New Research: Are BCAAs bad for you?
By Steve Blechman
New Research: Are BCAAs bad for you? Research in 2022 has confirmed that the branched-chain amino acids (BCAAs) are strongly linked and correlated with poor metabolic health including metabolic syndrome and cardiac arrhythmias (Can J Cardiol, 2022), and insulin resistance and diabetes (Diabetes, Metab Res Rev, Feb 2022). A new study suggested that BCAA blood measurements could potentially be used to select the most suitable diet to induce type 2 diabetes remission via nutritional strategies such as the Mediterranean diet (Mol Nut Food Res, Feb 2022). Also, higher blood levels of BCAAs are linked and associated to pancreatic cancer in humans (Cambridge University Press, March 23, 2022) and increased abdominal visceral fat, which has a negative effect on metabolic health, including inflammation, cardiovascular disease and type 2 diabetes (The Journal of Clinical Endocrinology & Metabolism, March 23, 2022). Also, research has shown that limiting BCAAS in the diet may delay aging and promote healthy longevity (Nature Reviews Molecular Cell Biology, January 2022).
Is BCAA Harmful? More BCAA Research
A new study published February 19th 2022 in the Journal Diabetes, Metabolic Syndrome and Obesity reported that the BCAA valine is strongly linked and correlated to insulin resistance and diabetes. The study involved a Chinese population of 816 individuals.
“The study aimed to evaluate the relationship among BCAAs oxidative stress and type 2 diabetes.” The conclusion of the study found that “L-valine is an independent risk factor of oxidative stress and that high valine levels with oxidative stress could be a significant risk factor for increased type 2 diabetes.”
It has been implicated that the branched-chain amino acids isoleucine and valine, but not leucine, are positively associated with increase of insulin resistance, diabetes and obesity in animals as well as humans. Over 70% of Americans are overweight. Medical researchers have projected that by 2030, one in two adults will be obese. A major health concern!
A study published May 4, 2021 in the Journal Cell Metabolism reported, “The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.” The researchers found that “reduced isoleucine or valine, but not leucine, promotes metabolic health in mice.” Also, that “dietary levels of isoleucine are positively associated with BMI in humans.” Body mass index or BMI is defined to help measure healthy weight or obesity in men and women. Also, by specifically reducing isoleucine in the diet, you can improve insulin sensitivity and increase energy expenditure. The researchers concluded that results suggest that reducing isoleucine, “May be a novel therapeutic and public health strategy to combat the twin epidemics of obesity and diabetes.”
A study that was presented at the 40th European Society for Clinical Nutrition and Metabolism (ESPEN) Congress in Madrid, Spain on September 1-4, 2018 further confirmed that elevated branched-chain amino acids are associated with obesity.
So, Are BCAAs Healthy?
In a previous article, I mentioned that branched-chain amino acids (BCAAs) had been identified in 2009 as a robust marker of obesity and insulin resistance in humans by Duke researchers led by Christopher Newgard, the director of the Duke Molecular Physiology Institute. This according to ScienceDaily on May 17, 2018 in addition to findings by Duke University researchers in Cell Metabolism, also on May 17, 2018. “The association between BCAA and insulin resistance had been present in the literature dating back to a 1969 study that appeared in the New England Journal of Medicine. And they have since been shown to be highly predictive of future diabetes development by the landmark Framingham Heart study,” the researchers concluded.
This study included 80 obese participants. High circulating BCAAs were negatively associated with free fatty acid concentrations. High blood levels of free fatty acids have been correlated in insulin resistance and type 2 diabetes (Diabetes, Obesity & Metab, June 2018). Elevated BCAA levels were significantly positively associated with deep visceral (abdominal fat) and hepatic (liver) fat. Liver fat content was assessed through magnetic resonance spectroscopy imaging (MRS), while visceral and subcutaneous adipose tissue were evaluated by magnetic resonance imaging (MRI). High visceral fat is strongly associated with the metabolic syndrome including inflammation, insulin resistance, diabetes, high triglycerides, high cholesterol, hypertension, and fatty liver.
