 0.04, CI: 94.5-124.5), and Berg balance scale (p = 0.03, CI: 41.6-52.6), but no interaction with intake timing was observed. Although the effect of the timing of supplementation on skeletal muscle mass was similar in both groups, BCAA intake with breakfast was effective for improving physical performance and decreasing body fat mass. The results suggest that a combination of BCAA intake with breakfast and an exercise program was effective for promoting rehabilitation of post-stroke patients.
-
10.
Supplementation with the Leucine Metabolite β-hydroxy-β-methylbutyrate (HMB) does not Improve Resistance Exercise-Induced Changes in Body Composition or Strength in Young Subjects: A Systematic Review and Meta-Analysis.
Jakubowski, JS, Nunes, EA, Teixeira, FJ, Vescio, V, Morton, RW, Banfield, L, Phillips, SM
Nutrients. 2020;(5)
Abstract
β-hydroxy-β-methylbutyrate (HMB) is a leucine metabolite that is purported to increase fat-free mass (FFM) gain and performance in response to resistance exercise training (RET). The aim of this systematic review and meta-analysis was to determine the efficacy of HMB supplementation in augmenting FFM and strength gains during RET in young adults. Outcomes investigated were: total body mass (TBM), FFM, fat mass (FM), total single repetition maximum (1RM), bench press (BP) 1RM, and lower body (LwB) 1RM. Databases consulted were: Medical Literature Analysis and Retrieval System Online (Medline), Excerpta Medica database (Embase), The Cumulative Index to Nursing and Allied Health Literature (CINAHL), and SportDiscus. Fourteen studies fit the inclusion criteria; however, 11 were analyzed after data extraction and funnel plot analysis exclusion. A total of 302 participants (18-45 y) were included in body mass and composition analysis, and 248 were included in the strength analysis. A significant effect was found on TBM. However, there were no significant effects for FFM, FM, or strength outcomes. We conclude that HMB produces a small effect on TBM gain, but this effect does not translate into significantly greater increases in FFM, strength or decreases in FM during periods of RET. Our findings do not support the use of HMB aiming at improvement of body composition or strength with RET.