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1.
Branched Chain Amino Acids in Metabolic Disease.
Arany, Z, Neinast, M
Current diabetes reports. 2018;(10):76
Abstract
PURPOSE OF REVIEW Elevations in circulating branched chain amino acids (BCAAs) have gained attention as potential contributors to the development of insulin resistance and diabetes. RECENT FINDINGS Epidemiological evidence strongly supports this conclusion. Suppression of BCAA catabolism in adipose and hepatic tissues appears to be the primary drivers of plasma BCAA elevations. BCAA catabolism may be shunted to skeletal muscle, where it indirectly leads to FA accumulation and insulin resistance, via a number of proposed mechanisms. BCAAs have an important role in the development of IR, but our understanding of how plasma BCAA elevations occur, and how these elevations lead to insulin resistance, is still limited.
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A novel NMR-based assay to measure circulating concentrations of branched-chain amino acids: Elevation in subjects with type 2 diabetes mellitus and association with carotid intima media thickness.
Wolak-Dinsmore, J, Gruppen, EG, Shalaurova, I, Matyus, SP, Grant, RP, Gegen, R, Bakker, SJL, Otvos, JD, Connelly, MA, Dullaart, RPF
Clinical biochemistry. 2018;:92-99
Abstract
OBJECTIVES Plasma branched-chain amino acid (BCAA) levels, measured on nuclear magnetic resonance (NMR) metabolomics research platforms or by mass spectrometry, have been shown to be associated with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). We developed a new test for quantification of BCAA on a clinical NMR analyzer and used this test to determine the clinical correlates of BCAA in 2 independent cohorts. DESIGN AND METHODS The performance of the NMR-based BCAA assay was evaluated. A method comparison study was performed with mass spectrometry (LC-MS/MS). Plasma BCAA were measured in the Insulin Resistance Atherosclerosis Study (IRAS, n = 1209; 376 T2DM subjects) and in a Groningen cohort (n = 123; 67 T2DM subjects). In addition, carotid intima media thickness (cIMT) was measured successfully in 119 subjects from the Groningen cohort. RESULTS NMR-based BCAA assay results were linear over a range of concentrations. Coefficients of variation for inter- and intra-assay precision ranged from 1.8-6.0, 1.7-5.4, 4.4-9.1, and 8.8-21.3%, for total BCAA, valine, leucine, and isoleucine, respectively. BCAA quantified from the same samples using NMR and LC-MS/MS were highly correlated (R2 = 0.97, 0.95 and 0.90 for valine, leucine and isoleucine). In both cohorts total and individual BCAA were elevated in T2DM (P = 0.01 to ≤0.001). Moreover, cIMT was associated with BCAA independent of age, sex, T2DM and metabolic syndrome (MetS) categorization or alternatively of individual MetS components. CONCLUSIONS BCAA levels, measured by NMR in the clinical laboratory, are elevated in T2DM and may be associated with cIMT, a proxy of subclinical atherosclerosis.
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Preconception Micronutrient Supplementation Reduced Circulating Branched Chain Amino Acids at 12 Weeks Gestation in an Open Trial of Guatemalan Women Who Are Overweight or Obese.
Borengasser, SJ, Baker, PR, Kerns, ME, Miller, LV, Palacios, AP, Kemp, JF, Westcott, JE, Morrison, SD, Hernandez, TL, Garces, A, et al
Nutrients. 2018;(9)
Abstract
Elevated branched chain amino acids (BCAAs: valine, leucine, and isoleucine) are well-established biomarkers of obesity-associated insulin resistance (IR). Mounting evidence suggests that low- and middle-income countries are suffering from a "double burden" of both undernutrition (growth stunting) and overnutrition (obesity) as these countries undergo a "nutrition transition". The purpose of this study was to examine if pre-pregnancy body mass index (BMI, kg/m²) and a daily lipid-based micronutrient supplement (LNS, Nutriset) would lead to cross-sectional differences in circulating levels of branched chain amino acids (BCAAs) in Guatemalan women experiencing short stature during early pregnancy. Using data from an ongoing randomized controlled trial, Women First, we studied women who were normal weight (NW, BMI range for this cohort = 20.1⁻24.1 kg/m²) or overweight/obese (OW/OB, BMI range for this cohort = 25.6⁻31.9 kg/m²), and divided into two groups: those who received daily LNS ≥ 3 months prior to conception through 12 weeks gestation (+LNS), or no LNS (-LNS) (n = 9⁻10/group). BCAAs levels were obtained from dried blood spot card samples (DBS) assessed at 12 weeks gestation. DBS cards provide a stable, efficient, and reliable means of collecting, transporting, and storing blood samples in low resource or field settings. Circulating maternal leptin, adiponectin, and insulin were determined by immunoassays from serum samples collected at 12 weeks gestation. We found maternal pre-pregnancy body mass index (ppBMI) was associated with higher circulating BCAAs (r² = 0.433, p = 0.002) and higher leptin/adiponectin ratio (r = 0.466, p = 0.044) in -LNS mothers at 12 weeks gestation. +LNS mothers demonstrated no correlations between BCAAs or leptin/adiponectin ratio across ppBMI suggesting LNS may be effective at improving metabolic status in OW/OB mothers during early pregnancy.