Research has shown that elevated levels of valine are present in the blood of diabetic rats, mice and humans (Nat Rev Endocrinol, 2014). It was reported in the journal Nature Medicine in 2015 that valine catabolite 3-hydroxyisobutyrate (3-HIB) promoted the accumulation of fat within muscle tissue by directly stimulating fatty uptake in the muscle. Scientists have discovered that 3-hydroxyisobutyrate (3-HIB), one of the intermediate products in the breakdown of the BCAA valine, plays a role in the transport of fatty acids into skeletal muscle cells, which creates fatty muscles – a contributor to insulin resistance. Could an increase in insulin resistance cause skeletal muscle breakdown and increase valine catabolite 3-HIB in the blood, and also increase abdominal (visceral) and liver fat as well as muscle fat? Is valine catabolite 3-HIB the metabolic culprit? Is that why high BCAAs are linked to obesity and diabetes.
CAN LEUCINE PROTECT AGAINST CARDIOVASCULAR DISEASE? (BCAA Side Effects on the Heart )
A study in the journal BioFactors (February 15, 2018) demonstrated that leucine might be protective of cardiovascular disease in humans by “…attenuating macrophage foam-cell formation by mechanisms related to the metabolism of cholesterol, triglycerides and energy production.” Researchers noted, “Foam cells are a type of macrophage that localize to fatty deposits on blood vessel walls, where they ingest low-density lipoproteins and become laden with lipids, giving them a foamy appearance. These cells secrete various substances involved in plaque growth and their death promotes inflammation, thereby contributing to cardiovascular disease.” (Nature, https://www.nature.com/subjects/foam-cells.)
HOW TO TAKE LEUCINE FOR MAXIMIZING PROTEIN SYNTHESIS, MUSCLE GROWTH & RECOVERY
For best results to use as an anabolic trigger, take 5 grams of leucine (on an empty stomach) 15-30 minutes before a post-workout meal. A meta-analysis (Nutrition, 2017) that combined the results of seven studies showed that BCAA supplements are best taken after exercise, not before, or during exercise (intra-workout)
Leucine, not branched-chain amino acids (BCAAs), is the most important chemical that turns on the mTOR pathway, so it is likely that consuming leucine after exercise would be more effective (and cheaper) than consuming BCAAs. The BCAAs share the same active transport system into cells and muscle cells. Indeed, isoleucine and valine have been shown to inhibit absorption of leucine (Nutrition, 2017; Biochem J, 1966; Int J of Sp Nutr & Exer Metab, 2018).
Robert R. Wolfe, noted amino acid researcher, states in the Journal of the International Society of Sports Nutrition (2017) that “BCAAs also compete with other amino acids for transport, including phenylalanine, and this competition could affect the intramuscular availability of other EAAs. As a result of competition for transporters, it is possible that leucine alone, for example, could have a transitory stimulatory effect on muscle protein synthesis where the BCAAs fail to elicit such response.”
Timing of leucine ingestion is critical! By taking pure leucine on an empty stomach after your workout, you will get a better spike in blood levels than if you take leucine with food, because food can slow leucine’s absorption. The addition of isoleucine and valine may hinder the benefits of leucine due to competition for transport into muscle cells. When leucine is taken on an empty stomach, it’s a powerful metabolic switch that turns on protein synthesis.
Leucine increases mTOR activity for several hours after training. Leucine should be taken on an empty stomach, after resistance exercise, and as an anabolic trigger before a post-workout, protein-containing meal (or protein shake) rich in essential amino acids. This will trigger greater protein synthesis for improved recovery and greater gains.
WHY LEUCINE IS STILL KING
Based on the latest scientific research, leucine is still king, and the most potent anabolic/amino acid trigger! For added benefits, it is best taken with creatine monohydrate and betaine (found in AML PostWorkout™). Creatine stimulates muscle growth and recovery by increasing muscle cell formation and protein synthesis. Research has shown that creatine monohydrate combined with leucine can inhibit the production of the muscle-wasting protein myostatin! Supplementing leucine post-exercise also enhances muscle creatine uptake via an insulin-stimulated effect. Betaine is an excellent post-workout supplement when combined with leucine and creatine. “2.5 grams of betaine reduces fatigue and increased power and strength after 15 days of high-intensity, high-volume bench press and squat training. Betaine is also an osmolyte, enhancing muscle cell swelling, stimulating protein synthesis and decreasing protein breakdown, resulting in muscle growth. Betaine also has been shown to increase growth hormone and insulin-like growth factor 1 (IGF-1).” (See my AML Article – Top 3 Post Workout Nutrients: Leucine, Creatine and Betaine.)
