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Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health.
Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, Cava E, Spelta F, Tosti V, Syed FA, Baar EL, Veronese N, Cottrell SE, Fenske RJ, Bertozzi B, Brar HK, Pietka T, Bullock AD, Figenshau RS, Andriole GL, Merrins MJ, Alexander CM, Kimple ME, Lamming DW
(2016) Cell Rep 16: 520-530
MeSH Terms: Adipose Tissue, White, Amino Acids, Branched-Chain, Animals, Blood Glucose, Dietary Proteins, Fibroblast Growth Factors, Gluconeogenesis, Glucose Intolerance, Humans, Insulin-Secreting Cells, Male, Mice, Inbred C57BL, Middle Aged, Obesity, Organ Size, Stress, Physiological
Show Abstract · Added August 2, 2016
Protein-restricted (PR), high-carbohydrate diets improve metabolic health in rodents, yet the precise dietary components that are responsible for these effects have not been identified. Furthermore, the applicability of these studies to humans is unclear. Here, we demonstrate in a randomized controlled trial that a moderate PR diet also improves markers of metabolic health in humans. Intriguingly, we find that feeding mice a diet specifically reduced in branched-chain amino acids (BCAAs) is sufficient to improve glucose tolerance and body composition equivalently to a PR diet via metabolically distinct pathways. Our results highlight a critical role for dietary quality at the level of amino acids in the maintenance of metabolic health and suggest that diets specifically reduced in BCAAs, or pharmacological interventions in this pathway, may offer a translatable way to achieve many of the metabolic benefits of a PR diet.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Branched-Chain Amino Acids and Cardiovascular Disease: Does Diet Matter?
Ferguson JF, Wang TJ
(2016) Clin Chem 62: 545-7
MeSH Terms: Amino Acids, Branched-Chain, Biomarkers, Cardiovascular Diseases, Diet, Mediterranean, Humans, Metabolomics
Added March 28, 2016
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6 MeSH Terms
Living donor liver transplantation from a heterozygous parent for classical maple syrup urine disease.
Kadohisa M, Matsumoto S, Sawada H, Honda M, Murokawa T, Hayashida S, Ohya Y, Lee KJ, Yamamoto H, Mitsubuchi H, Endo F, Inomata Y
(2015) Pediatr Transplant 19: E66-9
MeSH Terms: Amino Acids, Branched-Chain, Fathers, Female, Heterozygote, Humans, Infant, Liver Transplantation, Living Donors, Male, Maple Syrup Urine Disease, Postoperative Period, Treatment Outcome
Show Abstract · Added March 7, 2015
MSUD is a hereditary metabolic disorder that is characterized by impaired activity of the BCKADC. Liver transplantation has been approved as a treatment for some MSUD cases in which the control of BCAAs is insufficient. Although there have been several reports about DDLT for MSUD, few LDLT cases have been reported. Because either of parents who are heterozygote of this disease usually applies to be a candidate of donor in LDLT, the impairment of BCKADC activity of graft liver should be concerned. We performed LDLT for 10 month-old girl with a left lateral segment graft from her father. BCKADC activities of the patient and her parents were measured using lysates of lymphocytes isolated from peripheral blood specimen before the transplant. As a consequence, the activity of BCKADC of father was not inferior to a normal range. The patient tolerated the operation well. Postoperative course was uneventful and mixed milk was started at 8th POD. The serum BCAAs levels have remained within normal range. It should be necessary to follow the physical growth and mental development of the recipient in the future.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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12 MeSH Terms
Branched chain and aromatic amino acids change acutely following two medical therapies for type 2 diabetes mellitus.
