By Steve Blechman

 There’s an overwhelming amount of evidence over the years that elevated branched-chain amino acids are associated with obesity and insulin resistance. A study in the Journal of Physiology (February 2018) suggests that a diet low in BCAAs may help weight loss and prevent the metabolic problems that occur in diabetes and obesity. “We’ve identified an unanticipated role for dietary BCAAs in the regulation of energy balance, and we show that a diet with low levels of BCAAs promotes leanness and good control of blood sugar,” according to an article in Nutraingredients-USA.com, dated December 21, 2017.

 “…branched-chain amino acids, or BCAA, 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,” according to ScienceDaily on May 17, 2018 and most recently published, 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.”

 “This helps to explain how and why BCAAs are associated with disordered fat metabolism that can lead to type 2 diabetes,” said Newgard, who has worked on BCAA in metabolic disease for more than a decade.

 Two large human population studies showed an association of estimated dietary BCAA intake with T2D risk (Int J Epidemiol, 2016; Br J Nutr 2017). Other studies have reported that high BCAA intake along with a high animal protein diet contributes to the development of insulin resistance and interfering with the intracellular insulin signaling pathway (Cell Metab 2009; 9: 311-26; Diabetes 2005; 54: 2674-84). In a most recent study published in the prestigious journal The Lancet Public Health (August, 2018), Harvard researchers found that when individuals exchanged carbohydrates for animal protein such as beef, lamb, pork or chicken – their mortality risk increased. When carbs were exchanged for plant-based proteins, from sources including vegetables, nuts and whole grains, mortality risks decreased. This study was a meta-analysis of eight cohort studies that included more than 400,000 participants from 20 countries. The authors of the study said, “There are several possible explanations for our main findings. Low carbohydrate diets have tended to result in lower intake of vegetables, fruits, and grains and increased intakes of protein from animal sources as observed in the ARIC cohort, which has been associated with higher mortality. It is likely that different amounts of bioactive dietary components in low carbohydrate versus balanced diets, such as branched-chain amino acids, fatty acids, fibre, phytochemicals, haem iron, and vitamins and minerals are involved.”

 Because of the concern of BCAAs and their potential effect in diabetes, a governmental clinical trial has been underway entitled, The Effects of Branched Chain-Amino Acids in Glucose Tolerance Obese Pre-Diabetic Subjects (BCAA) (February 12, 2018, US Nat Libr of Med ClinicalTrials, gov Identifier: NCT02684565). The mechanisms underlining the role of dietary BCAAs on the risk of insulin resistance are not fully understood.

 Research has shown that elevated levels of valine are present in the blood of diabetic rats, mice and humans. (Nat Rev Endocrinol, 2014) When the mice were fed a diet without valine insulin sensitivity improved after only one day. Mice on the valine-free diet lasting an entire week decreased in blood glucose levels, indicating that there was improved insulin function. (Metabolism, 2014) It was reported in the journal Nature Medicine, 2015 that valine catabolite 3-hydroxyisobutyrate (3-HIB) promoted the accumulation of fat within muscle tissue by directly stimulating fatty uptake in the muscle. The intramuscular fat activates certain signaling cascades within the muscle cell that diminish insulin signaling, leading to insulin resistance. This study also found that inhibiting the production of 3-HIB prevented the uptake of fat. Other studies support the negative effect of 3-HIB on insulin signaling with elevated 3-HIB in the muscle of human subjects with diabetes. (J Lipid Res, 1989; Diabetologia, 2015) An article titled Insulin Resistance, And What May Contribute To It by Lila Abassi and published on the American Council on Science & Health website March 14, 2016 reported on “… a study published in Nature Medicine, [that] 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.” Abassi also also states, “Thus far, it has been a relative mystery as to how BCAAs play a role in insulin resistance. Skeletal muscles display resistance to insulin when there is excess fat inside their cells.” In closing of the article, Abassi said, “What the researchers found was that 3-HIB acted as a shuttle in muscle cells, allowing blood vessels in skeletal muscle tissue to move fat into skeletal muscle. The more 3-HIB, the more fat was transported — and conversely, when scientists blocked 3-HIB from being made, there was less uptake of fat into skeletal muscle.”