There is no need to take BCAAs supplements of isoleucine and valine that interfere with leucine and share the same active transport system into cells and muscle cells! Like I said earlier, isoleucine and valine have been shown to inhibit the absorption of leucine. Your diet and your post-workout meal will give you all the isoleucine, valine and other essential amino acids that you need!
In conclusion, based on the latest research on BCAAs, more is not necessarily better! Reduced valine and isoleucine, but not leucine, may promote metabolic health!!
- Hu W, Yang P, Fu Z, Wang Y, Zhou Y, Ye Z, Gong Y, Huang A, Sun L, Zhao Y, Yang T, Li Z, Jiang XC, Yu W, Zhou H. High L-Valine Concentrations Associate with Increased Oxidative Stress and Newly-Diagnosed Type 2 Diabetes Mellitus: A Cross-Sectional Study. Diabetes Metab Syndr Obes. 2022 Feb 19;15:499-509. doi: 10.2147/DMSO.S336736. PMID: 35221701; PMCID: PMC8865866.
- Zhang H, Xiang L, Huo M, Wu Y, Yu M, Lau CW, Tian D, Gou L, Huang Y, Luo JY, Wang L, Song W, Huang J, Cai Z, Chen S, Tian XY, Huang Y. Branched-chain amino acid supplementation impairs insulin sensitivity and promotes lipogenesis during exercise in diet-induced obese mice. Obesity (Silver Spring). 2022 Mar 31. doi: 10.1002/oby.23394. Epub ahead of print. PMID: 35357085.
- Rossi M, Turati F, Strikoudi P, Ferraroni M, Parpinel M, Serraino D, Negri E, La Vecchia C. Dietary intake of branched-chain amino acids and pancreatic cancer risk in a case-control study from Italy. Br J Nutr. 2022 Mar 23:1-19. doi: 10.1017/S0007114522000939. Epub ahead of print. PMID: 35317868.
- Orozco-Ruiz X, Anesi A, Mattivi F, Breteler MMB. Branched-chain and aromatic amino acids related to visceral adipose tissue impact metabolic health risk markers. J Clin Endocrinol Metab. 2022 Mar 23:dgac160. doi: 10.1210/clinem/dgac160. Epub ahead of print. PMID: 35325166.
- Green CL, Lamming DW, Fontana L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat Rev Mol Cell Biol. 2022 Jan;23(1):56-73. doi: 10.1038/s41580-021-00411-4. Epub 2021 Sep 13. PMID: 34518687; PMCID: PMC8692439.
- Rivera ME, Rivera CN, Vaughan RA. Branched-chain amino acids at supraphysiological but not physiological levels reduce myotube insulin sensitivity. Diabetes Metab Res Rev. 2022 Feb;38(2):e3490. doi: 10.1002/dmrr.3490. Epub 2021 Aug 24. PMID: 34397159.
- Karadeniz A, Babayiğit E, Görenek PB. Could Branched-Chain Amino Acids Be a New Landmark in Metabolic Syndrome and Cardiac Arrhythmias? Can J Cardiol. 2022 Mar 16:S0828-282X(22)00197-0. doi: 10.1016/j.cjca.2022.03.008. Epub ahead of print. PMID: 35306103.
- Cardelo MP, Alcala-Diaz JF, Gutierrez-Mariscal FM, Lopez-Moreno J, Villasanta-Gonzalez A, Arenas-de Larriva AP, Cruz-Ares S, Delgado-Lista J, Rodriguez-Cantalejo F, Luque RM, Ordovas JM, Perez-Martinez P, Camargo A, Lopez-Miranda J. Diabetes Remission Is Modulated by Branched Chain Amino Acids According to the Diet Consumed: From the CORDIOPREV Study. Mol Nutr Food Res. 2022 Feb;66(4):e2100652. doi: 10.1002/mnfr.202100652. Epub 2022 Jan 7. PMID: 34863046.