Walford GA, Davis J, Warner AS, Ackerman RJ, Billings LK, Chamarthi B, Fanelli RR, Hernandez AM, Huang C, Khan SQ, Littleton KR, Lo J, McCarthy RM, Rhee EP, Deik A, Stolerman E, Taylor A, Hudson MS, Wang TJ, Altshuler D, Grant RW, Clish CB, Gerszten RE, Florez JC
(2013) Metabolism 62: 1772-8
MeSH Terms: Aged, Amino Acids, Aromatic, Amino Acids, Branched-Chain, Biomarkers, Blood Glucose, Diabetes Mellitus, Type 2, Female, Glipizide, Humans, Hypoglycemic Agents, Insulin, Insulin Resistance, Male, Metformin, Middle Aged, Spectrum Analysis
Show Abstract · Added April 15, 2014
OBJECTIVE - Elevated circulating levels of branched chain and aromatic amino acids (BCAA/AAAs) are associated with insulin resistance and incident type 2 diabetes (T2D). BCAA/AAAs decrease acutely during an oral glucose tolerance test (OGTT), a diagnostic test for T2D. It is unknown whether changes in BCAA/AAAs also signal an early response to commonly used medical therapies for T2D.
MATERIALS AND METHODS - A liquid chromatography-mass spectrometry approach was used to measure BCAA/AAAs in 30 insulin sensitive (IS) and 30 insulin resistant (IR) subjects before and after: (1) one dose of a sulfonylurea medication, glipizide, 5 mg orally; (2) two days of twice daily metformin 500 mg orally; and (3) a 75-g OGTT. Percent change in BCAA/AAAs was determined after each intervention.
RESULTS - Following glipizide, which increased insulin and decreased glucose in both subject groups, BCAA/AAAs decreased in the IS subjects only (all P<0.05). Following metformin, which decreased glucose and insulin in only the IR subjects, 4 BCAA/AAAs increased in the IR subjects at or below P=0.05, and none changed in the IS subjects. Following OGTT, which increased glucose and insulin in all subjects, BCAA/AAAs decreased in all subjects (P<0.05).
CONCLUSIONS - BCAA/AAAs changed acutely during glipizide and metformin administration, and the magnitude and direction of change differed by the insulin resistance status of the individual and the intervention. These results indicate that BCAA/AAAs may be useful biomarkers for monitoring the early response to therapeutic interventions for T2D.
© 2013.
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16 MeSH Terms
A diabetes-predictive amino acid score and future cardiovascular disease.
Magnusson M, Lewis GD, Ericson U, Orho-Melander M, Hedblad B, Engström G, Ostling G, Clish C, Wang TJ, Gerszten RE, Melander O
(2013) Eur Heart J 34: 1982-9
MeSH Terms: Amino Acids, Aromatic, Amino Acids, Branched-Chain, Biomarkers, Carotid Artery Diseases, Carotid Intima-Media Thickness, Case-Control Studies, Diabetic Angiopathies, Diet, Dietary Proteins, Disease Susceptibility, Early Diagnosis, Exercise, Female, Humans, Male, Middle Aged, Myocardial Ischemia, Prospective Studies, Risk Assessment
Show Abstract · Added April 15, 2014
AIMS - We recently identified a metabolic signature of three amino acids (tyrosine, phenylalanine, and isoleucine) that strongly predicts diabetes development. As novel modifiable targets for intervention are needed to meet the expected increase of cardiovascular disease (CVD) caused by the diabetes epidemic, we investigated whether this diabetes-predictive amino acid score (DM-AA score) predicts development of CVD and its functional consequences.
METHODS AND RESULTS - We performed a matched case-control study derived from the population-based Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC), all free of CVD. During 12 years of follow-up, 253 individuals developed CVD and were matched for age, sex, and Framingham risk score with 253 controls. Amino acids were profiled in baseline plasma samples, using liquid chromatography-tandem mass spectrometry, and relationship to incident CVD was assessed using conditional logistic regression. We further examined whether the amino acid score also correlated with anatomical [intima-media thickness (IMT) and plaque formation] and functional (exercise-induced myocardial ischaemia) abnormalities. Compared with the lowest quartile of the DM-AA score, the odds ratio (95% confidence interval) for incident CVD in subjects belonging to quartiles 2, 3, and 4 was 1.27 (0.72-2.22), 1.96 (1.07-3.60), and 2.20 (1.12-4.31) (Ptrend = 0.010), respectively, after multivariate adjustment. Increasing quartile of the DM-AA score was cross-sectionally related to carotid IMT (Ptrend = 0.037) and with the presence of at least one plaque larger than 10 mm(2) (Ptrend = 0.001). Compared with the lowest quartile of the DM-AA score, the odds ratio (95% confidence interval) for inducible ischaemia in subjects belonging to quartiles 2, 3, and 4 was 3.31 (1.05-10.4), 4.24 (1.36-13.3), and 4.86 (1.47-16.1) (Ptrend = 0.011), respectively.