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Circulating Branched-Chain Amino Acids and Incident Cardiovascular Disease in a Prospective Cohort of US Women.
Tobias, DK, Lawler, PR, Harada, PH, Demler, OV, Ridker, PM, Manson, JE, Cheng, S, Mora, S
Circulation. Genomic and precision medicine. 2018;(4):e002157
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Abstract
BACKGROUND Circulating branched-chain amino acids (BCAAs; isoleucine, leucine, and valine) are strong predictors of type 2 diabetes mellitus (T2D), but their association with cardiovascular disease (CVD) is uncertain. We hypothesized that plasma BCAAs are positively associated with CVD risk and evaluated whether this was dependent on an intermediate diagnosis of T2D. METHODS Participants in the Women's Health Study prospective cohort were eligible if free of CVD at baseline blood collection (n=27 041). Plasma metabolites were measured via nuclear magnetic resonance spectroscopy. Multivariable Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for BCAAs with incident CVD (myocardial infarction, stroke, and coronary revascularization). RESULTS We confirmed 2207 CVD events over a mean 18.6 years of follow-up. Adjusting for age, body mass index, and other established CVD risk factors, total BCAAs were positively associated with CVD (per SD: HR, 1.13; 95% CI, 1.08-1.18), comparable to LDL-C (low-density lipoprotein cholesterol) with CVD (per SD: HR, 1.12; 95% CI, 1.07-1.17). BCAAs were associated with coronary events (myocardial infarction: HR, 1.16; 95% CI, 1.06-1.26; revascularization: HR, 1.17; 95% CI, 1.11-1.25), and borderline significant association with stroke (HR, 1.07; 95% CI, 0.99-1.15). The BCAA-CVD association was greater (P interaction=0.036) among women who developed T2D before CVD (HR, 1.20; 95% CI, 1.08-1.32) versus women without T2D (HR, 1.08; 95% CI, 1.03-1.14). Adjusting for LDL-C, an established CVD risk factor, did not attenuate these findings; however, adjusting for HbA1c and insulin resistance eliminated the associations of BCAAs with CVD. CONCLUSIONS Circulating plasma BCAAs were positively associated with incident CVD in women. Impaired BCAA metabolism may capture the long-term risk of the common cause underlying T2D and CVD.
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Reduced plasma concentration of branched-chain amino acids in sarcopenic older subjects: a cross-sectional study.
Ottestad, I, Ulven, SM, Øyri, LKL, Sandvei, KS, Gjevestad, GO, Bye, A, Sheikh, NA, Biong, AS, Andersen, LF, Holven, KB
The British journal of nutrition. 2018;(4):445-453
Abstract
Branched-chain amino acids (BCAA) are essential amino acids that are necessary for muscle mass maintenance. Little is known about the plasma concentrations of BCAA and the protein intake in relation to sarcopenia. We aimed to compare the non-fasting plasma concentrations of the BCAA and the dietary protein intake between sarcopenic and non-sarcopenic older adults. Norwegian older home-dwelling adults (≥70 years) were invited to a cross-sectional study with no other exclusion criteria than age. Sarcopenic subjects were defined by the diagnostic criteria by the European Working Group on Sarcopenia in Older People. Non-fasting plasma concentrations of eight amino acids were quantified using NMR spectroscopy. Protein intake was assessed using 2×24-h dietary recalls. In this study, ninety out of 417 subjects (22 %) were sarcopenic, and more women (32 %) than men (11 %) were sarcopenic (P<0·0001). Sex-adjusted non-fasting plasma concentrations of leucine and isoleucine, and the absolute intake of protein (g/d), were significantly lower among the sarcopenic subjects, when compared with non-sarcopenic subjects (P=0·003, P=0·026 and P=0·003, respectively). A similar protein intake was observed in the two groups when adjusted for body weight (BW) and sex (1·1 g protein/kg BW per d; P=0·50). We show that sarcopenia is associated with reduced non-fasting plasma concentration of the BCAA leucine and isoleucine, and lower absolute intake of protein. More studies are needed to clarify the clinical relevance of these findings, related to maintenance of muscle mass and prevention of sarcopenia.