- Mai K, Cando P, Trasino SE. mTOR1c Activation with the Leucine "Trigger" for Prevention of Sarcopenia in Older Adults During Lockdown. J Med Food. 2022 Feb;25(2):117-120. doi: 10.1089/jmf.2021.0094. Epub 2021 Oct 29. PMID: 34714145
- The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. Cell Metabolism. May 4, 2021. Deyang Yu, Nicole E. Richardson, Cara L. Green et al. https://doi.org/10.1016/j.cmet.2021.03.025
- Church DD, Schwarz NA, Spillane MB, et al. l-Leucine Increases Skeletal Muscle IGF-1 but Does Not Differentially Increase Akt/mTORC1 Signaling and Serum IGF-1 Compared to Ursolic Acid in Response to Resistance Exercise in Resistance-Trained Men. J Am Coll Nutr 2016;35(7):627-638. doi:10.1080/07315724.2015.1132019
- Yoshii at al. Nutrients 2018, 10(10), 1543; https://doi.org/10.3390/nu10101543 Effect of Mixed Meal and Leucine Intake on Plasma Amino Acid Concentrations in Young Men/
- Rahimi MH, Shab-Bidar S et al. Branched-chain amino acid supplementation and exercise-induced muscle damage in exercise recovery: A meta-analysis of randomized clinical trials. Nutrition 2017.
- Chad M Kerksick, Colin D Wilborn, Michael D. ISSN Exercise & Sports Nutrition Review Update: Research & Recommendations.
- Roberts, et al. Journal of the International Society of Sports Nutrition 2018;15:38 https://doi.org/10.1186/s12970-018-0242-y 1 June 2018
- Robert R. Wolfe. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality? Journal of the International Society of Sports Nutrition 2017;14:30 https://doi.org/10.1186/s12970-017-0184-9
- Szmelcman S, Guggenheim K. Interference between leucine, isoleucine and valine during intestinal absorption. Biochemical Journal 1966;100(1):7-11.
- Wilkinson, DJ et al. Effects of leucine and its metabolite beta-hydroxy-beta-methylbutyrateonhumanskeletalmuscleproteinmetabolism. J Physiol 2013;591,2911-2923.
- Cummings NE, Williams EM, Kasza I, Konon EN et al. (2018), Restoration of metabolic health by decreased consumption of branched‐chain amino acids. J Physiol, 596: 623-645. doi:10.1113/JP275075
- Duke University. Diabetes researchers find switch for fatty liver disease: Carbs, fats and protein: One molecule to rule them all? ScienceDaily, 17 May 2018. www.sciencedaily.com/releases/2018/05/180517113847.htm
- PJ White, RW McGarrah, PA Grimsrud, S Tso, W Yang, JM Haldeman, C Newgard et al. The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase. Cell Metabolism, 2018; DOI: 10.1016/j.cmet.2018.04.015
- NutraIngredients-USA.com, December 17, 2017. Nathan Gray. Could dropping specific amino acids from diet be key to weight loss?
- CB Newgard, J An, JR Bain et al. A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance Cell Metab 2009 April; 9(4): 311-326. doi:10.1016/j.cmet.2009.02.002
- Zheng Y, Li Y, Qi Q et al. Cumulative consumption of branched-chain amino acids and incidence of type 2 diabetes. Int J Epidemiol 2016; 45: 1482-92.
- Isanejad M, LaCroix AZ, Thomson CA et al. Branched-chain amino acid, meat intake and risk of type 2 diabetes in the Women’s Health Initiative. Br J Nutr 2017; 117:1523-30.
- Newgard CB, An J, Bain JR et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009; 9: 311-26
- Tremblay F, Krebs M, Dombrowski L et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 2005; 54: 2674-84.
- Tremblay F, Krebs M, Dombrowski L et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 2005; 54: 2674-84.
- Lee CC, Watkins SM, Lorenzo C et al. Branched-chain amino acids and insulin metabolism: The Insulin Resistance Atherosclerosis Study (IRAS). Diabetes Care 2016; 39: 582-8.
- Yoon M-S. The emerging role of branched-chain amino acids in insulin resistance and metabolism. Forum Nutr 2016; 8: 405-17.
- Abdul-Ghani MA, Tripathy D and DeFronzo RA. Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose. Diabetes Care 2006; 29:1130-9.