CONCLUSION - This study identifies branched-chain and aromatic amino acids as novel markers of CVD development and as an early link between diabetes and CVD susceptibility.
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19 MeSH Terms
Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents.
McCormack SE, Shaham O, McCarthy MA, Deik AA, Wang TJ, Gerszten RE, Clish CB, Mootha VK, Grinspoon SK, Fleischman A
(2013) Pediatr Obes 8: 52-61
MeSH Terms: Adolescent, Amino Acids, Branched-Chain, Biomarkers, Blood Glucose, Body Mass Index, Child, Child Nutrition Disorders, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Fasting, Female, Humans, Insulin, Insulin Resistance, Insulin Secretion, Isoleucine, Leucine, Longitudinal Studies, Male, Massachusetts, Obesity, Predictive Value of Tests, Valine
Show Abstract · Added April 15, 2014
UNLABELLED - What is already known about this subject Circulating concentrations of branched-chain amino acids (BCAAs) can affect carbohydrate metabolism in skeletal muscle, and therefore may alter insulin sensitivity. BCAAs are elevated in adults with diet-induced obesity, and are associated with their future risk of type 2 diabetes even after accounting for baseline clinical risk factors. What this study adds Increased concentrations of BCAAs are already present in young obese children and their metabolomic profiles are consistent with increased BCAA catabolism. Elevations in BCAAs in children are positively associated with insulin resistance measured 18 months later, independent of their initial body mass index.
BACKGROUND - Branched-chain amino acid (BCAA) concentrations are elevated in response to overnutrition, and can affect both insulin sensitivity and secretion. Alterations in their metabolism may therefore play a role in the early pathogenesis of type 2 diabetes in overweight children.
OBJECTIVE - To determine whether paediatric obesity is associated with elevations in fasting circulating concentrations of BCAAs (isoleucine, leucine and valine), and whether these elevations predict future insulin resistance.
METHODS - Sixty-nine healthy subjects, ages 8-18 years, were enrolled as a cross-sectional cohort. A subset of subjects who were pre- or early-pubertal, ages 8-13 years, were enrolled in a prospective longitudinal cohort for 18 months (n = 17 with complete data).
RESULTS - Elevations in the concentrations of BCAAs were significantly associated with body mass index (BMI) Z-score (Spearman's Rho 0.27, P = 0.03) in the cross-sectional cohort. In the subset of subjects that followed longitudinally, baseline BCAA concentrations were positively associated with homeostasis model assessment for insulin resistance measured 18 months later after controlling for baseline clinical factors including BMI Z-score, sex and pubertal stage (P = 0.046).
CONCLUSIONS - Elevations in the concentrations of circulating BCAAs are significantly associated with obesity in children and adolescents, and may independently predict future insulin resistance.
© 2012 The Authors. Pediatric Obesity © 2012 International Association for the Study of Obesity.
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23 MeSH Terms
Metabolite profiles and the risk of developing diabetes.
Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C, O'Donnell CJ, Carr SA, Mootha VK, Florez JC, Souza A, Melander O, Clish CB, Gerszten RE
(2011) Nat Med 17: 448-53
MeSH Terms: Aged, Amino Acids, Aromatic, Amino Acids, Branched-Chain, Biomarkers, Case-Control Studies, Causality, Cohort Studies, Diabetes Mellitus, Female, Humans, Logistic Models, Longitudinal Studies, Male, Metabolome, Middle Aged, Predictive Value of Tests, Prospective Studies, Risk Factors, Tandem Mass Spectrometry
Show Abstract · Added April 15, 2014
Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography-tandem mass spectrometry (LC-MS). Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine. A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.
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19 MeSH Terms
Accessing ns-micros side chain dynamics in ubiquitin with methyl RDCs.