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Effect of Oral Branched-Chain Amino Acids on Serum Albumin Concentration in Heart Failure Patients with Hypoalbuminemia: Results of a Preliminary Study.
Uchino, Y, Watanabe, M, Takata, M, Amiya, E, Tsushima, K, Adachi, T, Hiroi, Y, Funazaki, T, Komuro, I
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2018;(4):327-332
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Abstract
BACKGROUND We conducted a randomized, controlled trial to determine whether supplementation with oral branched-chain amino acids (BCAAs) improves serum albumin and clinical outcomes in heart failure (HF) patients with hypoalbuminemia. METHODS AND RESULTS We randomly assigned 18 in-hospital HF patients with serum albumin < 3.5 g/dL to receive oral BCAA granules (LIVACT®) for 28 days during their hospital stay or until discharge (BCAA group; N = 9) or to receive no supplementation (controls; N = 9), in addition to recommended HF therapy. The primary endpoints were changes from baseline in serum albumin and cardiothoracic ratio (CTR). Sixteen patients completed the study. The mean (± standard deviation) period of BCAA supplementation was 18.4 ± 8.4 days. Serum albumin significantly increased in the BCAA group [mean difference vs baseline, 0.44 g/dL; 95% confidence interval (CI) 0.13-0.76; P = 0.014] and did not change in controls (0.18 g/dL; 95% CI - 0.05 to 0.40; P = 0.108). CTR significantly decreased in the BCAA group (- 2.3%; 95% CI - 3.8 to - 0.8; P = 0.014) and did not change in controls (- 1.0%; 95% CI - 2.3 to 0.3; P = 0.111). CONCLUSION In-hospital HF patients with hypoalbuminemia supplemented with BCAAs showed increased serum albumin and decreased CTR. Clinical trial registration number UMIN000004488 [ http://www.umin.ac.jp/ctr/index.htm ].
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Effect of branched chain amino acids on perioperative temperature, glucose level and fat metabolism in patients with gastrointestinal tumors.
Wen, LY, Zhang, YS, Zhou, X, Li, G, Hu, CY, Li, Y, Jin, LJ
Journal of biological regulators and homeostatic agents. 2018;(2):357-363
Abstract
This study aimed to investigate the effect of branched chain amino acids (BCCAs) on perioperative temperature, glucose and fat metabolism in patients with gastrointestinal tumors. Fifty-six patients undergoing gastrointestinal tumor surgery were included in the study and randomly divided into two groups of 28 patients each: an experimental and a control group. During surgery, the experimental group received 5.64mL·Kg-1·h-1(4KJ·Kg-1·h-1) of BCCAs intravenously, through an infusion pump, and the control group received an equal volume of NaCl 0.9%. Vital signs were continuously monitored during the operation. Nasopharynx temperature levels of glucose, insulin, free fatty acid and ketone bodies in the blood were determined 30 min before anesthesia (t 0), after anesthesia and before surgery (t 1), 30 min after the start of surgery (t 2), 2 h after start of surgery (t 3) and 1 h after the end of surgery (T4). Patients shivering intensity (Wrench grading) and pain degree [Visual analogue scale (VAS)]) were estimated 1 h after the endotracheal tube was removed. Nasopharynx temperature was decreased (p less than 0.05) in both groups after anesthesia induction, while 1 h after the tube was removed it was higher in the experimental group than the control group (p less than 0.05); compared with pre-surgery values, blood glucose levels were increased during surgery in both groups, but the experimental group had a lower increasing trend compared to the control group, though without statistical significance (p>0.05). Insulin levels were significantly different between the two groups at all time-points during surgery (p less than 0.05). However, the rising trend of the experimental group was more dramatic during the period from t 0 to t 3. One hour after surgery (t 4), the insulin levels varied, but still at higher levels than pre-surgery, with a significant difference (p less than 0.05); levels of free fatty acids had a downward trend in both groups, and levels in the experimental group continued to decline until 1 h after surgery. Patients who received branched chain amino acids had less temperature decrease during surgery. Moreover, blood glucose levels were not increased, which limits fat mobilization and leads to production of ketone bodies, reduces the shivering and its intensity after surgery.
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Branching Out: Alterations in Bacterial Physiology and Virulence Due to Branched-Chain Amino Acid Deprivation.