- Jang C, Oh, SF, et al A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med 22, 421-426
- Sara B Seidelmann, Brian Claggett, Susan Cheng, Mir Henglin, Amil Shah, Lyn M Steffen, Aaron R Folsom, Eric B Rimm, Walter C Willett, Scott D Solomon, Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis, The Lancet Public Health, 2018, ISSN 2468-2667, https://doi.org/10.1016/S2468-2667(18)30135-X.
- Zhaoping Li, Professor of Medicine, UCLA, US National Library of Medicine www. ClinicalTrials.gov Identifier: NCT02684565 Last Update Posted: February 12, 2018 https://clinicaltrials.gov/ct2/show/NCT02684565
- Lotta LA, Scott RA, Sharp SJ, Burgess S, Luan J, et al. (2016) Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomization Analysis. PLOS Medicine 13(11): e1002179. https://doi.org/10.1371/journal.pmed.1002179
- Avogaro A and Bier DM (1989) Contribution of 3-hydroxyisobutyrate to the measurement of 3-hydroxybutyrate in human plasma: comparison of enzymatic and gas-liquid chromatography-mass spectrometry assays in normal and in diabetic subjects. J Lipid Res 30, 1811-1817
- Giesbertz P, Padberg I et al. (2015) Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes. Diabetologia 58, 2133-2143.
- Insulin Resistance, And What May Contribute to It, by Lila Abassi on March 14, 2016. American Council on Science & Health https://www.acsh.org/news/2016/03/14/branched-chain-amino-metabolite-a-culprit-in-insulin-resistance
- Lydia-Ann LS Harris, Gordon I Smith, Bruce W Patterson, Raja S Ramaswamy et al. Alterations in 3-Hydroxyisobutyrate and FGF21 Metabolism Are Associated With Protein Ingestion-Induced Insulin Resistance Diabetes 2017;66:1871-1878 https://doi.org/10.2337/db16-1475
- Mardinoglu, Adil et al. Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes EBioMedicine, Volume 27, 151-155, Jan. 2018.
- Ulrika Andersson-Hall, Carolina Gustavsson, Anders Pedersen, Daniel Malmodin, Louise Joelsson, and Agneta Holmäng, Higher Concentrations of BCAAs and 3-HIB Are Associated with Insulin Resistance in the Transition from Gestational Diabetes to Type 2 Diabetes, Journal of Diabetes Research, vol. 2018, Article ID 4207067, 12 pages, 2018. https://doi.org/10.1155/2018/4207067.
- Macotela Y, Emanuelli B, Bang AM et al. (2011) Dietary leucine – an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS One 6, e21187.
- Cunxi Nie, Ting He, Wenju Zhang, Guolong Zhang, Xi Ma. Branched Chain Amino Acids: Beyond Nutrition Metabolism. Int J Mol Sci. 2018 Apr; 19(4): 954. Published online 2018 Mar 23. doi: 10.3390/ijms19040954
- Y Zhang, K Guo, RE LeBlanc, D Loh, GJ Schwartz and Y Yu. Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms. Diabetes Jun 2007, 56 (6) 1647-1654; DOI: 10.2337/db07-0123
- Deirdre K Tobias, Clary Clish, Samia Mora, Jun Li, Liming Liang, Frank B. Hu, JoAnn E. Manson, Cuilin Zhang. Dietary Intakes and Circulating Concentrations of Branched-Chain Amino Acids in Relation to Incident Type 2 Diabetes Risk Among High-Risk Women with a History of Gestational Diabetes Mellitus Clinical Chemistry Aug 2018, 64 (8) 1203-1210; DOI: 10.1373/clinchem.2017.285841
- McCormack S.E, Shaham O, McCarthy MA, Deik AA, Wang TJ, Gerszten RE, Clish CB, Mootha VK, Grinspoon SK and Fleischman A. (2013), Branched‐chain amino acids and IR in children. Pediatric Obesity, 8: 52-61. doi:10.1111/j.2047-6310.2012.00087.x.