 One of the authors of the study, Dr. Zoltan Arany, said to Abassi: “In this study we showed a new mechanism to explain how 3-HIB, by regulating the transport of fatty acids in and out of muscle, links the breakdown of branched-chained amino acids with fatty acid accumulation, showing how increased amino acid flux can cause diabetes.”

 More recent studies have confirmed that the branched-chain amino acid valine metabolite 3-HIB is involved in the pathogenesis of insulin resistance in skeletal muscle and might be involved in insulin resistance in humans (Diabetes, July 2017; EbioMedicine, 2018; J Diab Rsch, 2018). Unlike valine, leucine has been shown to improve insulin function. Leucine consumption alone has been shown to rescue insulin-signaling deficiency (PLoS, 2011). A most recent study (Exp Clin Endocrinol Diabetes, 2018) has found that oral administration of leucine improved endothelial function in healthy individuals when infused with glucose. Acute hyperglycemia impairs endothelial function in healthy individuals. This study found that leucine administration prevented hyperglycemia-mediated endothelial function. Unlike leucine, which avoids insulin resistance by increasing mitochondrial-driven fat loss, valine does not encourage mitochondrial biogenesis. “Impaired mitochondrial function in skeletal muscle is one of the major predisposing factors to metabolic diseases, such as insulin resistance, type 2 diabetes and cardiovascular disease.” Leucine supplementation increases insulin sensitivity by activating SIRT1 activity. SIRT1 is known to “promote mitochondrial biogenesis and oxidative capacity and prevent the mitochondrial dysfunction in skeletal muscle.” (Journal of Nutrition and Metabolism, 2014) Leucine may also attenuate adiposity and promote weight loss during energy restriction (Nutrition 2006, Diabetes, 2007). These effects are in part by activating the SIRT1-dependent pathway, stimulating mitochondrial biogenesis and increased oxygen consumption (Nutrition Metabolism, 2008). Mitochondrial biogenesis and SIRT1 expression in skeletal muscle has also been shown to increase lifespan in middle-aged mice (Cell Metabolism, 2010). As far as isoleucine is concerned, unlike valine, it has been shown to improve insulin sensitivity by increasing glucose into muscle cells (Am J Physiol Endocrinol Metab, 2007).

 Leucine is an essential amino acid that serves as a building block for muscle protein synthesis. Leucine is a powerful anabolic trigger— it’s the most potent branched-chain amino acid (BCAA) and a key activator of the mTOR pathway that is critical for muscle protein synthesis that promotes muscle growth. So, it is likely that consuming leucine after exercise would be more effective (and cheaper) than consuming BCAAs. The addition of isoleucine and valine may hinder the benefits. In the March 2018 issue of the International Journal of Sports Nutrition and Exercise Metabolism, it was reported that men fed 6 grams of whey protein supplemented with leucine, isoleucine and valine observed less protein synthesis than whey protein supplemented with just leucine!

 For best results 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, says 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.”

 By taking pure leucine on an empty stomach, 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. When leucine is taken after resistance exercise and before a post-workout, protein-containing meal rich in essential amino acids, it triggers greater protein synthesis for improved recovery and greater gains.  

 In conclusion, “There's growing evidence to suggest that BCAAs isn't just a passive marker of diabetes but may actually play a role in driving the disease,” Gerszten said. “It gives us the motivation to test whether changes in the amino acid intake in our diets would be worth exploring.”

 It’s clear based on scientific research that high-circulating BCAAs are associated with obesity and diabetes. The latest available literature has shown that the branched-chain amino acid valine (catabolite 3-HIB) might be the villain!

References:

Cummings, N.E., Williams, E.M., Kasza, I., Konon, 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. ScienceDaily, 17 May 2018. www.sciencedaily.com/releases/2018/05/180517113847.htm

P.J. White, R.W. McGarrah, P.A. Grimsrud, S. Tso, W. Yang, J. M. 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?