Farès C, Lakomek NA, Walter KF, Frank BT, Meiler J, Becker S, Griesinger C
(2009) J Biomol NMR 45: 23-44
MeSH Terms: Algorithms, Amino Acids, Branched-Chain, Carbon Isotopes, Chemical Phenomena, Humans, Models, Chemical, Models, Molecular, Nitrogen Isotopes, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Reproducibility of Results, Solvents, Ubiquitin
Show Abstract · Added January 24, 2015
This study presents the first application of the model-free analysis (MFA) (Meiler in J Am Chem Soc 123:6098-6107, 2001; Lakomek in J Biomol NMR 34:101-115, 2006) to methyl group RDCs measured in 13 different alignment media in order to describe their supra-tau (c) dynamics in ubiquitin. Our results indicate that methyl groups vary from rigid to very mobile with good correlation to residue type, distance to backbone and solvent exposure, and that considerable additional dynamics are effective at rates slower than the correlation time tau (c). In fact, the average amplitude of motion expressed in terms of order parameters S (2) associated with the supra-tau (c) window brings evidence to the existence of fluctuations contributing as much additional mobility as those already present in the faster ps-ns time scale measured from relaxation data. Comparison to previous results on ubiquitin demonstrates that the RDC-derived order parameters are dominated both by rotameric interconversions and faster libration-type motions around equilibrium positions. They match best with those derived from a combined J-coupling and residual dipolar coupling approach (Chou in J Am Chem Soc 125:8959-8966, 2003) taking backbone motion into account. In order to appreciate the dynamic scale of side chains over the entire protein, the methyl group order parameters are compared to existing dynamic ensembles of ubiquitin. Of those recently published, the broadest one, namely the EROS ensemble (Lange in Science 320:1471-1475, 2008), fits the collection of methyl group order parameters presented here best. Last, we used the MFA-derived averaged spherical harmonics to perform highly-parameterized rotameric searches of the side chains conformation and find expanded rotamer distributions with excellent fit to our data. These rotamer distributions suggest the presence of concerted motions along the side chains.
1 Communities
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13 MeSH Terms
Rapid high-performance liquid chromatographic method to measure plasma leucine: importance in the study of leucine kinetics in vivo.
Brown LL, Williams PE, Becker TA, Ensley RJ, May ME, Abumrad NN
(1988) J Chromatogr 426: 370-5
MeSH Terms: Amino Acids, Branched-Chain, Chromatography, High Pressure Liquid, Humans, Insulin, Leucine, Spectrometry, Fluorescence, o-Phthalaldehyde
Added December 10, 2013
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7 MeSH Terms
Role of insulin and branched-chain amino acids in regulating protein metabolism during fasting.
Frexes-Steed M, Warner ML, Bulus N, Flakoll P, Abumrad NN
(1990) Am J Physiol 258: E907-17
MeSH Terms: Adult, Amino Acids, Amino Acids, Branched-Chain, Blood Glucose, Epinephrine, Fasting, Glucagon, Humans, Hydrocortisone, Infusions, Intravenous, Insulin, Leucine, Male
Show Abstract · Added December 10, 2013
This study examines the independent effects of insulin and amino acids on protein metabolism after a 12-h and 4-day fast in healthy volunteers. Leucine (Leu) kinetics were examined during sequential insulin infusions of 0 (group I) or 0.0125 (groups II and III), 1.2, and 10 mU.kg-1.min-1. Plasma Leu was maintained at 12-h fasted levels in groups I and II and at 84-h fasted levels in group III. Four-day fast (vs. 1 day, P less than 0.01) was associated with a 79% drop in plasma insulin and elevations in plasma Leu (122%), Leu rates of appearance (Ra) (21%), and Leu oxidation (56%), and no change in nonoxidative rates of disappearance (Rd). Insulin resulted in a dose-dependent suppression of endogenous Leu Ra with group III = I greater than II. Leu oxidation rose 1.7-fold in group III at the highest insulin dose but remained stable in the two other groups. In conclusion, 4-day fasting is associated with enhanced proteolysis and Leu oxidation with no change in nonoxidative Rd (protein synthesis). Elevated branched-chain (and other) amino acids were required to restore tissue sensitivity and specificity to the effects of insulin on protein metabolism after 4 days of fasting.
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13 MeSH Terms