- Sina S Ullrich, Penelope CE Fitzgerald, Gudrun Schober, Robert E Steinert, Michael Horowitz, Christine Feinle-Bisset; Intragastric administration of leucine or isoleucine lowers the blood glucose response to a mixed-nutrient drink by different mechanisms in healthy, lean volunteers, The American Journal of Clinical Nutrition, Volume 104, Issue 5, 1 November 2016, Pages 1274-1284, https://doi.org/10.3945/ajcn.116.140640.
- Haufe S. et al. Branched-chain and aromatic amino acids, insulin resistance and liver specific ectopic fat storage in overweight to obese subjects. Nutrition, Metabolism and Cardiovascular Diseases, Volume 26, Issue 7, 637-642
- Li H, Xu M, Lee J, He C and Xie Z. (2012). Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice. American Journal of Physiology - Endocrinology and Metabolism, 303(10), E1234-E1244. http://doi.org/10.1152/ajpendo.00198.2012
- Chunzi Liang, Benjamin J Curry, Patricia L Brown and Michael B. Zemel, Leucine Modulates Mitochondrial Biogenesis and SIRT1-AMPK Signaling in C2C12 Myotubes, Journal of Nutrition and Metabolism, vol. 2014, Article ID 239750, 11 pages, 2014. https://doi.org/10.1155/2014/239750.
- Binder E, Bermúdez-Silva FJ, André C, Elie M, Romero-Zerbo SY, et al. Leucine Supplementation Protects from Insulin Resistance by Regulating Adiposity Levels (2013). Leucine Supplementation Protects from Insulin Resistance by Regulating Adiposity Levels. PLOS ONE 8(9): e74705. https://doi.org/10.1371/journal.pone.0074705
- Banerjee, Jheelam et al. Activation of the AMPK/Sirt1 pathway by a leucine-metformin combination increases insulin sensitivity in skeletal muscle, and stimulates glucose and lipid metabolism and increases life span in Caenorhabditis elegans. Metabolism - Clinical and Experimental, Volume 65, Issue 11, 1679-1691
- Jiao J, Han S-F, Zhang W, Xu J-Y, Tong X, Yin X-B, Qin L-Q (2016). Chronic leucine supplementation improves lipid metabolism in C57BL/6J mice fed with a high-fat/cholesterol diet. Food & Nutrition Research, 60, 10.3402/fnr.v60.31304. http://doi.org/10.3402/fnr.v60.31304
- Cholsoon Jang, Sungwhan F Oh, Shogo Wada, Glenn C Rowe, Laura Liu, Mun Chun Chan, James Rhee, Atsushi Hoshino, Boa Kim, Ayon Ibrahim, Luisa G Baca, Esl Kim, Chandra C Ghosh, Samir M Parikh, Aihua Jiang, Qingwei Chu, Daniel E Forman, Stewart H Lecker, Saikumari Krishnaiah, Joshua D Rabinowitz, Aalim M Weljie, Joseph A Baur, Dennis L Kasper & Zoltan Arany. Published: 07 March 2016. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nature Medicine volume 22, pages 421-426 (2016)
- D’Antona G, Ragni M, Cardile A, Tedesco L, Dossena M, Bruttini F et al. (2010). Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab. 12, 362-372. doi: 10.1016/j.cmet.2010.08.016
- Szmelcman S, Guggenheim K. Interference between leucine, isoleucine and valine during intestinal absorption. Biochemical Journal. 1966;100(1):7-11.
- Robert R. Wolfe. Branched-chain amino acids and muscle protein synthesis in humans: myth or reality? Journal of the International Society of Sports Nutrition201714:30 https://doi.org/10.1186/s12970-017-0184-9
- L Deldicque, C Sanchez Canedo and S Horman. Antagonistic effects of leucine and glutamine on the mTOR pathway in myogenic C2C12 cells. Amino Acids, 2008, Volume 35, Number 1, Page 147
- Amy Hector, Stuart M. Phillips. Protein Recommendations for Weight Loss in Elite Athletes: A Focus on Body Composition and Performance. Int J Sport Nutr Exerc Metab 2017
- Rahimi MH, Shab-Bidar S, Mollahosseini M, Djafarian K. Nutrition 2017. Leucine, Not Total Protein, Content of a Supplement Is the Primary Determinant of Muscle Protein Anabolic Responses in Healthy Older Women, The Journal of Nutrition, nxy091, June 13, 2018
- Branched-chain amino acid supplementation and exercise-induced muscle damage in exercise recovery: A meta-analysis of randomized clinical trials.