Kaiser, JC, Heinrichs, DE
mBio. 2018;(5)
Abstract
The branched-chain amino acids (BCAAs [Ile, Leu, and Val]) represent important nutrients in bacterial physiology, with roles that range from supporting protein synthesis to signaling and fine-tuning the adaptation to amino acid starvation. In some pathogenic bacteria, the adaptation to amino acid starvation includes induction of virulence gene expression: thus, BCAAs support not only proliferation during infection, but also the evasion of host defenses. A body of research has accumulated over the years to describe the multifaceted physiological roles of BCAAs and the mechanisms bacteria use to maintain their intracellular levels. More recent studies have focused on understanding how fluctuations in their intracellular levels impact global regulatory pathways that coordinate the adaptation to nutrient limitation, especially in pathogenic bacteria. In this minireview, we discuss how these studies have refined the individual roles of BCAAs, shed light on how BCAA auxotrophy might promote higher sensitivity to exogenous BCAA levels, and revealed pathogen-specific responses to BCAA deprivation. These advancements improve our understanding of how bacteria meet their nutritional requirements for growth while simultaneously remaining responsive to changes in environmental nutrient availability to promote their survival in a range of environments.
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Effect of a high-protein, high-fiber diet plus supplementation with branched-chain amino acids on the nutritional status of patients with cirrhosis.
Ruiz-Margáin, A, Macías-Rodríguez, RU, Ríos-Torres, SL, Román-Calleja, BM, Méndez-Guerrero, O, Rodríguez-Córdova, P, Torre, A
Revista de gastroenterologia de Mexico (English). 2018;(1):9-15
Abstract
INTRODUCTION AND OBJECTIVES The potential benefits of branched-chain amino acids (BCAAs) in cirrhosis extend beyond just the improvement of nutritional status. Their effects include improvement of glucose tolerance, oxidative stress, and inflammatory markers, as has been shown in several studies. A dual nutritional approach of a high-protein, high-fiber diet plus BCAAs in cirrhosis could have additional benefits, compared with BCAAs alone. Such an approach has not been explored and therefore the aim of the present study was to evaluate the effect of a combination of a high-protein, high-fiber diet plus BCAA supplementation over a 6-month period of time on the nutritional status of patients with cirrhosis, as well as its safety and tolerability for those same patients. METHODS An open, randomized clinical trial was conducted. Patients were randomized to one of two groups: the BCAAs+HPHF diet intervention group: a high-protein, high-fiber diet with 1.2g/kg protein and 30g of fiber plus supplementation with oral branched-chain amino acids 110g daily and the HPHF diet control group: a high-protein, high-fiber diet with 1.2g/kg protein and 30g of fiber. The differences between the treatment groups were compared using the unpaired T test and the differences at the end of treatment were compared using the paired T test. RESULTS A total of 72 patients were included, 37 in the intervention group and 35 in the control group. At the end of the study period, ammonia and glucose levels showed no significant increase in either group, reflecting the safety of the BCAA supplement. Furthermore, muscle and fat mass were evaluated through triceps skinfold thickness and mid-arm muscle circumference measurements. There was an increase in muscle mass and a decrease in fat mass in the BCAA group, but not in the control group. After the intervention, there were no significant changes in the Psychometric Hepatic Encephalopathy Score or the Critical Flicker Frequency score results in either group, and no episodes of hepatic encephalopathy were observed during the treatment period. CONCLUSION Supplementation with branched-chain amino acids plus a high-fiber, high-protein diet is a safe intervention in patients with cirrhosis. It helps increase muscle mass and does not raise the levels of ammonia or glucose, nor is it associated with the development of hepatic encephalopathy.
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Altered Dairy Protein Intake Does Not Alter Circulatory Branched Chain Amino Acids in Healthy Adults: A Randomized Controlled Trial.
Prodhan, UK, Milan, AM, Thorstensen, EB, Barnett, MPG, Stewart, RAH, Benatar, JR, Cameron-Smith, D
Nutrients. 2018;(10)
Abstract
Dairy, as a major component of a high protein diet, is a critical dietary source of branched chain amino acids (BCAA), which are biomarkers of health and diseases. While BCAA are known to be key stimulators of protein synthesis, elevated circulatory BCAA is an independent risk factor for type 2 diabetes mellitus. This study examined the impact of altered dairy intake on plasma BCAA and their potential relationship to insulin sensitivity. Healthy adults (n = 102) were randomized to receive dietary advice to reduce, maintain, or increase habitual dairy intake for 1 month. Food intake was recorded with food frequency questionnaires. Self-reported protein intake from dairy was reported to be reduced (-14.6 ± 3.0 g/day), maintained (-4.0 ± 2.0 g/day) or increased (+13.8 ± 4.1 g/day) according to group allocation. No significant alterations in circulating free amino acids (AA), including BCAA, were measured. Insulin sensitivity, as assessed by homeostatic model assessment-insulin resistance (HOMA-IR), was also unaltered. A significant change in dairy protein intake showed no significant effect on fasting circulatory BCAA and insulin sensitivity in healthy populations.