C.B Newgard, J. An, J.R 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 Let 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, 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.

Binder E, Bermudez-Silva FJ, Andre C et al. Leucine supplementation protects from insulin resistance by regulating adiposity levels. PLoS One. 2013; 8:e74705.

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: 1647-54.

Lynch, C.J. and Adams, S.H. (2014) Branched-chain amino acids in metabolic signaling and insulin resistance. Nat Rev Endrocrinol 10, 723-736.

Xiao, F., Yu, J, Guo, Y, Deng, J, Li, K, et al (2014) Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice. Metabolism 63, 841-850.

Jang C, Oh, S.F., 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 Randomisation Analysis. PLOS Medicine 13(11): e1002179. https://doi.org/10.1371/journal.pmed.1002179

Avogaro, A. and Bier, D.M. (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

Alterations in 3-Hydroxyisobutyrate and FGF21 Metabolism Are Associated With Protein Ingestion–Induced Insulin Resistance Lydia-Ann L.S. Harris, Gordon I. Smith, Bruce W. Patterson, Raja S. Ramaswamy et al. Diabetes 2017;66:1871-1878 https://doi.org/10.2337/db16-1475

Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes Mardinoglu, Adil et al. 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, A.M. et al. (2011) Dietary leucine – an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS One 6, e21187.

Branched Chain Amino Acids: Beyond Nutrition Metabolism. Cunxi Nie, Ting He, Wenju Zhang, Guolong Zhang, Xi Ma Int J Mol Sci. 2018 Apr; 19(4): 954. Published online 2018 Mar 23. doi: 10.3390/ijms19040954

Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms. Y. Zhang, K. Guo, R.E. LeBlanc, D. Loh, G.J. Schwartz, Y. Yu Diabetes Jun 2007, 56 (6) 1647-1654; DOI: 10.2337/db07-0123

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 Deirdre K. Tobias, Clary Clish, Samia Mora, Jun Li, Liming Liang, Frank B. Hu, JoAnn E. Manson, Cuilin Zhang Clinical Chemistry Aug 2018, 64 (8) 1203-1210; DOI: 10.1373/clinchem.2017.285841

McCormack, S. E., Shaham, O., McCarthy, M.A., Deik, A.A., Wang, T.J., Gerszten, R.E., Clish, C.B., Mootha, V.K., Grinspoon, S. K. 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.

Branched-chain and aromatic amino acids, insulin resistance and liver specific ectopic fat storage in overweight to obese subjects. Haufe, S. et al. Nutrition, Metabolism and Cardiovascular Diseases , Volume 26 , Issue 7, 637-642

Li, H., Xu, M., Lee, J., He, C., & 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.

Leucine Supplementation Protects from Insulin Resistance by Regulating Adiposity Levels. Binder E, Bermúdez-Silva FJ, André C, Elie M, Romero-Zerbo SY, et al. (2013) Leucine Supplementation Protects from Insulin Resistance by Regulating Adiposity Levels. PLOS ONE 8(9): e74705. https://doi.org/10.1371/journal.pone.0074705

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. Banerjee, Jheelam et al. 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

Published: 07 March 2016. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. 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 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.

Branched-chain amino acids and muscle protein synthesis in humans: myth or reality? Robert R. Wolfe Journal of the International Society of Sports Nutrition201714:30 https://doi.org/10.1186/s12970-017-0184-9

Antagonistic effects of leucine and glutamine on the mTOR pathway in myogenic C2C12 cells. Amino Acids, 2008, Volume 35, Number 1, Page 147 L. Deldicque, C. Sanchez Canedo, S. Horman,

Protein Recommendations for Weight Loss in Elite Athletes: A Focus on Body Composition and Performance. Amy Hector, Stuart M. Phillips Int J Sport Nutr Exerc Metab. 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. Rahimi MH, Shab-Bidar S, Mollahosseini M, Djafarian K. Nutrition. 2017