- Jiao J, Han S.F, Zhang W, Xu JY, Tong X, Yin XB, Yuan LX, Qin LQ (2016). Chronic leucine supplementation improves lipid metabolism in C57BL/6J mice fed with a high-fat/cholesterol diet. Food & nutrition research, 60, 31304. doi:10.3402/fnr.v60.31304
- Macotela Y, Emanuelli B, Ba˚ng AM, Espinoza DO, Boucher J, Beebe K, et al. Dietary leucine an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS One 2011; 6: e21187.
- Zhang Y, Guo K, LeBlanc RE, Loh D, Schwartz GJ, Yu YH. Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 2007; 56: 164754.
- Khan M, Joseph F. Adipose tissue and adipokines: the association with and application of adipokines in obesity. Scientifica (Cairo) 2014; 2014: 328592
- Zemel MB, Bruckbauer A. Effects of a leucine and pyridoxine containing nutraceutical on fat oxidation, and oxidative and inflammatory stress in overweight and obese subjects. Nutrients 2012; 4: 52941
- Ricoult SJ, Manning BD. The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep 2013; 14: 24251
- Freudenberg A, Petzke KJ, Klaus S. Comparison of high protein diets and leucine supplementation in the prevention of metabolic syndrome and related disorders in mice. J Nutr Biochem 2012; 3: 152430.
- Vaughan RA, Garcia-Smith R, Gannon NP, Bisoffi M, Trujillo KA, Conn CA. Leucine treatment enhances oxidative capacity through complete carbohydrate oxidation and increased mitochondrial density in skeletal muscle cells. Amino Acids 2013; 45: 90111.
- Zhang Y et al. (2007) Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 56(6):1647-1654
- Okekunle AP, Zhang M, Wang Z. et al. Dietary branched-chain amino acids intake exhibited a different relationship with type 2 diabetes and obesity risk: a meta-analysis. Acta Diabetol (2018). https://doi.org/10.1007/s00592-018-1243-7
- Binder E, Bermúdez-Silva FJ, André C, Elie M, Romero-Zerbo SY, et al. Leucine Supplementation Protects from Insulin Resistance by Regulating Adiposity Levels (2013) Leucine Supplementation Protects from Insulin Resistance by Regulating Adiposity Levels. PLOS ONE 8(9): e74705. https://doi.org/10.1371/journal.pone.0074705
- Binder E, Bermúdez‐Silva FJ, Elie M, Leste‐Lasserre T, Belluomo I, Clark S, Duchampt A, Mithieux G and Cota D. (2014) Leucine supplementation modulates fuel substrates utilization and glucose metabolism in previously obese mice. Obesity, 22: 713-720. doi:10.1002/oby.20578
- Li H, Xu M, Lee J, He C and Xie Z (2012). Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice. American journal of physiology. Endocrinology and metabolism, 303(10), E1234-44.
- Pedroso JA, Zampieri TT and and Donato J. (2015). Reviewing the Effects of L-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis. Nutrients, 7 (5), 3914-37. https://dx.doi.org/10.3390%2Fnu705391
- Caoileann H Murphy, Nelson I Saddler, Michaela C Devries, Chris McGlory, Steven K Baker and Stuart M Phillips. Leucine supplementation enhances integrative myofibrillar protein synthesis in free-living older men consuming lower- and higher-protein diets: a parallel-group crossover study, The American Journal of Clinical Nutrition, Volume 104, Issue 6, 1 December 2016, Pages 1594-1606, https://doi.org/10.3945/ajcn.116.136424
- Yadao DR, MacKenzie S and Bergdahl A. (2018) Reducing branched‐chain amino acid intake to reverse metabolic complications in obesity and type 2 diabetes. J Physiol, 596: 3455-3456. doi:10.1113/JP276274
- Leucine supplementation attenuates macrophage foam-cell formation: studies in humans, mice, and cultured macrophages. BioFactors, February 15, 2018. Grajeda-Iglesias, et al.
- Diabetes researchers find switch for fatty liver disease. ScienceDaily, May 17, 2018.